Skip to main content
PMC home page
Wiley Open Access Collection logoLink to Wiley Open Access Collection
. 2022 Feb 2;179(4):625–641. doi: 10.1111/bph.15677

The role of glucagon‐like peptide 1 (GLP‐1) in addictive disorders

Mette Kruse Klausen 1, Morgane Thomsen 2, Gitta Wortwein 2,3, Anders Fink‐Jensen 1,2,✉
PMCID: PMC8820218  PMID: 34532853

Abstract

Drug, alcohol and tobacco use disorders are a global burden affecting millions of people. Despite decades of research, treatment options are sparse or missing, and relapse rates are high. Glucagon‐like peptide 1 (GLP‐1) is released in the small intestine, promotes blood glucose homeostasis, slows gastric emptying and reduces appetite. GLP‐1 receptor agonists approved for treating Type 2 diabetes mellitus and obesity have received attention as a potential anti‐addiction treatment. Studies in rodents and non‐human primates have demonstrated a reduction in intake of alcohol and drugs of abuse, and clinical trials have been initiated to investigate whether the preclinical findings can be translated to patients. This review will give an overview of current findings and discuss the possible mechanisms of action. We suggest that effects of GLP‐1 in alcohol and substance use disorders is mediated centrally, at least partly through dopamine signalling, but precise mechanisms are still to be uncovered.

LINKED ARTICLES

This article is part of a themed issue on GLP1 receptor ligands (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.4/issuetoc

Keywords: addiction, alcohol, alcohol use disorder, amphetamine, cocaine, dopamine, GLP‐1, glucagon‐like peptide‐1, nicotine, opioids, substance use disorder, tobacco

graphic file with name BPH-179-625-g003.jpg

Abbreviations

AUD

alcohol use disorder

DAT

dopamine transporter

DPP‐4

dipeptidyl peptidase‐4

EMA

European Medicines Agency

FDA

U.S. Food and Drug Administration

fMRI

functional MRI

GLP‐1

glucagon‐like peptide 1

NAc

nucleus accumbens

NTS

nucleus tractus solitarius

OUD

opioid use disorder

SPECT

single‐photon emission CT

SUD

substance use disorder

VTA

ventral tegmental area

1. INTRODUCTION

Worldwide, an estimated 35 million people suffer from substance use disorders (SUDs) (United Nations Publication, 2020) and 280 million people from alcohol use disorder (AUD) (World Health Organization [WHO], 2018). In 2015, a quarter of the global adult population (above 15 years of age) were current users of tobacco (WHO, 2019). AUD is associated with high mortality due to medical complications, injuries (Carvalho et al., 2019) and suicide (Borges et al., 2017). AUD has serious consequences not only for the individual suffering from this disease but also for the relatives (Connor et al., 2016) and society at large due to high healthcare and socio‐economical costs (WHO, 2018). Harmful use of alcohol is globally estimated to account for over 5% of deaths, making it a leading cause of preventable deaths (WHO, 2018), and the treatment gap is wide when compared with other psychiatric disorders (Kohn et al., 2004).

Globally, an estimated 19 million people are users of cocaine (United Nations Publication, 2020), and about five million people suffer from cocaine use disorder (CUD) (Peacock et al., 2018). Deaths caused by cocaine overdose are rapidly increasing in recent years, now rivalling or exceeding opioid overdose deaths in some American populations (Kampman, 2019). When it comes to stimulants, an estimated 27 million people used amphetamines in 2018 (United Nations Publication, 2020). Amphetamines are associated with severe physical health consequences, psychiatric illness, aggressive behaviours, risky sexual behaviour and the risk of contracting blood‐borne viruses after needle sharing (Lee et al., 2018). In 2018, an estimated 58 million people used opioids; this number includes those who misused pharmaceutical synthetic opioids (United Nations Publication, 2020). In 2016, more than 100,000 people died from opioid overdose, most likely from respiratory depression. The societal costs are high, due to harm to family cohesion, reduced employment and the cost of crimes (Strang et al., 2020).

Together with alcohol, tobacco use is one of the largest preventable causes of premature death, but still, six million people die due to tobacco‐related diseases every year (The Tobacco Atlas, 2021). Despite the available treatment options, many smokers attempt to quit without medication or support, with a failure rate of 95–98% (Prochaska & Benowitz, 2016). There is also a high prevalence of co‐use of two or more substances. This has consequences for the associated disease burden, treatment strategies and outcomes. Most (50 ‐ 90%) people who use cocaine also consume alcohol simultaneously (Goldstein et al., 2009), and 80% of individuals who use cocaine or opioids are also smoking tobacco (Kalman et al., 2005). A review based on preclinical and clinical studies has shown that co‐use of alcohol and nicotine potentiates craving and self‐administration of both substances (McKee & Weinberger, 2013).

The mechanisms behind addictive disorders have been extensively reviewed by several authors and comprise drug‐induced dysregulations of numerous neurocircuits and neurochemicals, such as dopamine, opioid peptides, corticotropin‐releasing factor (CRF), dynorphin, glutamate and GABA, and also vulnerability factors such as genetics, initial drug exposure and social environment (Badiani et al., 2011; Berridge & Robinson, 2016; Koob & Volkow, 2016; Volkow, Michaelides, et al., 2019; Zorrilla & Koob, 2019). Attention has also been directed to the behavioural, cognitive and neurobiological heterogeneity of different SUDs, even though they are all classified diagnostically, without regard to drug class (Badiani et al., 2011).

There are several theories about the development of addiction, but among the most dominant is the idea that a process termed ‘incentive sensitization’ underlies the excessive ‘wanting’ triggered by reward cues in addicted individuals, without necessarily ‘liking’ the drug. ‘Wanting’ is believed to be generated in the dopaminergic mesolimbic system, projecting from the ventral tegmental area (VTA) to the nucleus accumbens (NAc), whereas ‘liking’ comes from tiny hedonic hotspots in the brain and is not dependent on dopamine release. As an individual becomes more addicted, ‘wanting’ will overshadow ‘liking’ and become independent of ‘liking’ (Berridge & Robinson, 2016). ‘The dark side’ theory of addiction contends that impulsivity, compulsivity and negative urgency are derived from stress experienced during withdrawal or ‘negative affect stage’, even several months into abstinence. The neurocircuitry identified involves several neuropeptides, including CRF (Zorrilla & Koob, 2019). Dopamine plays a prominent role in the immediate reinforcing/rewarding effects of drugs—‘the dopamine theory’, and dysregulation of the dopamine system is thought to contribute to the addicted state as a predisposing factor and/or a consequence of chronic substance use (Volkow, Michaelides, et al., 2019).

Pharmacological treatments against AUD, opioid use disorder (OUD) and tobacco use disorder are available (see Table 1) (European Monitoring Centre for Drugs and Drug Addiction, 2012; Kampman, 2019; Kranzler & Soyka, 2018; Lee et al., 2018; Prochaska & Benowitz, 2016; Wang et al., 2019). The U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) do not approve any medications for the treatment of cocaine or stimulant use disorders. Even when pharmacotherapy is available, success rates for achieving long‐term abstinence are modest, highlighting the urgent need for new, effective medications against SUD and AUD (Kampman, 2019; Lee et al., 2018; Lyon, 2017; National Institute on Drug Abuse [NIDA], 2020; Volkow, 2020; Volkow, Jones, et al., 2019).

TABLE 1.

Current FDA‐ and EMA‐approved pharmacological treatments for alcohol and substance use disorders

SUD FDA and EMA approved Reference
Alcohol (AUD) Disulfiram, acamprosate, naltrexone, nalmefene (only EMA‐approved) Kranzler & Soyka, 2018
Cocaine (CUD) No approved medications Kampman, 2019
Stimulants No approved medications Lee et al., 2018
Opioids (OUD) Opioid agonist therapy: methadone and buprenorphine, naltrexone, supervised injectable heroin (few countries) Wang et al., 2019; European Monitoring Centre for Drugs and Drug Addiction, 2012
Nicotine Bupropion, varenicline Prochaska & Benowitz, 2016
Nicotine replacement therapies: lozenges, patch, gum, spray, inhaler
Open in a new tab

Abbreviations: AUD, alcohol use disorder; CUD, cocaine use disorder; EMA, European Medicines Agency; FDA, U.S. Food and Drug Administration; OUD, opioid use disorder; SUD, substance use disorder.

2. GLUCAGON‐LIKE PEPTIDE 1

In the search for new treatments of AUD (Lyon, 2017), nicotine use disorder (Polosa & Benowitz, 2011) and SUD (Klein, 2016), the gut hormone glucagon‐like peptide 1 (GLP‐1) has received much attention (Eren‐Yazicioglu et al., 2021; Fink‐Jensen & Vilsbøll, 2016; Jerlhag, 2020; Reddy et al., 2014; Skibicka, 2013). Endogenous GLP‐1 is produced by cleavage of the prohormone proglucagon in the intestinal endocrine L cells and is released in response to food intake. It is rapidly inactivated with a half‐life of just 1–2 min by the enzyme, dipeptidyl peptidase 4 (DPP‐4). GLP‐1 receptors are present in many tissues throughout the body, and GLP‐1 potentiates insulin secretion, inhibits glucagon secretion, slows gastric emptying and reduces appetite (Holst, 2007). GLP‐1 is also produced in the nucleus tractus solitarius (NTS) of the brain stem and is released as a neurotransmitter in several brain regions. GLP‐1 receptors are expressed in brain regions believed to be involved in reward and addiction (Cork et al., 2015; Han et al., 1986; Jensen et al., 2018; Merchenthaler et al., 1999; Rinaman, 2010; Vrang & Grove, 2011). Studies in mice indicate that several GLP‐1 receptor agonists can cross the blood–brain barrier at least to some extent when administered systemically (Gabery et al., 2020; Kastin et al., 2002; Salinas et al., 2018; Secher et al., 2014; Zhang et al., 2020). A recent clinical trial including patients with Parkinson's disease reported that systemically administered exenatide, a GLP‐1 receptor agonist, in a licensed dose for the treatment of Type 2 diabetes, did cross the blood–brain barrier (Athauda et al., 2017). In contrast, another clinical study including patients with Type 2 diabetes treated with the GLP‐1 receptor agonist liraglutide found limited transfer of liraglutide to the CSF (Christensen et al., 2015). Still, it remains to be determined if other available GLP‐1 receptor agonists differ with respect to brain penetration in humans.

2.1. Types of GLP‐1 receptor agonists and safety

One attractive aspect of GLP‐1 receptor agonists, as opposed to other neuropeptides examined in the context of addiction (such as orexin, relaxin, ghrelin, NPY, CART, dynorphin, neurotensin, oxytocin and α‐MSH—for an overview, see ‘The Role of Neuropeptides in Addiction and Disorders of Excessive Consumption’, International Review of Neurobiology, Vol. 136, 2017, Edited by Todd E. Thiele), is that a number of these compounds are already used clinically, meaning that they could become available rapidly to AUD or SUD patients if the approach proves successful. The FDA and EMA have approved a number of GLP‐1 receptor agonists, but in this review, we will focus on those compounds that have been investigated preclinically, that is, exenatide, liraglutide, semaglutide and dulaglutide. GLP‐1 receptor agonists differ in pharmacokinetic and pharmacodynamic properties, with newer agonists developed to be much longer acting relative to the native GLP‐1 peptide and the first synthetic GLP‐1 receptor agonists. The ligands also differ in their ability to activate second messenger systems (biased agonism; see another chapter in this themed issue), and with respect to the degree of receptor internalization they stimulate, all of which may influence their effectiveness as possible AUD or SUD treatments.

Early observational studies (Chis & Fodor, 2017; Elashoff et al., 2011) reported an increased risk of pancreatitis or pancreatic cancer when patients were treated with GLP‐1 receptor agonist. This might have hampered the incentive to investigate the potential effects of GLP‐1 receptor agonists as a treatment against AUD, as patients are already at a higher risk for developing pancreatitis or pancreatic cancer (National Institute for Health and Care Excellence, 2011). However, a recent systematic review and meta‐analysis including three high‐quality long‐term randomized clinical trials with 9347 patients with Type 2 diabetes allocated to GLP‐1 receptor agonist treatment, found no significant association (Storgaard et al., 2017). Another meta‐analysis confirmed this finding in data based on GLP‐1 receptor agonist therapy and cardiovascular outcome, including 55,921 patients (Abd El Aziz et al., 2020), as well as studies comparing the risk of pancreatitis (Azoulay et al., 2016a) or pancreatic cancer (Azoulay et al., 2016b) between GLP‐1 receptor agonists and other antidiabetic medications.

3. ROLE OF GLP‐1 IN ALCOHOL USE DISORDER

3.1. Basic research, effects of GLP‐1 receptor agonists

The effects of GLP‐1 receptor activation on alcohol consumption in laboratory animals have been investigated more extensively compared with other substances of abuse. Several GLP‐1 receptor agonists have been tested in male rats, mice and non‐human primates. Most studies have focused on acute effects, but more recent investigations have also assessed the effects of subchronic or repeated dosing regimens (Marty et al., 2020; Thomsen, Barrett, et al., 2017). This is important, as AUD is a chronic, relapsing illness that typically requires long‐term treatment, and acute effects do not always adequately predict the effectiveness of repeated or chronic dosing.

Systemic administration of the GLP‐1 receptor agonist exenatide has been reported to decrease or abolishe the rewarding effects of systemically injected alcohol, measured by conditioned place preference. This was the case when treatment was administered during the conditioning phase and also during the expression phase (Egecioglu, Steensland, et al., 2013; Shirazi et al., 2013) or when injected directly into the NTS (Vallöf, Vestlund, et al., 2019) or into the shell region of the NAc (Vallöf, Kalafateli, et al., 2019). Similar results were reported for the GLP‐1 receptor agonist liraglutide (Vallöf et al., 2016).

Systemically administered exenatide (Egecioglu, Steensland, et al., 2013; Shirazi et al., 2013; Sirohi et al., 2016) or the exenatide analogue AC3174 (Suchankova et al., 2015) and centrally administered exenatide into the VTA (Colvin et al., 2020; Shirazi et al., 2013), NTS (Vallöf, Vestlund, et al., 2019), NAc, dorsal hippocampus, lateral hypothalamus (Colvin et al., 2020), NAc shell (Colvin et al., 2020; Vallöf, Kalafateli, et al., 2019) and laterodorsal tegmental area (Vallöf, Kalafateli, et al., 2019) has been reported to significantly decrease alcohol intake in a two‐bottle choice paradigm. Exenatide also decreases operant oral alcohol self‐administration in rats when injected systemically (Egecioglu, Steensland, et al., 2013) or into the VTA (Dixon et al., 2020). However, all those treatment modalities also affect food consumption (Grill, 2020), and it is therefore not clear, if the effects of GLP‐1 receptor agonists in these models can be distinguished from potential effects due to the caloric value of alcohol.

The effects of systemically injected exenatide were abolished in mice where GLP‐1‐receptors were ablated in the CNS, indicating that the effects on alcohol intake are most likely to be centrally rather than peripherally mediated (Sirohi et al., 2016).

Effects of chronic or repeated GLP‐1 receptor agonist administration are less consistent: In one study, the GLP‐1 receptor agonists liraglutide and semaglutide potently decreased ethanol intake when given acutely, but when testing repeated administration, effects were transient, not lasting more than 48 h (Marty et al., 2020). Another study found modest or variable indications of development of tolerance after repeated liraglutide administration (Vallöf et al., 2016). However, once‐weekly injections of the long‐acting GLP‐1 receptor agonist dulaglutide for 5 or 9 weeks decreased alcohol intake in male and female rats with no indication of tolerance (Vallöf et al., 2020). Also, subchronic administration of liraglutide reduced operant oral alcohol self‐administration in rats (Vallöf et al., 2016). Finally, a model of relapse behaviour reported an attenuated binge‐like increase in alcohol drinking, with protracted latency to the first drink and reduced drinking bouts, after subchronic treatment with exenatide (Thomsen, Dencker, et al., 2017).

The effects of GLP‐1 receptor stimulation on alcohol intake have also been reported in non‐human primates (Thomsen et al., 2018). The GLP‐1 receptor agonists exenatide and liraglutide were tested in alcohol‐preferring African vervet monkeys with long‐term alcohol experience. In the exenatide experiment, exenatide or vehicle was administered for 5 weeks, and in the liraglutide experiment, liraglutide or vehicle was administered for 2 weeks, to obtain steady‐state blood levels. In both studies, no alcohol was available under up‐titration of the study‐drug. Alcohol was then reintroduced for 2 weeks, and alcohol intake was recorded while the assigned GLP‐1 receptor agonist treatment was continued. Both GLP‐1 receptor agonists reduced alcohol consumption without emetic events (Thomsen et al., 2018).

To investigate the effect of endogenous GLP‐1 on alcohol intake, GLP‐1 release from the small intestines (as the precursor proglucagon) was stimulated using two different receptor agonists of the orphan receptor GPR119, AR231453 and APD668. However, neither receptor agonist decreased alcohol intake (Marty et al., 2020). This might be due to rapid degradation or limited access to the brain of systemically released native GLP‐1 and supports the contention that GLP‐1 effects on alcohol consumption are centrally mediated. Another approach employed to increase levels of endogenous GLP‐1 is the inhibition of DPP‐4, an enzyme responsible for the degradation of GLP‐1 and other peptides, by compounds such as sitagliptin. Still, this approach did not significantly affect alcohol intake (Marty et al., 2020). However, systemic administration of the GLP‐1 receptor antagonist exendin‐9 increased alcohol intake (Shirazi et al., 2013), supporting a role for endogenous GLP‐1 in modulating alcohol consumption. DPP‐4 degrades endogenous GLP‐1 within minutes, and DPP‐4 inhibitors are approved for treatment of Type 2 diabetes (Deacon, 2020) as an indirect way to stimulate GLP‐1 receptors (Łupina et al., 2020). One study of ethanol withdrawal‐induced anxiety in rats reports delayed withdrawal‐induced anxiety after treatment with a DPP‐4 inhibitor (Sharma et al., 2015a), but it is not clear what the neural mechanism behind this effect might be.

Regarding interactions between alcohol consumption and the endogenous GLP‐1 system, elevated GLP‐1 receptor expression in the NAc has been reported in high alcohol‐consuming animals compared with low alcohol‐consuming animals (Vallöf, Kalafateli, et al., 2019). No changes in GLP‐1 receptor expression in the VTA, amygdala, hippocampus, prefrontal cortex or striatum were observed in the same study (Vallöf, Kalafateli, et al., 2019).

A notable omission from the published reports are those on the effects of GLP‐1 receptor agonists on truly alcohol‐dependent animals. In most of the studies described above, animals were exposed to modest quantities of alcohol in models focusing on the reinforcing aspects of alcohol consumption. AUD is characterized by continued drinking despite negative consequences, and studies addressing this aspect of AUD are lacking. Also, studies addressing the effects of GLP‐1 receptor agonists on the long‐term adaptations of the brain to high levels of alcohol consumption are needed (see Figure 1 for a summary).

FIGURE 1.

FIGURE 1

Open in a new tab

Effects of glucagon‐like peptide 1 (GLP‐1) receptor stimulation on alcohol reward‐related behaviours in preclinical models. CPP, conditioned place preference; DHipp, dorsal hippocampus; ex‐4, exenatide; ex‐9, exendin 9–39; LDTg, laterodorsal tegmental nucleus; LH, lateral hypothalamus; NAc, nucleus accumbens; NAcs, nucleus accumbens shell; NTS, nucleus tractus solitarius; VTA, ventral tegmental area

3.2. Clinical/human studies

The potential effects of GLP‐1 receptor agonists in reducing alcohol intake in humans were first reported in a scientific meeting abstract from 2011, in a cross‐sectional review among patients with Type 2 diabetes treated with liraglutide for 3 months (Kalra, 2011).

Two clinical trials have investigated the effects of GLP‐1 receptor agonists on alcohol intake in ‘heavy drinkers’ or patients diagnosed with AUD (Table 2). The first study—performed by our group—is a randomized, double‐blinded, placebo‐controlled clinical trial investigating reduction in heavy drinking days after treatment with exenatide once weekly for 26 weeks in patients diagnosed with AUD. A subgroup of the patients had functional MRI (fMRI) and single‐photon emission CT (SPECT) scans performed at baseline and after 26 weeks of treatment, to investigate potential neurobiological changes (the clinical study has been completed, and the manuscript is in preparation, ClinicalTrials.gov identifier NCT03232112) (Antonsen et al., 2018). The second trial is a double‐blind, randomized, placebo‐controlled, crossover study design investigating the acute effects of exenatide on alcohol intake in heavy drinkers (ClinicalTrials.gov identifier NCT03645408; recruitment is ongoing [April 2021]).

TABLE 2.

Unpublished or ongoing clinical trials of GLP‐1‐based therapies for addictive disorders

SUD Study name Drug Administration Estimated patient enrolment Primary outcome(s) Expected end date NCT identifier
Alcohol EXALT Exenatide s.c., 2 mg, once weekly 127 Reduction in heavy drinking days in patients with AUD, after 26 weeks of treatment October 2020 NCT03232112
Alcohol Exenatide s.c. single injection, 5 μg 36 Alcohol consumption for 4 h in heavy drinkers, alcohol craving for 4 h in heavy drinkers December 2021 NCT03645408
Alcohol/nicotine GHADD Exenatide i.v. dose 0.06 pmol·kg−1·min−1 95 Functional MRI measure of brain activation during cigarette, alcohol and food picture evaluation task. August 2020 NCT02690987
Nicotine DAL Liraglutide s.c., 3.0 mg, once daily 40/80? 7‐day point prevalence smoking abstinence at 12 weeks, 7‐day point prevalence smoking abstinence at 26 weeks May 2021 NCT03712098
Nicotine SKIP Dulaglutide s.c., 1.5 mg, once weekly 256 Point prevalence abstinence rate at Week 12 March 2021 NCT03204396
Opioids Liraglutide s.c., 3.0 mg, once daily 40 Change in self‐reported cue‐elicited drug craving, change in ambient drug craving over time December 2021 NCT04199728
Open in a new tab

Abbreviations: AUD, alcohol use disorder; GLP‐1, glucagon‐like peptide 1; NCT, National Clinical Trial; SUD, substance use disorder.

In terms of GLP‐1‐related mechanisms that might affect vulnerability to or development of AUD, a genetic study composed of four human genetic association studies has shown that the GLP‐1 receptor 168Ser allele is associated with increased alcohol self‐administration and a higher fMRI blood‐oxygen‐level‐dependent (BOLD) response in the globus pallidus when receiving rewarding feedback in the monetary incentive delay task. This suggests a more dysfunctional reward system, which might contribute to a higher vulnerability to AUD (Suchankova et al., 2015). A clinical trial investigating the effects of alcohol given intravenously or intragastrically reports no changes in plasma GLP‐1 concentrations in healthy male volunteers (Lanng et al., 2019). This is supported by other studies in healthy volunteers, consuming alcohol before an oral glucose test (Svartberg et al., 1998), after an overnight fast (Calissendorff et al., 2012) or after consumption of red wine (Abraham et al., 2016). However, in patients with Type 2 diabetes, who consumed alcohol and a fat‐rich meal, postprandial GLP‐1 levels were decreased (Dalgaard et al., 2004). It is thus unclear whether the latter result can be attributed to alcohol ingestion, as opposed to other nutrients.

Detoxified patients with AUD have been reported to have a lower serum DPP‐4 concentration than healthy controls, and it is hypothesized that this diminished activity, may be involved in the neuroendocrine pathophysiology of alcohol dependence (Maes et al., 1999).

4. ROLE OF GLP‐1 IN SUBSTANCE USE DISORDER

4.1. Cocaine: Basic and clinical research

Modulation of the addiction‐related effects of cocaine by GLP‐1 receptor agonists is also well documented (Hernandez & Schmidt, 2019). Systemic exenatide administration has been reported to suppress both the acquisition and the expression of cocaine‐conditioned place preference in mice (Egecioglu, Engel, & Jerlhag, 2013a; Graham et al., 2013). Two studies examined the acute effects of exenatide on intravenous cocaine self‐administration and this is considered the ‘gold standard’ approach for studying the effects of injectable drugs including cocaine. Both systemically administered in mice and centrally administered exenatide into the VTA in rats decreased cocaine self‐administration (Schmidt et al., 2016; Sørensen et al., 2015). Exenatide injected systemically or into the NAc, VTA or laterodorsal tegmental nucleus suppressed operant responding during reinstatement paradigms thought to reflect cocaine seeking; that is, reinstatement of lever pressing was induced by cocaine injections or cues previously associated with cocaine reinforcement (Hernandez et al., 2018, 2019, 2020).

Acute exenatide has been reported to inhibit cocaine‐stimulated locomotor hyperactivity and decrease or abolish cocaine‐induced dopamine release in the NAc and lateral septum in mice (Egecioglu, Engel, & Jerlhag, 2013a; Reddy et al., 2016; Sørensen et al., 2015). This effect appears to be centrally mediated, as exenatide administered into the lateral ventricles of the brain similarly suppressed cocaine‐evoked dopamine signalling in the NAc (Fortin & Roitman, 2017). Mice lacking GLP‐1 receptors showed exaggerated locomotor and conditioned place preference responses to cocaine (Harasta et al., 2015). The effects were reversed by viral vector‐mediated expression of GLP‐1 receptors in the lateral septum, indicating a crucial role of this structure in GLP‐1 modulation of cocaine effects (Harasta et al., 2015).

Self‐administration of cocaine, and expectancy of cocaine injections, increased endogenous GLP‐1 in rats (You et al., 2019). In contrast, a human study reported decreased GLP‐1 levels 1 h after intravenous cocaine injection in experienced cocaine users (Bouhlal et al., 2017). These findings were replicated in a recent study with 13 non‐treatment‐seeking patients with CUD (Angarita et al., 2021). However, the latter study could not demonstrate an effect of acute pretreatment with exenatide on cocaine self‐administration or cocaine‐induced subjective effects. Although these early findings in human subjects are somewhat surprising, as pointed out by the authors, they do not preclude the possibility that different doses, ligands, dosing regimens (e.g., subchronic) could modulate cocaine‐taking behaviour in patients with CUD (Angarita et al., 2021).

In summary, preclinical studies show promising effects of GLP‐1 receptor agonists against cocaine intake, but little information is yet available regarding possible effects of cocaine use on the GLP‐1 system or GLP‐1 as a predisposing factor to developing CUD.

4.2. Amphetamine: Basic and clinical research

Fewer studies have examined the effects of GLP‐1 receptor activation on central stimulant effects, all of them using d‐amphetamine. Two studies investigated the acute effects of systemically injected exenatide on the expression of amphetamine‐conditioned place preference in mice. Both studies reported attenuated amphetamine‐conditioned place preference (Egecioglu, Engel, & Jerlhag, 2013a; Sirohi et al., 2016). The psychomotor stimulant effects of amphetamine were also reduced by exenatide or liraglutide administration, measured by locomotor activity in rats and mice, respectively (Chaves Filho et al., 2020; Erreger et al., 2012). Moreover, liraglutide inhibited the deleterious effects of amphetamine on cognitive performance in some assays (Chaves Filho et al., 2020). DPP‐4 inhibitors reduced amphetamine‐induced hyperactivity in rats receiving an acute dose of d‐amphetamine (Lautar et al., 2005).

To the best of our knowledge, no clinical trials have or are currently investigating GLP‐1 receptor activation as a treatment of central stimulant use disorder in humans.

4.3. Opioids: Basic and clinical research

Two larger preclinical studies have reported on the effects of exenatide on opioid‐related behaviours in rodents. The first study was performed in male mice and reported that morphine‐conditioned place preference, intravenous self‐administration of the short‐acting synthetic opioid remifentanil, morphine‐stimulated locomotor activity and somatic symptoms of morphine withdrawal (measured as jumps) were not affected by exenatide treatment (Bornebusch et al., 2019). Neither did exenatide significantly affect the analgesic effects of morphine in a hotplate assay (including male and female mice) (Bornebusch et al., 2019). Reinforcing effects of remifentanil (self‐administration assay) were comparable or increased in mice lacking GLP‐1 receptors in the CNS, compared with wild‐type controls (Bornebusch et al., 2019).

The second study investigated the behavioural and neurochemical effects of exenatide and oxycodone in rats. In discordance with the previous study, it was reported that exenatide injected systemically or centrally into the NAc shell region decreased oxycodone self‐administration, as well as responding in a reinstatement paradigm (Zhang et al., 2020). However, in agreement with the previous study, exenatide did not significantly affect the analgesic effects of oxycodone using a tail immersion test (Zhang et al., 2020). To identify the central mechanisms of action, a group of rats was injected systemically with fluorescently labelled exenatide, which was shown to cross the blood–brain barrier and bind putative GLP‐1 receptors expressed on dopamine D1 and D2 receptors, expressing GABAergic medium spiny neurons in the NAc shell (Zhang et al., 2020). The discrepant results in the self‐administration paradigm may indicate species differences between rats and mice. Indeed, another rat study reported that exenatide reduced responding for cues previously associated with heroin injections in a reinstatement procedure of operant behaviour (Douton et al., 2021). Treatment with the selective DPP‐4 inhibitor linagliptin was also reported to reduce morphine‐conditioned place preference and facilitate extinction of the morphine preference in rats (Łupina et al., 2020).

One randomized, double‐blinded clinical trial (ClinicalTrials.gov identifier NCT04199728) is currently investigating the effects of the GLP‐1 receptor agonist liraglutide, 3.0 mg daily for 30 days, on craving in patients diagnosed with OUD (Table 2).

4.4. Nicotine: Basic and clinical research

Two rodent nicotine studies have been reported. The first study reported attenuation of nicotine‐induced locomotor hyperactivity and sensitization, nicotine‐conditioned place preference and nicotine‐induced accumbal dopamine release (measured by microdialysis) after acute systemic exenatide administration (Egecioglu, Engel, & Jerlhag, 2013b). The second study found that systemic exenatide or the DPP‐4 inhibitor sitagliptin decreased intravenous nicotine self‐administration in mice and that GLP‐1 receptor knockout mice, that is, mice lacking GLP‐1 receptors, self‐administered more nicotine than the wild‐type controls (Tuesta et al., 2017). The study further reports that exenatide injected into the interpeduncular nucleus decreased nicotine self‐administration and prevented nicotine from modulating intracranial self‐stimulation threshold in rats (Tuesta et al., 2017). Chemogenetic activation of GLP‐1 neurons in NTS similarly decreased nicotine intake. This is consistent with a central site of action for GLP‐1 regulation of motivational properties of nicotine. The authors (Tuesta et al., 2017) suggest that endogenous GLP‐1 released from the NTS decreases nicotine intake by activating the medial habenula interpeduncular nucleus circuit.

According to ClinicalTrials.gov, three human clinical trials are investigating the potential effects of a GLP‐1 receptor agonist against tobacco use disorder (Table 2), and one randomized clinical pilot trial has investigated the effects of exenatide, 2.0 mg once weekly, in combination with transdermal nicotine replacement therapy on smoking cessation. They have reported that exenatide increased smoking abstinence and reduced craving (Yammine et al., 2021). Two other clinical trials investigating subcutaneous liraglutide, 3.0 mg daily (ClinicalTrials.gov identifier NCT03712098), and subcutaneous dulaglutide, 1.5 mg once weekly (ClinicalTrials.gov identifier NCT03204396), are still recruiting. In addition to the randomized clinical trials, one fMRI study is investigating whether intravenous exenatide reduces cue reactivity when patients are presented with visual stimuli of alcohol and tobacco (ClinicalTrials.gov identifier NCT02690987).

4.5. Influence of GLP‐1 receptor agonists on dopamine regulation

Dopamine plays a prominent role in the immediate reinforcing/rewarding effects of drugs, and dysregulation of the dopamine system is thought to contribute (as a predisposing factor and/or a consequence of chronic substance use) to the addicted state (Volkow, Michaelides, et al., 2019). Dopaminergic neurons emerging from the VTA project to the NAc, amygdala, hippocampus and prefrontal cortex, and dopamine neurons emerging from substantia nigra (SN) project to the dorsal striatum (Volkow et al., 2017). Disinhibition/stimulation of dopaminergic VTA neurons is known to play a critical role in the reinforcing effects of alcohol, nicotine and opioids (Volkow et al., 2017). Cocaine inhibits dopamine reuptake by blocking the dopamine transporter (DAT), increasing or prolonging synaptic dopamine levels (Volkow et al., 2002). Other central stimulants can increase synaptic dopamine levels by several modes of action, for example, blockade of dopamine reuptake, ‘reverse’ DAT function and dopamine release (Lee et al., 2018). Radiotracer imaging studies in patients with AUD (Volkow et al., 1996), cocaine users (Volkow et al., 1993) and methamphetamine users (Volkow et al., 2001) have reported of decreased postsynaptic dopamine receptor availability, which is suggested as one of the explanations for lower dopamine function in this group of patients (Nutt et al., 2015). Another mechanism explaining the abnormal radiotracer imaging results could be a blunted dopamine response, compensating for other neurotransmitter deficits, that is, glutamate or GABA (Volkow et al., 2011). Several preclinical studies have tried to elucidate how GLP‐1 systems modulate dopamine signalling. Microdialysis or fast‐scan cyclic voltammetry studies have repeatedly reported that GLP‐1 receptor agonists acutely decrease accumbal dopamine efflux induced by substances of abuse. However, information from chronic dosing studies is lacking. Systemically injected liraglutide (Vallöf et al., 2016) and exenatide (Egecioglu, Steensland, et al., 2013) attenuate alcohol‐induced accumbal dopamine release, and exenatide injection into the NTS also attenuates this response as well (Vallöf, Vestlund, et al., 2019). Exenatide can similarly suppress cocaine‐induced increases in accumbal and lateral septal dopamine levels (Fortin & Roitman, 2017; Reddy et al., 2016; Sørensen et al., 2015) and amphetamine‐ and nicotine‐induced accumbal dopamine levels in rats (Egecioglu, Engel, & Jerlhag, 2013a, 2013b). GLP‐1 receptor agonists do not seem to suppress baseline accumbal dopamine, as opposed to the modulation of stimulated levels, and modulation may differ between NAc shell and core regions (Egecioglu, Engel, & Jerlhag, 2013a; Fortin & Roitman, 2017). Dulaglutide treatment for 9 weeks decreased dopamine tissue levels in the amygdala and striatum of rats, relative to vehicle (Vallöf et al., 2020).

The mechanisms by which GLP‐1 receptor stimulation modulates dopamine function are less clear. Experiments in mice indicate that stimulation of GLP‐1 receptors in the VTA weakens the synaptic strength of VTA–NAc projections (Wang et al., 2015), but relatively few VTA neurons express GLP‐1 receptors (Cork et al., 2015; Harasta et al., 2015). Experiments in rats indicate that GLP‐1 receptor stimulation in the VTA could increase dopaminergic neuron activity via a presynaptic mechanism of action (Mietlicki‐Baase et al., 2013). One study focused on the lateral septum in mice, an area previously associated with reward (Harasta et al., 2015; Luo et al., 2011; Olds & Milner, 1954), and reported that GLP‐1 receptor stimulation might dampen addiction‐related effects by increasing the expression of DAT on the neuronal cell surface, thereby reducing free dopamine levels in the synapses (Reddy et al., 2016). These findings are supported by another study in rats investigating the effect of GLP‐1 receptor activation on DAT up‐regulation in striatal brain slices as well as in vivo by use of striatal microdialysis (Jensen et al., 2020). However, other studies reported unaffected DAT after exenatide treatment in rats (Fortin & Roitman, 2017), or mice (Jensen et al., 2020), or by genetic ablation of GLP‐1 receptors, that is, knockout mice (Jensen et al., 2020).

To the best of our knowledge, only a single human study has investigated the acute effects of GLP‐1 receptor activation on DAT availability as the primary endpoint. Ten healthy volunteers with no previous history of drug or alcohol abuse received intravenous infusions of the GLP‐1 receptor agonist exenatide, while being in a SPECT scanner. The results showed no acute changes in DAT availability (Jensen et al., 2020). This is in line with findings from another clinical trial, investigating the effects of exenatide once weekly in patients with Parkinson's disease, where an effect on off‐medication motor scores was reported, but no significant effect on DAT availability after 48 weeks of treatment (Athauda et al., 2017). Thus, it has been proposed that the GLP‐1 receptor agonist‐induced up‐regulation of DAT availability might be species dependent, with no DAT–GLP‐1 interaction in humans (Jensen et al., 2020).

5. POSSIBLE MECHANISMS OF ACTION

Despite the preclinical research discussed above and a small number of clinical trials, it is still unclear how GLP‐1 receptor stimulation modulates the effects of drugs of abuse and alcohol. At a behavioural level, the focus of most research has been on the rewarding/reinforcing effects. Currently, the FDA‐approved medications to treat AUD, that is, disulfiram, naltrexone and acamprosate, reduce drinking through three different mechanisms of action: (i) unpleasant effects when consuming alcohol, (ii) reduced rewarding/reinforcing effects of alcohol and (iii) reduced negative state when abstinent. In the published reports, it has largely been assumed that GLP‐1 receptor agonists reduce alcohol intake by decreased rewarding/reinforcing effects of alcohol, and the possibility that GLP‐1 receptor stimulation might decrease alcohol intake through additional mechanisms has not been published. Similarly, studies on cocaine and amphetamine have focused on rewarding/reinforcing effects. An alternative mechanism (not mutually exclusive with reward modulation) is suggested by a study on nicotine, namely, that GLP‐1 receptor stimulation may promote satiety and avoidance of aversive effects of the drug, in this case nicotine, via a habenula‐dependent mechanism (Tuesta et al., 2017). Another study suggested that cocaine produces a GLP‐1‐dependent negative feedback loop through activation of stress circuits including corticosterone, limiting cocaine intake (Schmidt et al., 2016), which could also be interpreted as a form of GLP‐1‐potentiated cocaine ‘satiety’. Mechanisms involving some form of satiation would be consistent with the known effects of GLP‐1 system stimulation on the regulation of nutrient intake. However, several studies have reported that GLP‐1 receptor stimulation can suppress drug‐conditioned behaviours, in both classical conditioning (CPP procedures) and operant conditioning (drug seeking using reinstatement procedures), that is, tests during which the drug is unavailable (Douton et al., 2021; Egecioglu, Steensland, et al., 2013; Egecioglu, Engel, & Jerlhag, 2013a, 2013b; Graham et al., 2013; Harasta et al., 2015; Hernandez et al., 2018, 2019, 2020; Shirazi et al., 2013; Sirohi et al., 2016; Vallöf et al., 2016; Vallöf, Kalafateli, et al., 2019; Vallöf, Vestlund, et al., 2019). This would suggest that GLP‐1 receptor stimulation also modulates mechanisms underlying drug and alcohol ‘seeking’ or ‘wanting’, and not only intake and satiation.

5.1. GLP‐1 and the stress system

One of the possible mechanisms proposed to suppress cocaine self‐administration involves modulation of stress systems (Schmidt et al., 2016). The CRF neurons of the hypothalamus express GLP‐1 receptors, and GLP‐1 receptor stimulation has been shown to enhance CRF signalling (Kinzig et al., 2003; Larsen et al., 1997; Liu et al., 2017). This was also examined in the lateral septum, and in contrast to the findings in hypothalamus, blockade of the GLP‐1 receptors with a GLP‐1 antagonist did not reduce stress‐induced corticosterone release (Terrill et al., 2018). GLP‐1 receptor knockout mice also exhibited increased corticosterone responses to stress (MacLusky et al., 2000), suggesting a more complex relationship between GLP‐1 and the stress systems. A large literature suggests that activation of stress systems contributes to the addictive effects of various drugs of abuse, in the withdrawal and ‘negative affect’ stages of addiction (Koob, 2008; Koob & Volkow, 2016). Thus, chronic use of alcohol, central stimulants, nicotine and opioids have all been shown to increase CRF levels, and CRF antagonists reduce drug seeking (Mantsch et al., 2016; Park et al., 2015). GLP‐1 receptor agonists prevented ‘relapse’ to binge‐like alcohol drinking after deprivation and attenuated alcohol withdrawal‐induced anxiety‐like behaviour (Sharma et al., 2015b; Thomsen, Dencker, et al., 2017; Vallöf et al., 2016). Taken together, although stress system activation may curb cocaine‐taking behaviour by acting similarly to cocaine (Schmidt et al., 2016), GLP‐1 receptor‐mediated activation of CRF signalling more generally might be expected to facilitate relapse to drug or alcohol intake.

5.2. Ingestive regulatory effects

Because the GLP‐1 systems regulate food and fluid intake, and GLP‐1 receptor agonists can decrease food consumption at doses comparable with those that decrease alcohol intake, non‐specific effects may contribute to the observed decrease in alcohol drinking (Dickson et al., 2012; Tang‐Christensen et al., 1996). These effects may relate to nausea or general malaise, to the regulation of nutrient intake and consummatory behaviours, or both. However, the fact that exenatide also reduced intravenous self‐administration of alcohol (Sørensen et al., 2016) and GLP‐1 receptor agonists reduced rewarding effects of alcohol injections as measured by place conditioning (Egecioglu, Steensland, et al., 2013; Shirazi et al., 2013; Vallöf et al., 2016) indicates that GLP‐1 receptor stimulation modulates the rewarding and reinforcing effects of alcohol independently of its effects on oral consummatory behaviour. Rodents lack the ability of vomiting when nauseated, but nausea and malaise can be measured indirectly by pica, which is the consumption of the non‐nutritive substance, kaolin clay (Kanoski et al., 2012). Twelve days of treatment with exenatide has been reported to increase pica, but the pica response following treatment with liraglutide was more transient (Kanoski et al., 2012). However, GLP‐1 receptor activation with exenatide in the VTA, NAc core and NAc shell (Alhadeff et al., 2012) and in the NTS (Richard et al., 2015) have been reported not to produce a pica response. In non‐human primates treated with the GLP‐1 receptor agonists exenatide or liraglutide, no signs of nausea, that is, vomiting and/or reduced food intake, were registered (Thomsen et al., 2018). In humans, a recent systematic analysis of reported gastrointestinal side effects during treatment with GLP‐1 receptor agonists, including 32 clinical trials and 10,367 patients, reports that the level of nausea and vomiting depends on several factors: (i) the higher the dose, the higher the frequency of nausea, (ii) other medication and (iii) long‐acting GLP‐1 receptor agonists compared with more short‐acting GLP‐1 receptor agonists, were associated with less nausea (Bettge et al., 2017). Although it is possible that some of the effect of GLP‐1 receptor stimulation on alcohol drinking relates to consummatory behaviour and/or caloric intake from alcohol, this does not necessarily make the approach less useful in clinical practice. AUD sufferers are a heterogeneous group encompassing patients with malnutrition and low body weight, and patients with co‐morbid metabolic syndrome (Jeynes & Gibson, 2017; Vancampfort et al., 2016). Clinical observations from patients treated with GLP‐1 receptor agonists for Type 2 diabetes suggest that GLP‐1 receptor agonists may reduce body weight more in subjects with higher baseline body mass index (Niswender et al., 2013), so, in future clinical trials, it may be useful to evaluate the effects of GLP‐1 receptor agonists on alcohol intake in more specific subgroups of AUD patients, for example, in AUD patients with co‐morbid obesity.

5.3. Central versus peripheral effects

At a neurocircuit level, some effort has been devoted to identify neuron populations or brain regions that mediate decreases in alcohol intake in rats and mice. Evidence from genetically engineered mice lacking GLP‐1 receptors in specific tissues, infusion of GLP‐1 receptor agonists directly into the brain, and optogenetic or chemogenetic stimulation of neuron populations all indicate that central rather than peripheral mechanisms underlie the ability of GLP‐1 receptor agonists to reduce intake of drugs and alcohol (Abtahi et al., 2018; Colvin et al., 2020; Dixon et al., 2020; Harasta et al., 2015; Hernandez et al., 2018, 2019, 2020; Schmidt et al., 2016; Shirazi et al., 2013; Sirohi et al., 2016; Tuesta et al., 2017; Vallöf, Kalafateli, et al., 2019; Vallöf, Vestlund, et al., 2019). It is also reported that GLP‐1‐producing NTS neurons project directly to the VTA and NAc (core and shell) (Alhadeff et al., 2012) and that GLP‐1 receptor activation of the NTS alters expression of dopamine‐related genes in the VTA (Richard et al., 2015) However, the growing number of brain regions that have shown a positive effect upon GLP‐1 agonist infusion does not immediately suggest a clear and defined circuit‐level mechanism. Instead, GLP‐1 receptors seem to modulate brain circuits involved in reward and addiction at multiple levels. Effects in the classic mesolimbic reward pathway such as the VTA and NAc, which express GLP‐1 receptors at moderate levels, are perhaps not surprising. A straightforward explanation for effects in the NTS could be that stimulation of GLP‐1 autoreceptors in the NTS would be expected to reduce release of GLP‐1 to other brain regions, removing a tonic inhibitory modulation on reward/consummatory functions. Such an inhibitory effect of endogenous GLP‐1 is consistent with the reduction reported of GLP‐1 receptor antagonists on drug and alcohol intake (Shirazi et al., 2013). At a synaptic or molecular level, basic electrophysiology studies and studies using food suggest that both presynaptic and postsynaptic mechanisms are likely to be involved in the effects of GLP‐1 receptor agonists on reward pathways (Liu & Pang, 2016; Mietlicki‐Baase et al., 2014, 2013; Wang et al., 2015) even though there are few such mechanistic studies for drugs of abuse and alcohol.

5.4. GLP‐1 receptor heterogeneity

It has also become clear that GLP‐1 receptors in the brain are heterogeneous and can exert both inhibitory effects, as in the CA3 of hippocampus and lateral septum, and stimulatory effects, as in the CA1 of hippocampus and hypothalamic nuclei, at the cellular level (Liu & Pang, 2016). Thus, it may be appropriate to think of different functional subtypes of GLP‐1 receptors, likely brought about by GLP‐1 receptor ligands showing different signalling bias for different second messenger pathways, whose expression may vary by tissue (Fletcher et al., 2016; Zhang et al., 2015). Indeed, different GLP‐1 receptor agonists display tissue‐specific pharmacology (Pabreja et al., 2014). Based on rodent studies, GLP‐1 receptor agonists also vary with respect to brain availability and how discrete or extensive brain regions show GLP‐1 receptor binding after systemic GLP‐1 receptor agonist administration (Gabery et al., 2020; Salinas et al., 2018; Secher et al., 2014). GLP‐1 receptors show desensitization and internalization after chronic GLP‐1 receptor agonist treatment, which vary between different agonists and between different tissues or cell type (Fletcher et al., 2016; Roed et al., 2014). All those differences might explain differential adaptations (tolerance or no tolerance) depending on the agonist and dosing regimen.

5.5. Gender differences

Almost all preclinical studies reported included only male animals. However, a recent investigation used female rats and reported that exenatide microinfused into the NAc shell region, decreased alcohol intake in a two‐bottle choice system (Abtahi et al., 2018). Water intake was decreased, and alcohol preference, although not reported, may not have been decreased based on the relative effect sizes for water and alcohol intake. Because only female animals were tested, it is difficult to conclude any possible sex differences (Abtahi et al., 2018). Dulaglutide treatment was tested in both male and female rats and was found to reduce alcohol intake more in male rats than in female rats (Vallöf et al., 2020). Another study used both male and female mice to investigate the effects of GLP‐1 receptor agonists on nicotine self‐administration, but analyses of the sex variable were not reported, and data were only shown as sexes combined (Tuesta et al., 2017). Sex differences in the effects of GLP‐1 receptor agonists have been reported for other endpoints, such as modulation of feeding behaviours in rats (López‐Ferreras et al., 2018; Richard et al., 2016). In humans, the genetic association of the GLP‐1 receptor allele with risk of AUD was most robust in men (Suchankova et al., 2015), suggesting a sex difference in sensitivity to GLP‐1 receptor modulation of alcohol effects. Higher GLP‐1 response after an oral glucose test in healthy women than in men has been reported. However, this difference was abolished when glucose tolerance was worsening (Faerch et al., 2015). A smaller study, including 14 healthy volunteers, reported that GLP‐1 infusion changed taste preference in women significantly compared with men (Baretić et al., 2019). Another study reported higher GLP‐1 plasma levels in premenopausal women compared with postmenopausal women, but this might be due to different microbiota compositions (Santos‐Marcos et al., 2018). Clearly, it will be important to include both male and female subjects in future studies.

6. SUMMARY AND FUTURE PERSPECTIVE

The global burden of SUD, tobacco use disorder and AUD is increasing. Not only the individual suffering from these disorders is affected but also the families and society at large. Many patients are co‐using several substances, drastically increasing the risks associated with each substance alone. Pharmacological treatment options are sparse (AUD, OUD and tobacco use disorder), if not non‐existing (CUD and central stimulant use disorder). However, emerging evidence from basic research has pointed to GLP‐1 receptors as a possible target for developing new pharmacological treatment options. In addition to the GLP‐1 produced in the small intestines after food intake, GLP‐1 is also produced in the NTS of the brain and is released as a neurotransmitter in several brain regions. GLP‐1 receptors are expressed in regions previously identified as important players in the neurobiology of addiction, and importantly, GLP‐1 receptor agonists seem to cross the blood–brain barrier. Overall, preclinical research has identified potent reductions in substance use and attenuation of drug‐seeking behaviour with several different GLP‐1 receptor agonists, especially regarding alcohol (alcohol, see Figure 1; nicotine, stimulants, opioids and cocaine, see Figure 2). A human genetic association study has reported on a GLP‐1 receptor variant associated with increased alcohol self‐administration and changes in brain response in reward‐related areas, as revealed by fMRI brain imaging. It is also suggested that individuals suffering from obesity and individuals suffering from addiction have overlapping brain dysregulations, and the anti‐obesity effects of GLP‐1 receptor agonists support the potential usefulness of GLP‐1 receptor agonists for the treatment of SUD and AUD. The possibility that rewarding effects (of alcohol at least) may relate to consummatory behaviour does not necessarily make the approach less useful in clinical practice. The precise mechanisms of GLP‐1 receptor agonists' actions on addiction‐related endpoints have yet to be established, but the effects seem to be mediated centrally, at least in part through modification of dopamine signalling. No clear and well‐defined circuit‐level mechanism has been identified yet, instead GLP‐1 seems to modulate brain circuits at multiple levels, and the relevant mechanisms of action may well be species dependent. It is important to note that the present data pointing towards a beneficial effect of GLP‐1 receptor agonists have not yet been translated into humans, except for (i) a pilot trial indicating positive effects of the GLP‐1 receptor agonist exenatide, on nicotine abstinence and craving, and (ii) a minor study reporting no effect of acute low dose exenatide on cocaine self‐administration. Although a few human studies have been initiated, further data have not yet been published (see Table 2).

FIGURE 2.

FIGURE 2

Open in a new tab

Effects of glucagon‐like peptide 1 (GLP‐1) receptor stimulation in various substance reward‐related behaviours in preclinical models. CPP, conditioned place preference; LS, lateral septum; NAc, nucleus accumbens; NTS, nucleus tractus solitarius; VTA, ventral tegmental area

Newer systematic reviews and meta‐analyses including long‐term randomized clinical trials in patients with Type 2 diabetes have found no association between GLP‐1 receptor agonist treatment and pancreatitis or pancreatic cancer, which is critically important if treatment with GLP‐1 receptor agonists should be contemplated in this vulnerable group of high‐risk patients with AUD or SUD. With the approval of an oral GLP‐1 receptor agonist, better adherence to treatment might be hoped for in the future, but only new clinical trials will show if treatment with oral GLP‐1 receptor agonists is as effective as that with injected treatments. Many questions still need to be answered: Is there a gender difference in treatment response, as most preclinical trials have been performed on male animals only; is there a genetic variability in GLP‐1 receptors, production or degradation that contributes measurably to AUD or SUD pathogenesis, widely or in subpopulations; which agonist(s) are best suited to target AUD and SUD, also in consideration of potential side effects, the latter may not be a ‘one size fits all’ both regarding the various addictive substances and regarding individual patient characteristics. Summing up, the stage is set for further basic research and for large‐scale clinical trials to go ahead and bring to fruition the promising results from preliminary clinical studies and basic research.

6.1. Nomenclature of targets and ligands

Key protein targets and ligands in this article are hyperlinked to corresponding entries in the IUPHAR/BPS Guide to PHARMACOLOGY (http://www.guidetopharmacology.org) and are permanently archived in the Concise Guide to PHARMACOLOGY 2019/20 (Alexander, Christopoulos, et al., 2019; Alexander, Fabbro, et al., 2019; Alexander, Kelly, et al., 2019).

CONFLICT OF INTEREST

A.F.‐J. has received an unrestricted research grant from Novo Nordisk A/S to investigate the effects of GLP‐1 receptor stimulation on metabolic disturbances and weight gain in antipsychotic‐treated patients with schizophrenia. There is no other possible conflicts of interest, for the remaining authors.

7.

ACKNOWLEDGEMENTS

M.K.K. was supported by grants from the Novavi Foundation, Denmark, and The Research Foundation (Mental Health Services, Capital Region of Denmark) while working on this manuscript; M.T. was supported by Grant R01AA025071 from the NIH National Institute on Alcohol Abuse and Alcoholism (NIAAA).

Klausen, M. K. , Thomsen, M. , Wortwein, G. , & Fink‐Jensen, A. (2022). The role of glucagon‐like peptide 1 (GLP‐1) in addictive disorders. British Journal of Pharmacology, 179(4), 625–641. 10.1111/bph.15677

Funding information The Novavi Foundation, Denmark; NIH National Institute on Alcohol Abuse and Alcoholism (NIAAA), Grant/Award Number: R01AA025071; The Research Foundation (Mental Health Services, Capital Region of Denmark)

DATA AVAILABILITY STATEMENT

Data sharing does not apply to this article because no new data were created or analysed in this study.

REFERENCES

  1. Abd El Aziz, M. , Cahyadi, O. , Meier, J. J. , Schmidt, W. E. , & Nauck, M. A. (2020). Incretin‐based glucose‐lowering medications and the risk of acute pancreatitis and malignancies: A meta‐analysis based on cardiovascular outcomes trials. Diabetes, Obesity and Metabolism, 22(4), 699–704. 10.1111/dom.13924 [DOI] [PubMed] [Google Scholar]
  2. Abraham, K. A. , Kearney, M. L. , Reynolds, L. J. , & Thyfault, J. P. (2016). Red wine enhances glucose‐dependent insulinotropic peptide (GIP) and insulin responses in type 2 diabetes during an oral glucose tolerance test. Diabetology International, 7(2), 173–180. 10.1007/s13340-015-0234-y [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Abtahi, S. , Howell, E. , & Currie, P. J. (2018). Accumbal ghrelin and glucagon‐like peptide 1 signaling in alcohol reward in female rats. Neuroreport, 29(12), 1046–1053. 10.1097/WNR.0000000000001071 [DOI] [PubMed] [Google Scholar]
  4. Alexander, S. P. H. , Christopoulos, A. , Davenport, A. P. , Kelly, E. , Mathie, A. , Peters, J. A. , Veale, E. L. , Armstrong, J. F. , Faccenda, E. , Harding, S. D. , Pawson, A. J. , Sharman, J. L. , Southan, C. , Davies, J. A. , & CGTP Collaborators . (2019). The Concise Guide to PHARMACOLOGY 2019/20: G protein‐coupled receptors. British Journal of Pharmacology, 176(S1), S21–S141. 10.1111/bph.14748 [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Alexander, S. P. H. , Fabbro, D. , Kelly, E. , Mathie, A. , Peters, J. A. , Veale, E. L. , Armstrong, J. F. , Faccenda, E. , Harding, S. D. , Pawson, A. J. , Sharman, J. L. , Southan, C. , Davies, J. A. , & CGTP Collaborators . (2019). The Concise Guide to PHARMACOLOGY 2019/20: Enzymes. British Journal of Pharmacology, 176(S1), S297–S396. 10.1111/bph.14752 [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Alexander, S. P. H. , Kelly, E. , Mathie, A. , Peters, J. A. , Veale, E. L. , Armstrong, J. F. , Faccenda, E. , Harding, S. D. , Pawson, A. J. , Sharman, J. L. , Southan, C. , Davies, J. A. , & CGTP Collaborators . (2019). The Concise Guide to PHARMACOLOGY 2019/20: Transporters. British Journal of Pharmacology, 176(S1), S397–S493. 10.1111/bph.14753 [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Alhadeff, A. L. , Rupprecht, L. E. , & Hayes, M. R. (2012). GLP‐1 neurons in the nucleus of the solitary tract project directly to the ventral tegmental area and nucleus accumbens to control for food intake. Endocrinology, 153(2), 647–658. 10.1210/en.2011-1443 [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Angarita, G. A. , Matuskey, D. , Pittman, B. , Costeines, J. L. , Potenza, M. N. , Jastreboff, A. M. , Schmidt, H. D. , & Malison, R. T. (2021). Testing the effects of the GLP‐1 receptor agonist exenatide on cocaine self‐administration and subjective responses in humans with cocaine use disorder. Drug and Alcohol Dependence, 221(October 2020), 108614. 10.1016/j.drugalcdep.2021.108614 [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Antonsen, K. K. , Klausen, M. K. , Brunchmann, A. S. , le Dous, N. , Jensen, M. E. , Miskowiak, K. W. , Fisher, P. M. , Thomsen, G. K. , Rindom, H. , Fahmy, T. P. , Vollstaedt‐Klein, S. , Benveniste, H. , Volkow, N. D. , Becker, U. , Ekstrøm, C. , Knudsen, G. M. , Vilsbøll, T. , & Fink‐Jensen, A. (2018). Does glucagon‐like peptide‐1 (GLP‐1) receptor agonist stimulation reduce alcohol intake in patients with alcohol dependence: Study protocol of a randomised, double‐blinded, placebo‐controlled clinical trial. BMJ Open, 8(7), e019562. 10.1136/bmjopen-2017-019562 [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Athauda, D. , Maclagan, K. , Skene, S. S. , Bajwa‐Joseph, M. , Letchford, D. , Chowdhury, K. , Hibbert, S. , Budnik, N. , Zampedri, L. , Dickson, J. , Li, Y. , Aviles‐Olmos, I. , Warner, T. T. , Limousin, P. , Lees, A. J. , Greig, N. H. , Tebbs, S. , & Foltynie, T. (2017). Exenatide once weekly versus placebo in Parkinson's disease: A randomised, double‐blind, placebo‐controlled trial. The Lancet, 390(10103), 1664–1675. 10.1016/S0140-6736(17)31585-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Azoulay, L. , Filion, K. B. , Platt, R. W. , Dahl, M. , Dormuth, C. R. , Clemens, K. K. , Durand, M. , Hu, N. , Juurlink, D. N. , Paterson, J. M. , Targownik, L. E. , Turin, T. C. , Ernst, P. , & Canadian Network for Observational Drug Effect Studies (CNODES) Investigators . (2016a). Association between incretin‐based drugs and the risk of acute pancreatitis. JAMA Internal Medicine, 176(10), 1464–1473. 10.1001/jamainternmed.2016.1522 [DOI] [PubMed] [Google Scholar]
  12. Azoulay, L. , Filion, K. B. , Platt, R. W. , Dahl, M. , Dormuth, C. R. , Clemens, K. K. , Durand, M. , Juurlink, D. N. , Targownik, L. E. , Turin, T. C. , Paterson, J. M. , Ernst, P. , & Canadian Network for Observational Drug Effect Studies Investigators . (2016b). Incretin based drugs and the risk of pancreatic cancer: International multicentre cohort study. The BMJ, 352, i581. 10.1136/bmj.i581 [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Badiani, A. , Belin, D. , Epstein, D. , Calu, D. , & Shaham, Y. (2011). Opiate versus psychostimulant addiction: The differences do matter. Nature Reviews Neuroscience, 12(11), 685–700. 10.1038/nrn3104 [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Baretić, M. , Kušec, V. , Uroić, V. , Pavlić‐Renar, I. , & Altabas, V. (2019). Glucagon‐like peptide‐1 affects taste perception differently in women: A randomized, placebo‐controlled crossover study. Acta Clinica Croatica, 58(2), 240–248. 10.20471/acc.2019.58.02.06 [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Berridge, K. C. , & Robinson, T. E. (2016). Liking, wanting, and the incentive‐sensitization theory of addiction. American Psychologist, 71(8), 670–679. 10.1037/amp0000059 [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Bettge, K. , Kahle, M. , Abd El Aziz, M. S. , Meier, J. J. , & Nauck, M. A. (2017). Occurrence of nausea, vomiting and diarrhoea reported as adverse events in clinical trials studying glucagon‐like peptide‐1 receptor agonists: A systematic analysis of published clinical trials. Diabetes, Obesity and Metabolism, 19(3), 336–347. 10.1111/dom.12824 [DOI] [PubMed] [Google Scholar]
  17. Borges, G. , Bagge, C. , Cherpitel, C. , Conner, K. , Orozco, R. , & Rossow, I. (2017). A meta‐analysis of acute use of alcohol and the risk of suicide attempt. Psychological Bulletin, 47(5), 949–957. 10.1017/S0033291716002841 [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Bornebusch, A. B. , Fink‐Jensen, A. , Wörtwein, G. , Seeley, R. J. , & Thomsen, M. (2019). Glucagon‐like peptide‐1 receptor agonist treatment does not reduce abuse‐related effects of opioid drugs. ENeuro, 6(2), ENEURO.0443‐18.2019. 10.1523/ENEURO.0443-18.2019 [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Bouhlal, S. , Ellefsen, K. N. , Sheskier, M. B. , Singley, E. , Pirard, S. , Gorelick, D. A. , Huestis, M. A. , & Leggio, L. (2017). Acute effects of intravenous cocaine administration on serum concentrations of ghrelin, amylin, glucagon‐like peptide‐1, insulin, leptin and peptide YY and relationships with cardiorespiratory and subjective responses. Drug and Alcohol Dependence, 180, 68–75. 10.1016/j.drugalcdep.2017.07.033 [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Calissendorff, J. , Gustafsson, T. , Holst, J. J. , Brismar, K. , & Röjdmark, S. (2012). Alcohol intake and its effect on some appetite‐regulating hormones in man: Influence of gastroprotection with sucralfate. Endocrine Research, 37(3), 154–162. 10.3109/07435800.2012.662662 [DOI] [PubMed] [Google Scholar]
  21. Carvalho, A. F. , Heilig, M. , Perez, A. , Probst, C. , & Rehm, J. (2019). Alcohol use disorders. The Lancet, 394(10200), 781–792. 10.1016/S0140-6736(19)31775-1 [DOI] [PubMed] [Google Scholar]
  22. Chaves Filho, A. J. M. , Cunha, N. L. , de Souza, A. G. , Soares, M. V.‐R. , Jucá, P. M. , de Queiroz, T. , Oliveira, J. V. S. , Valvassori, S. S. , Barichello, T. , Quevedo, J. , de Lucena, D. , & Macedo, D. S. (2020). The GLP‐1 receptor agonist liraglutide reverses mania‐like alterations and memory deficits induced by D‐amphetamine and augments lithium effects in mice: Relevance for bipolar disorder. Progress in Neuro‐Psychopharmacology and Biological Psychiatry, 99, 109872. 10.1016/j.pnpbp.2020.109872 [DOI] [PubMed] [Google Scholar]
  23. Chis, B. A. , & Fodor, D. (2017). Acute pancreatitis during GLP‐1 receptor agonist treatment. A case report. Clujul Medical, 91(1), 117–119. 10.15386/cjmed-804 [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Christensen, M. , Sparre‐Ulrich, A. H. , Hartmann, B. , Grevstad, U. , Rosenkilde, M. M. , Holst, J. J. , Vilsbøll, T. , & Knop, F. K. (2015). Transfer of liraglutide from blood to cerebrospinal fluid is minimal in patients with type 2 diabetes. International Journal of Obesity, 39(11), 1651–1654. 10.1038/ijo.2015.136 [DOI] [PubMed] [Google Scholar]
  25. Colvin, K. J. , Killen, H. S. , Kanter, M. J. , Halperin, M. C. , Currie, P. J. , & Engel, L. (2020). Brain site‐specific inhibitory effects of the GLP‐1 analogue exendin‐4 on alcohol intake and operant responding for palatable food. International Journal of Molecular Sciences, 21(24), 1–15. 10.3390/ijms21249710 [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Connor, J. P. , Haber, P. S. , & Hall, W. D. (2016). Alcohol use disorders. The Lancet, 387(10022), 988–998. 10.1016/S0140-6736(15)00122-1 [DOI] [PubMed] [Google Scholar]
  27. Cork, S. C. , Richards, J. E. , Holt, M. K. , Gribble, F. M. , Reimann, F. , & Trapp, S. (2015). Distribution and characterisation of glucagon‐like peptide‐1 receptor expressing cells in the mouse brain. Molecular Metabolism, 4(10), 718–731. 10.1016/j.molmet.2015.07.008 [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Dalgaard, M. , Thomsen, C. , Rasmussen, B. M. , Holst, J. J. , & Hermansen, K. (2004). Ethanol with a mixed meal decreases the incretin levels early postprandially and increases postprandial lipemia in type 2 diabetic patients. Metabolism: Clinical and Experimental, 53(1), 77–83. 10.1016/j.metabol.2003.08.011 [DOI] [PubMed] [Google Scholar]
  29. Deacon, C. F. (2020). Dipeptidyl peptidase 4 inhibitors in the treatment of type 2 diabetes mellitus. Nature Reviews Endocrinology, 16(11), 642–653. 10.1038/s41574-020-0399-8 [DOI] [PubMed] [Google Scholar]
  30. Dickson, S. L. , Shirazi, R. H. , Hansson, C. , Bergquist, F. , Nissbrandt, H. , & Skibicka, K. P. (2012). The glucagon‐like peptide 1 (GLP‐1) analogue, exendin‐4, decreases the rewarding value of food: A new role for mesolimbic GLP‐1 receptors. Journal of Neuroscience, 32(14), 4812–4820. 10.1523/JNEUROSCI.6326-11.2012 [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Dixon, T. N. , McNally, G. P. , & Ong, Z. Y. (2020). Glucagon‐like peptide‐1 receptor signaling in the ventral tegmental area reduces alcohol self‐administration in male rats. Alcoholism: Clinical and Experimental Research, 44(10), 2118–2129. 10.1111/acer.14437 [DOI] [PubMed] [Google Scholar]
  32. Douton, J. E. , Augusto, C. , Stoltzfus, B. , Carkaci‐Salli, N. , Vrana, K. E. , & Grigson, P. S. (2021). Glucagon‐like peptide‐1 receptor agonist, exendin‐4, reduces reinstatement of heroin‐seeking behavior in rats. Behavioural Pharmacology, 32(4), 265–277. 10.1097/fbp.0000000000000609 [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Egecioglu, E. , Engel, J. A. , & Jerlhag, E. (2013a). The glucagon‐like peptide 1 analogue, exendin‐4, attenuates the rewarding properties of psychostimulant drugs in mice. PLoS ONE, 8(7), 1–7. 10.1371/journal.pone.0069010 [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Egecioglu, E. , Engel, J. A. , & Jerlhag, E. (2013b). The glucagon‐like peptide 1 analogue exendin‐4 attenuates the nicotine‐induced locomotor stimulation, accumbal dopamine release, conditioned place preference as well as the expression of locomotor sensitization in mice. PLoS ONE, 8(10), 1–7. 10.1371/journal.pone.0077284 [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Egecioglu, E. , Steensland, P. , Fredriksson, I. , Feltmann, K. , Engel, J. A. , & Jerlhag, E. (2013). The glucagon‐like peptide 1 analogue Exendin‐4 attenuates alcohol mediated behaviors in rodents. Psychoneuroendocrinology, 38(8), 1259–1270. 10.1016/j.psyneuen.2012.11.009 [DOI] [PubMed] [Google Scholar]
  36. Elashoff, M. , Matveyenko, A. V. , Gier, B. , Elashoff, R. , & Butler, P. C. (2011). Pancreatitis, pancreatic, and thyroid cancer with glucagon‐like peptide‐1‐based therapies. Gastroenterology, 141(1), 150–156. 10.1053/j.gastro.2011.02.018 [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Eren‐Yazicioglu, C. Y. , Yigit, A. , Dogruoz, R. E. , & Yapici‐Eser, H. (2021). Can GLP‐1 be a target for reward system related disorders? A qualitative synthesis and systematic review analysis of studies on palatable food, drugs of abuse, and alcohol. Frontiers in Behavioral Neuroscience, 14(January), 1–15. 10.3389/fnbeh.2020.614884 [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Erreger, K. , Davis, A. R. , Poe, A. M. , Greig, N. H. , Stanwood, G. D. , & Galli, A. (2012). Exendin‐4 decreases amphetamine‐induced locomotor activity. Physiology & Behavior, 106(4), 574–578. 10.1016/j.physbeh.2012.03.014 [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. European Monitoring Centre for Drugs and Drug Addiction . (2012). New heroin‐assisted treatment. 10.2810/50141 [DOI]
  40. Færch, K. , Torekov, S. S. , Vistisen, D. , Johansen, N. B. , Witte, D. R. , Jonsson, A. , Pedersen, O. , Hansen, T. , Lauritzen, T. , Sandbæk, A. , Holst, J. J. , & Jørgensen, M. E. (2015). GLP‐1 response to oral glucose is reduced in prediabetes, screen‐detected type 2 diabetes, and obesity and influenced by sex: The ADDITION‐PRO study. Diabetes, 64(7), 2513–2525. 10.2337/db14-1751 [DOI] [PubMed] [Google Scholar]
  41. Fink‐Jensen, A. , & Vilsbøll, T. (2016). Glucagon‐like peptide‐1 (GLP‐1) analogues: A potential new treatment for alcohol use disorder? Nordic Journal of Psychiatry, 70(8), 561–562. 10.1080/08039488.2016.1176252 [DOI] [PubMed] [Google Scholar]
  42. Fletcher, M. M. , Halls, M. L. , Christopoulos, A. , Sexton, P. M. , & Wootten, D. (2016). The complexity of signalling mediated by the glucagon‐like peptide‐1 receptor. Biochemical Society Transactions, 44(2), 582–588. 10.1042/BST20150244 [DOI] [PubMed] [Google Scholar]
  43. Fortin, S. M. , & Roitman, M. F. (2017). Central GLP‐1 receptor activation modulates cocaine‐evoked phasic dopamine signaling in the nucleus accumbens core. Physiology & Behavior, 176(3), 17–25. 10.1016/j.physbeh.2017.03.019 [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Gabery, S. , Salinas, C. G. , Paulsen, S. J. , Ahnfelt‐Rønne, J. , Alanentalo, T. , Baquero, A. F. , Buckley, S. T. , Farkas, E. , Fekete, C. , Frederiksen, K. S. , Hogendorf, W. F. J. , Helms, H. C. C. , Jeppesen, J. F. , John, L. M. , Pyke, C. , Nøhr, J. , Lu, T. T. , Polex‐Wolf, J. , Prevot, V. , … Knudsen, L. B. (2020). Semaglutide lowers body weight in rodents via distributed neural pathways. JCI Insight, 5(6), e133429. 10.1172/jci.insight.133429 [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Goldstein, R. A. , DesLauriers, C. , & Burda, A. M. (2009). Cocaine: History, social implications, and toxicity: A review. Disease‐a‐Month, 55(1), 6–38. 10.1016/j.disamonth.2008.10.002 [DOI] [PubMed] [Google Scholar]
  46. Graham, D. L. , Erreger, K. , Galli, A. , & Stanwood, G. D. (2013). GLP‐1 analog attenuates cocaine reward. Molecular Psychiatry, 18(9), 961–962. 10.1038/mp.2012.141 [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Grill, H. J. (2020). A role for GLP‐1 in treating hyperphagia and obesity. Endocrinology, 161(8), 1–14. 10.1210/endocr/bqaa093 [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Han, V. K. M. , Hynes, M. A. , Jin, C. , Towle, A. C. , Lauder, J. M. , & Lund, P. K. (1986). Cellular localization of proglucagon/glucagon‐like peptide I messenger RNAs in rat brain. Journal of Neuroscience Research, 16(1), 97–107. 10.1002/jnr.490160110 [DOI] [PubMed] [Google Scholar]
  49. Harasta, A. E. , Power, J. M. , von Jonquieres, G. , Karl, T. , Drucker, D. J. , Housley, G. D. , Schneider, M. , & Klugmann, M. (2015). Septal glucagon‐like peptide 1 receptor expression determines suppression of cocaine‐induced behavior. Neuropsychopharmacology, 40(8), 1969–1978. 10.1038/npp.2015.47 [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Hernandez, N. S. , Ige, K. Y. , Mietlicki‐Baase, E. G. , Molina‐Castro, G. C. , Turner, C. A. , Hayes, M. R. , & Schmidt, H. D. (2018). Glucagon‐like peptide‐1 receptor activation in the ventral tegmental area attenuates cocaine seeking in rats. Neuropsychopharmacology, 43(10), 2000–2008. 10.1038/s41386-018-0010-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Hernandez, N. S. , O'Donovan, B. , Ortinski, P. I. , & Schmidt, H. D. (2019). Activation of glucagon‐like peptide‐1 receptors in the nucleus accumbens attenuates cocaine seeking in rats. Addiction Biology, 24(2), 170–181. 10.1111/adb.12583 [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Hernandez, N. S. , & Schmidt, H. D. (2019). Central GLP‐1 receptors: Novel molecular targets for cocaine use disorder. Physiology & Behavior, 206(1), 93–105. 10.1016/j.physbeh.2019.03.026 [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Hernandez, N. S. , Weir, V. R. , Ragnini, K. , Merkel, R. , Zhang, Y. , Mace, K. , Rich, M. T. , Christopher Pierce, R. , & Schmidt, H. D. (2020). GLP‐1 receptor signaling in the laterodorsal tegmental nucleus attenuates cocaine seeking by activating GABAergic circuits that project to the VTA. Molecular Psychiatry. 10.1038/s41380-020-00957-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Holst, J. J. (2007). The physiology of glucagon‐like peptide 1. Physiological Reviews, 87(4), 1409–1439. 10.1152/physrev.00034.2006 [DOI] [PubMed] [Google Scholar]
  55. Jensen, C. B. , Pyke, C. , Rasch, M. G. , Dahl, A. B. , Knudsen, L. B. , & Secher, A. (2018). Characterization of the glucagonlike peptide‐1 receptor in male mouse brain using a novel antibody and in situ hybridization. Endocrinology, 159(2), 665–675. 10.1210/en.2017-00812 [DOI] [PubMed] [Google Scholar]
  56. Jensen, M. E. , Galli, A. , Thomsen, M. , Jensen, K. L. , Thomsen, G. K. , Klausen, M. K. , Vilsbøll, T. , Christensen, M. B. , Holst, J. J. , Owens, A. , Robertson, S. , Daws, L. , Zanella, D. , Gether, U. , Knudsen, G. M. , & Fink‐Jensen, A. (2020). Glucagon‐like peptide‐1 receptor regulation of basal dopamine transporter activity is species‐dependent. Neurochemistry International, 138(December 2019), 104772. 10.1016/j.neuint.2020.104772 [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Jerlhag, E. (2020). Alcohol‐mediated behaviours and the gut‐brain axis; with focus on glucagon‐like peptide‐1. Brain Research, 1727(October 2019), 146562. 10.1016/j.brainres.2019.146562 [DOI] [PubMed] [Google Scholar]
  58. Jeynes, K. D. , & Gibson, E. L. (2017). The importance of nutrition in aiding recovery from substance use disorders: A review. Drug and Alcohol Dependence, 179, 229–239. 10.1016/j.drugalcdep.2017.07.006 [DOI] [PubMed] [Google Scholar]
  59. Kalman, D. , Morissette, S. B. , & George, T. P. (2005). Co‐morbidity of smoking in patients with psychiatric and substance use disorders. American Journal on Addictions, 14(2), 106–123. 10.1080/10550490590924728 [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Kalra, S. (2011). Change in alcohol consumption following liraglutide initiation: A real‐life experience. 71st Am. Diabetes Assoc. Conf. 2011, Poster 1029, 93.
  61. Kampman, K. M. (2019). The treatment of cocaine use disorder. Science Advances, 5(10), 1–8. 10.1126/sciadv.aax1532 [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Kanoski, S. E. , Rupprecht, L. E. , Fortin, S. M. , De Jonghe, B. C. , & Hayes, M. R. (2012). The role of nausea in food intake and body weight suppression by peripheral GLP‐1 receptor agonists, exendin‐4 and liraglutide. Neuropharmacology, 62(5–6), 1916–1927. 10.1016/j.neuropharm.2011.12.022 [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Kastin, A. J. , Akerstrom, V. , & Pan, W. (2002). Interactions of glucagon‐like peptide‐1 (GLP‐1) with the blood‐brain barrier. Journal of Molecular Neuroscience, 18, 7–14. [DOI] [PubMed] [Google Scholar]
  64. Kinzig, K. P. , D'Alessio, D. A. , Herman, J. P. , Sakai, R. R. , Vahl, T. P. , Figueredo, H. F. , Murphy, E. K. , & Seeley, R. J. (2003). CNS glucagon‐like peptide‐1 receptors mediate endocrine and anxiety responses to interoceptive and psychogenic stressors. Journal of Neuroscience, 23(15), 6163–6170. 10.1523/jneurosci.23-15-06163.2003 [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Klein, J. W. (2016). Pharmacotherapy for substance use disorders. Medical Clinics of North America, 100(4), 891–910. 10.1016/j.mcna.2016.03.011 [DOI] [PubMed] [Google Scholar]
  66. Kohn, R. , Saxena, S. , Levav, I. , & Saraceno, B. (2004). The treatment gap in mental health care. Bulletin of the World Health Organization, 82(11), 858–866. [PMC free article] [PubMed] [Google Scholar]
  67. Koob, G. F. (2008). A role for brain stress systems in addiction. Neuron, 59(1), 11–34. 10.1016/j.neuron.2008.06.012 [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Koob, G. F. , & Volkow, N. D. (2016). Neurobiology of addiction: A neurocircuitry analysis. The Lancet Psychiatry, 3(8), 760–773. 10.1016/S2215-0366(16)00104-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. Kranzler, H. R. , & Soyka, M. (2018). Diagnosis and pharmacotherapy of alcohol use disorder: A review. JAMA, 320(8), 815–824. 10.1001/jama.2018.11406 [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Lanng, A. R. , Gasbjerg, L. S. , Bergmann, N. C. , Bergmann, S. , Helsted, M. M. , Gillum, M. P. , Hartmann, B. , Holst, J. J. , Vilsbøll, T. , & Knop, F. K. (2019). Gluco‐metabolic effects of oral and intravenous alcohol administration in men. Endocrine Connections, 8(10), 1372–1382. 10.1530/EC-19-0317 [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. Larsen, P. J. , Tang‐Christensen, M. , & Jessop, D. S. (1997). Central administration of glucagon‐like peptide‐1 activates hypothalamic neuroendocrine neurons in the rat. Endocrinology, 138(10), 4445–4455. 10.1210/endo.138.10.5270 [DOI] [PubMed] [Google Scholar]
  72. Lautar, S. L. , Rojas, C. , Slusher, B. S. , Wozniak, K. M. , Wu, Y. , Thomas, A. G. , Waldon, D. , Li, W. , Ferraris, D. , & Belyakov, S. (2005). DPP IV inhibitor blocks mescaline‐induced scratching and amphetamine‐induced hyperactivity in mice. Brain Research, 1048(1–2), 177–184. 10.1016/j.brainres.2005.04.069 [DOI] [PubMed] [Google Scholar]
  73. Lee, N. K. , Jenner, L. , Harney, A. , & Cameron, J. (2018). Pharmacotherapy for amphetamine dependence: A systematic review. Drug and Alcohol Dependence, 191, 309–337. 10.1016/j.drugalcdep.2018.06.038 [DOI] [PubMed] [Google Scholar]
  74. Liu, J. , Conde, K. , Zhang, P. , Lilascharoen, V. , Xu, Z. , Lim, B. K. , Seeley, R. J. , Zhu, J. J. , Scott, M. M. , & Pang, Z. P. (2017). Enhanced AMPA receptor trafficking mediates the anorexigenic effect of endogenous glucagon‐like peptide‐1 in the paraventricular hypothalamus. Neuron, 96(4), 897–909.e5. 10.1016/j.neuron.2017.09.042 [DOI] [PMC free article] [PubMed] [Google Scholar]
  75. Liu, J. , & Pang, Z. P. (2016). Glucagon‐like peptide‐1 drives energy metabolism on the synaptic highway. FEBS Journal, 283(24), 4413–4423. 10.1111/febs.13785 [DOI] [PubMed] [Google Scholar]
  76. López‐Ferreras, L. , Richard, J. E. , Noble, E. E. , Eerola, K. , Anderberg, R. H. , Olandersson, K. , Taing, L. , Kanoski, S. E. , Hayes, M. R. , & Skibicka, K. P. (2018). Lateral hypothalamic GLP‐1 receptors are critical for the control of food reinforcement, ingestive behavior and body weight. Molecular Psychiatry, 23(5), 1157–1168. 10.1038/mp.2017.187 [DOI] [PMC free article] [PubMed] [Google Scholar]
  77. Luo, A. H. , Tahsili‐Fahadan, P. , Wise, R. A. , Lupica, C. R. , & Aston‐Jones, G. (2011). Linking context with reward: A functional circuit from hippocampal CA3 to ventral tegmental area. Science, 333(6040), 353–357. 10.1126/science.1204622 [DOI] [PMC free article] [PubMed] [Google Scholar]
  78. Łupina, M. , Talarek, S. , Kotlińska, J. , Gibuła‐Tarłowska, E. , Listos, P. , & Listos, J. (2020). The role of linagliptin, a selective dipeptidyl peptidase‐4 inhibitor, in the morphine rewarding effects in rats. Neurochemistry International, 133(November 2019), 1–9. 10.1016/j.neuint.2019.104616 [DOI] [PubMed] [Google Scholar]
  79. Lyon, J. (2017). More treatments on deck for alcohol use disorder. JAMA, 317(22), 2267–2269. 10.1001/jama.2017.4760 [DOI] [PubMed] [Google Scholar]
  80. MacLusky, N. J. , Cook, S. , Scrocchi, L. , Shin, J. , Kim, J. , Vaccarino, F. , Asa, S. L. , & Drucker, D. J. (2000). Neuroendocrine function and response to stress in mice with complete disruption of glucagon‐like peptide‐1 receptor signaling. Endocrinology, 141(2), 752–762. 10.1210/endo.141.2.7326 [DOI] [PubMed] [Google Scholar]
  81. Maes, M. , Lin, A. , Bonaccorso, S. , Vandoolaeghe, E. , Song, C. , Goossens, F. , De Meester, I. , Degroote, J. , Neels, H. , Scharpé, S. , & Janca, A. (1999). Lower activity of serum peptidases in abstinent alcohol‐dependent patients. Alcohol, 17(1), 1–6. 10.1016/s0741-8329(98)00022-6 [DOI] [PubMed] [Google Scholar]
  82. Mantsch, J. R. , Baker, D. A. , Funk, D. , Lê, A. D. , & Shaham, Y. (2016). Stress‐induced reinstatement of drug seeking: 20 years of progress. Neuropsychopharmacology, 41(1), 335–356. 10.1038/npp.2015.142 [DOI] [PMC free article] [PubMed] [Google Scholar]
  83. Marty, V. N. , Farokhnia, M. , Munier, J. J. , Mulpuri, Y. , Leggio, L. , & Spigelman, I. (2020). Long‐acting glucagon‐like peptide‐1 receptor agonists suppress voluntary alcohol intake in male Wistar rats. Frontiers in Neuroscience, 14(December), 1–16. 10.3389/fnins.2020.599646 [DOI] [PMC free article] [PubMed] [Google Scholar]
  84. McKee, S. A. , & Weinberger, A. H. (2013). How can we use our knowledge of alcohol‐tobacco interactions to reduce alcohol use? Annual Review of Clinical Psychology, 9(1), 649–674. 10.1146/annurev-clinpsy-050212-185549 [DOI] [PMC free article] [PubMed] [Google Scholar]
  85. Merchenthaler, I. , Lane, M. , & Shughrue, P. (1999). Distribution of pre‐pro‐glucagon and glucagon‐like peptide‐1 receptor messenger RNAs in the rat central nervous system. Journal of Comparative Neurology, 403(2), 261–280. [DOI] [PubMed] [Google Scholar]
  86. Mietlicki‐Baase, E. G. , Ortinski, P. I. , Reiner, D. J. , Sinon, C. G. , McCutcheon, J. E. , Pierce, R. C. , Roitman, M. F. , & Hayes, M. R. (2014). Glucagon‐like peptide‐1 receptor activation in the nucleus accumbens core suppresses feeding by increasing glutamatergic AMPA/kainate signaling. Journal of Neuroscience, 34(20), 6985–6992. 10.1523/JNEUROSCI.0115-14.2014 [DOI] [PMC free article] [PubMed] [Google Scholar]
  87. Mietlicki‐Baase, E. G. , Ortinski, P. I. , Rupprecht, L. E. , Olivos, D. R. , Alhadeff, A. L. , Christopher Pierce, R. , & Hayes, M. R. (2013). The food intake‐suppressive effects of glucagon‐like peptide‐1 receptor signaling in the ventral tegmental area are mediated by AMPA/kainate receptors. American Journal of Physiology ‐ Endocrinology and Metabolism, 305(11), 1367–1374. 10.1152/ajpendo.00413.2013 [DOI] [PMC free article] [PubMed] [Google Scholar]
  88. National Institute for Health and Care Excellence . (2011). Alcohol‐use disorders: Diagnosis, assessment and management of harmful drinking (high‐risk drinking) and alcohol dependence. Clinical guideline, revised 2019. Clinical guideline (Vol. 4). Retrieved from www.nice.org.uk/guidance/cg115
  89. National Institute on Drug Abuse . (2020). Tobacco, nicotine, and e‐cigarettes research report (January), 59. Retrieved from https://www.drugabuse.gov/download/1344/tobacco-nicotine-e-cigarettes-research-report.pdf?v=2af15ced378ee345c81758ed06a4cc27
  90. Niswender, K. , Pi‐Sunyer, X. , Buse, J. , Jensen, K. H. , Toft, A. D. , Russell‐Jones, D. , & Zinman, B. (2013). Weight change with liraglutide and comparator therapies: An analysis of seven phase 3 trials from the liraglutide diabetes development programme. Diabetes, Obesity and Metabolism, 15(1), 42–54. 10.1111/j.1463-1326.2012.01673.x [DOI] [PubMed] [Google Scholar]
  91. Nutt, D. J. , Lingford‐Hughes, A. , Erritzoe, D. , & Stokes, P. R. A. (2015). The dopamine theory of addiction: 40 years of highs and lows. Nature Reviews Neuroscience, 16(5), 305–312. 10.1038/nrn3939 [DOI] [PubMed] [Google Scholar]
  92. Olds, J. , & Milner, P. (1954). Positive reinforcement produced by electrical stimulation of septal area and other regions of rat brain. Journal of Comparative and Physiological Psychology, 47(6), 419–427. 10.1037/h0058775 [DOI] [PubMed] [Google Scholar]
  93. Pabreja, K. , Mohd, M. A. , Koole, C. , Wootten, D. , & Furness, S. G. B. (2014). Molecular mechanisms underlying physiological and receptor pleiotropic effects mediated by GLP‐1R activation. British Journal of Pharmacology, 171(5), 1114–1128. 10.1111/bph.12313 [DOI] [PMC free article] [PubMed] [Google Scholar]
  94. Park, P. E. , Schlosburg, J. E. , Vendruscolo, L. F. , Schulteis, G. , Edwards, S. , & Koob, G. F. (2015). Chronic CRF1 receptor blockade reduces heroin intake escalation and dependence‐induced hyperalgesia. Addiction Biology, 20(2), 275–284. 10.1111/adb.12120 [DOI] [PMC free article] [PubMed] [Google Scholar]
  95. Peacock, A. , Leung, J. , Larney, S. , Colledge, S. , Hickman, M. , Rehm, J. , Giovino, G. A. , West, R. , Hall, W. , Griffiths, P. , Ali, R. , Gowing, L. , Marsden, J. , Ferrari, A. J. , Grebely, J. , Farrell, M. , & Degenhardt, L. (2018). Global statistics on alcohol, tobacco and illicit drug use: 2017 status report. Addiction, 113(10), 1905–1926. 10.1111/add.14234 [DOI] [PubMed] [Google Scholar]
  96. Polosa, R. , & Benowitz, N. L. (2011). Treatment of nicotine addiction: Present therapeutic options and pipeline developments. Trends in Pharmacological Sciences, 32(5), 281–289. 10.1016/j.tips.2010.12.008 [DOI] [PMC free article] [PubMed] [Google Scholar]
  97. Prochaska, J. J. , & Benowitz, N. L. (2016). The past, present, and future of nicotine addiction therapy. Annual Review of Medicine, 67(1), 467–486. 10.1146/annurev-med-111314-033712 [DOI] [PMC free article] [PubMed] [Google Scholar]
  98. Reddy, I. A. , Pino, J. A. , Weikop, P. , Osses, N. , Sørensen, G. , Bering, T. , Valle, C. , Bluett, R. J. , Erreger, K. , Wortwein, G. , Reyes, J. G. , Graham, D. , Stanwood, G. D. , Hackett, T. A. , Patel, S. , Fink‐Jensen, A. , Torres, G. E. , & Galli, A. (2016). Glucagon‐like peptide 1 receptor activation regulates cocaine actions and dopamine homeostasis in the lateral septum by decreasing arachidonic acid levels. Translational Psychiatry, 6(5), e809. 10.1038/tp.2016.86 [DOI] [PMC free article] [PubMed] [Google Scholar]
  99. Reddy, I. A. , Stanwood, G. D. , & Galli, A. (2014). Moving beyond energy homeostasis: New roles for glucagon‐like peptide‐1 in food and drug reward. Neurochemistry International, 73(1), 49–55. 10.1016/j.neuint.2013.10.003 [DOI] [PMC free article] [PubMed] [Google Scholar]
  100. Richard, J. E. , Anderberg, R. H. , Göteson, A. , Gribble, F. M. , Reimann, F. , & Skibicka, K. P. (2015). Activation of the GLP‐1 receptors in the nucleus of the solitary tract reduces food reward behavior and targets the mesolimbic system. PLoS ONE, 10(3), 1–21. 10.1371/journal.pone.0119034 [DOI] [PMC free article] [PubMed] [Google Scholar]
  101. Richard, J. E. , Anderberg, R. H. , López‐Ferreras, L. , Olandersson, K. , & Skibicka, K. P. (2016). Sex and estrogens alter the action of glucagon‐like peptide‐1 on reward. Biology of Sex Differences, 7(1), 1–16. 10.1186/s13293-016-0059-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
  102. Rinaman, L. (2010). Ascending projections from the caudal visceral nucleus of the solitary tract to brain regions involved in food intake and energy expenditure. Brain Research, 1350(412), 18–34. 10.1016/j.brainres.2010.03.059 [DOI] [PMC free article] [PubMed] [Google Scholar]
  103. Roed, S. N. , Wismann, P. , Underwood, C. R. , Kulahin, N. , Iversen, H. , Cappelen, K. A. , Schäffer, L. , Lehtonen, J. , Hecksher‐Soerensen, J. , Secher, A. , Mathiesen, J. M. , Bräuner‐Osborne, H. , Whistler, J. L. , Knudsen, S. M. , & Waldhoer, M. (2014). Real‐time trafficking and signaling of the glucagon‐like peptide‐1 receptor. Molecular and Cellular Endocrinology, 382(2), 938–949. 10.1016/j.mce.2013.11.010 [DOI] [PubMed] [Google Scholar]
  104. Salinas, C. B. G. , Lu, T. T. H. , Gabery, S. , Marstal, K. , Alanentalo, T. , Mercer, A. J. , Cornea, A. , Conradsen, K. , Hecksher‐Sørensen, J. , Dahl, A. B. , Knudsen, L. B. , & Secher, A. (2018). Integrated brain atlas for unbiased mapping of nervous system effects following liraglutide treatment. Scientific Reports, 8(1), 10310. 10.1038/s41598-018-28496-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
  105. Santos‐Marcos, J. A. , Rangel‐Zuñiga, O. A. , Jimenez‐Lucena, R. , Quintana‐Navarro, G. M. , Garcia‐Carpintero, S. , Malagon, M. M. , Landa, B. B. , Tena‐Sempere, M. , Perez‐Martinez, P. , Lopez‐Miranda, J. , Perez‐Jimenez, F. , & Camargo, A. (2018). Influence of gender and menopausal status on gut microbiota. Maturitas, 116(July 2018), 43–53. 10.1016/j.maturitas.2018.07.008 [DOI] [PubMed] [Google Scholar]
  106. Schmidt, H. D. , Mietlicki‐Baase, E. G. , Ige, K. Y. , Maurer, J. J. , Reiner, D. J. , Zimmer, D. J. , van Nest, D. S. , Guercio, L. A. , Wimmer, M. E. , Olivos, D. R. , de Jonghe, B. C. , & Hayes, M. R. (2016). Glucagon‐like peptide‐1 receptor activation in the ventral tegmental area decreases the reinforcing efficacy of cocaine. Neuropsychopharmacology, 41(7), 1917–1928. 10.1038/npp.2015.362 [DOI] [PMC free article] [PubMed] [Google Scholar]
  107. Secher, A. , Jelsing, J. , Baquero, A. F. , Hecksher‐Sørensen, J. , Cowley, M. A. , Dalbøge, L. S. , Hansen, G. , Grove, K. L. , Pyke, C. , Raun, K. , Schäffer, L. , Tang‐Christensen, M. , Verma, S. , Witgen, B. M. , Vrang, N. , & Bjerre Knudsen, L. (2014). The arcuate nucleus mediates GLP‐1 receptor agonist liraglutide‐dependent weight loss. Journal of Clinical Investigation, 124(10), 4473–4488. 10.1172/JCI75276 [DOI] [PMC free article] [PubMed] [Google Scholar]
  108. Sharma, A. N. , Pise, A. , Sharma, J. N. , & Shukla, P. (2015a). Dipeptidyl‐peptidase IV (DPP‐IV) inhibitor delays tolerance to anxiolytic effect of ethanol and withdrawal‐induced anxiety in rats. Metabolic Brain Disease, 30(3), 659–667. 10.1007/s11011-014-9603-7 [DOI] [PubMed] [Google Scholar]
  109. Sharma, A. N. , Pise, A. , Sharma, J. N. , & Shukla, P. (2015b). Glucagon‐like peptide‐1 (GLP‐1) receptor agonist prevents development of tolerance to anti‐anxiety effect of ethanol and withdrawal‐induced anxiety in rats. Metabolic Brain Disease, 30(3), 719–730. 10.1007/s11011-014-9627-z [DOI] [PubMed] [Google Scholar]
  110. Shirazi, R. H. , Dickson, S. L. , & Skibicka, K. P. (2013). Gut peptide GLP‐1 and its analogue, Exendin‐4, decrease alcohol intake and reward. PLoS ONE, 8(4), 1–7. 10.1371/journal.pone.0061965 [DOI] [PMC free article] [PubMed] [Google Scholar]
  111. Sirohi, S. , Schurdak, J. D. , Seeley, R. J. , Benoit, S. C. , & Davis, J. F. (2016). Central & peripheral glucagon‐like peptide‐1 receptor signaling differentially regulate addictive behaviors. Physiology and Behavior, 161(2016), 140–144. 10.1016/j.physbeh.2016.04.013 [DOI] [PubMed] [Google Scholar]
  112. Skibicka, K. P. (2013). The central GLP‐1: Implications for food and drug reward. Frontiers in Neuroscience, 7(7 OCT), 1–10. 10.3389/fnins.2013.00181 [DOI] [PMC free article] [PubMed] [Google Scholar]
  113. Sørensen, G. , Caine, S. B. , & Thomsen, M. (2016). Effects of the GLP‐1 agonist exendin‐4 on intravenous ethanol self‐administration in mice. Alcoholism: Clinical and Experimental Research, 40(10), 2247–2252. 10.1111/acer.13199 [DOI] [PMC free article] [PubMed] [Google Scholar]
  114. Sørensen, G. , Reddy, I. A. , Weikop, P. , Graham, D. L. , Stanwood, G. D. , Wortwein, G. , Galli, A. , & Fink‐Jensen, A. (2015). The glucagon‐like peptide 1 (GLP‐1) receptor agonist exendin‐4 reduces cocaine self‐administration in mice. Physiology & Behavior, 149, 262–268. 10.1016/j.physbeh.2015.06.013 [DOI] [PMC free article] [PubMed] [Google Scholar]
  115. Storgaard, H. , Cold, F. , Gluud, L. L. , Vilsbøll, T. , & Knop, F. K. (2017). Glucagon‐like peptide‐1 receptor agonists and risk of acute pancreatitis in patients with type 2 diabetes. Diabetes, Obesity and Metabolism, 19(6), 906–908. 10.1111/dom.12885 [DOI] [PubMed] [Google Scholar]
  116. Strang, J. , Volkow, N. D. , Degenhardt, L. , Hickman, M. , Johnson, K. , Koob, G. F. , Marshall, B. D. L. , Tyndall, M. , & Walsh, S. L. (2020). Opioid use disorder. Nature Reviews Disease Primers, 6(1), 3. 10.1038/s41572-019-0137-5 [DOI] [PubMed] [Google Scholar]
  117. Suchankova, P. , Yan, J. , Schwandt, M. L. , Stangl, B. L. , Caparelli, E. C. , Momenan, R. , Jerlhag, E. , Engel, J. A. , Hodgkinson, C. A. , Egli, M. , Lopez, M. F. , Becker, H. C. , Goldman, D. , Heilig, M. , Ramchandani, V. A. , & Leggio, L. (2015). The glucagon‐like peptide‐1 receptor as a potential treatment target in alcohol use disorder: Evidence from human genetic association studies and a mouse model of alcohol dependence. Translational Psychiatry, 5(6), e583. 10.1038/tp.2015.68 [DOI] [PMC free article] [PubMed] [Google Scholar]
  118. Svartberg, J. , Holst, J. J. , Gutniak, M. , & Adner, N. (1998). The ethanol augmentation of glucose‐induced insulin secretion is abolished by calcium antagonism with nifedipine: No evidence for a role of glucagon‐like peptide‐1 (GLP‐1). Pancreas, 16(1), 66–71. 10.1097/00006676-199801000-00011 [DOI] [PubMed] [Google Scholar]
  119. Tang‐Christensen, M. , Larsen, P. J. , Göke, R. , Fink‐Jensen, A. , Jessop, D. S. , Møller, M. , & Sheikh, S. P. (1996). Central administration of GLP‐1‐(7‐36) amide inhibits food and water intake in rats. American Journal of Physiology—Regulatory, Integrative and Comparative Physiology, 271, R848–R856. 10.1152/ajpregu.1996.271.4.r848 [DOI] [PubMed] [Google Scholar]
  120. Terrill, S. J. , Maske, C. B. , & Williams, D. L. (2018). Endogenous GLP‐1 in lateral septum contributes to stress‐induced hypophagia. Physiology & Behavior, 192(5), 17–22. 10.1016/j.physbeh.2018.03.001 [DOI] [PMC free article] [PubMed] [Google Scholar]
  121. The Tobacco Atlas . (2021). Retrieved February 1, 2021, from https://tobaccoatlas.org/topic/health-effects/
  122. Thomsen, M. , Barrett, A. C. , Butler, P. , Negus, S. S. , & Caine, S. B. (2017). Effects of acute and chronic treatments with dopamine D2 and D3 receptor ligands on cocaine versus food choice in rats. Journal of Pharmacology and Experimental Therapeutics, 362(1), 161–176. 10.1124/jpet.117.241141 [DOI] [PMC free article] [PubMed] [Google Scholar]
  123. Thomsen, M. , Dencker, D. , Wörtwein, G. , Weikop, P. , Egecioglu, E. , Jerlhag, E. , Fink‐Jensen, A. , & Molander, A. (2017). The glucagon‐like peptide 1 receptor agonist Exendin‐4 decreases relapse‐like drinking in socially housed mice. Pharmacology Biochemistry and Behavior, 160(July), 14–20. 10.1016/j.pbb.2017.07.014 [DOI] [PubMed] [Google Scholar]
  124. Thomsen, M. , Holst, J. J. , Molander, A. , Linnet, K. , Ptito, M. , & Fink‐jensen, A. (2018). Effects of glucagon‐like peptide 1 analogs on alcohol intake in alcohol‐preferring vervet monkeys. Psychopharmacology, 236(2), 603–611. 10.1007/s00213-018-5089-z [DOI] [PMC free article] [PubMed] [Google Scholar]
  125. Tuesta, L. M. , Chen, Z. , Duncan, A. , Fowler, C. D. , Ishikawa, M. , Lee, B. R. , Liu, X. A. , Lu, Q. , Cameron, M. , Hayes, M. R. , Kamenecka, T. M. , Pletcher, M. , & Kenny, P. J. (2017). GLP‐1 acts on habenular avoidance circuits to control nicotine intake. Nature Neuroscience, 20(5), 708–716. 10.1038/nn.4540 [DOI] [PMC free article] [PubMed] [Google Scholar]
  126. United Nations Publication . (2020). World drug report 2020, 2. Drug use and health consequences. United Nations Publication, Sales No. E.20.XI.6. Retrieved from https://wdr.unodc.org/wdr2020/field/WDR20_Booklet_2.pdf
  127. Vallöf, D. , Kalafateli, A. L. , & Jerlhag, E. (2019). Brain region specific glucagon‐like peptide‐1 receptors regulate alcohol‐induced behaviors in rodents. Psychoneuroendocrinology, 103(February 2019), 284–295. 10.1016/j.psyneuen.2019.02.006 [DOI] [PubMed] [Google Scholar]
  128. Vallöf, D. , Kalafateli, A. L. , & Jerlhag, E. (2020). Long‐term treatment with a glucagon‐like peptide‐1 receptor agonist reduces ethanol intake in male and female rats. Translational Psychiatry, 10(1), 1–12. 10.1038/s41398-020-00923-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
  129. Vallöf, D. , Maccioni, P. , Colombo, G. , Mandrapa, M. , Jörnulf, J. W. , Egecioglu, E. , Engel, J. A. , & Jerlhag, E. (2016). The glucagon‐like peptide 1 receptor agonist liraglutide attenuates the reinforcing properties of alcohol in rodents. Addiction Biology, 21(2), 422–437. 10.1111/adb.12295 [DOI] [PMC free article] [PubMed] [Google Scholar]
  130. Vallöf, D. , Vestlund, J. , & Jerlhag, E. (2019). Glucagon‐like peptide‐1 receptors within the nucleus of the solitary tract regulate alcohol‐mediated behaviors in rodents. Neuropharmacology, 149(February), 124–132. 10.1016/j.neuropharm.2019.02.020 [DOI] [PubMed] [Google Scholar]
  131. Vancampfort, D. , Hallgren, M. , Mugisha, J. , De Hert, M. , Probst, M. , Monsieur, D. , & Stubbs, B. (2016). The prevalence of metabolic syndrome in alcohol use disorders: A systematic review and meta‐analysis. Alcohol and Alcoholism, 51(5), 515–521. 10.1093/alcalc/agw040 [DOI] [PubMed] [Google Scholar]
  132. Volkow, N. D. (2020). Personalizing the treatment of substance use disorders. American Journal of Psychiatry, 177(2), 113–116. 10.1176/APPI.AJP.2019.19121284 [DOI] [PubMed] [Google Scholar]
  133. Volkow, N. D. , Chang, L. , Wang, G. J. , Fowler, J. S. , Ding, Y. S. , Sedler, M. , Logan, J. , Franceschi, D. , Gatley, J. , Hitzemann, R. , Gifford, A. , Wong, C. , & Pappas, N. (2001). Low level of brain dopamine D2 receptors in methamphetamine abusers: Association with metabolism in the orbitofrontal cortex. American Journal of Psychiatry, 158(12), 2015–2021. 10.1176/appi.ajp.158.12.2015 [DOI] [PubMed] [Google Scholar]
  134. Volkow, N. D. , Fowler, J. S. , Wang, G. J. , & Goldstein, R. Z. (2002). Role of dopamine, the frontal cortex and memory circuits in drug addiction: Insight from imaging studies. Neurobiology of Learning and Memory, 78(3), 610–624. 10.1006/nlme.2002.4099 [DOI] [PubMed] [Google Scholar]
  135. Volkow, N. D. , Fowler, J. S. , Wang, G. ‐J. , Hitzemann, R. , Logan, J. , Schlyer, D. J. , Dewey, S. L. , & Wolf, A. P. (1993). Decreased dopamine D2 receptor availability is associated with reduced frontal metabolism in cocaine abusers. Synapse, 14(2), 169–177. 10.1002/syn.890140210 [DOI] [PubMed] [Google Scholar]
  136. Volkow, N. D. , Jones, E. B. , Einstein, E. B. , & Wargo, E. M. (2019). Prevention and treatment of opioid misuse and addiction: A review. JAMA Psychiatry, 76(2), 208–216. 10.1001/jamapsychiatry.2018.3126 [DOI] [PubMed] [Google Scholar]
  137. Volkow, N. D. , Michaelides, M. , & Baler, R. (2019). The neuroscience of drug reward and addiction. Physiological Reviews, 99(4), 2115–2140. 10.1152/physrev.00014.2018 [DOI] [PMC free article] [PubMed] [Google Scholar]
  138. Volkow, N. D. , Wang, G. J. , Fowler, J. S. , Tomasi, D. , & Telang, F. (2011). Addiction: Beyond dopamine reward circuitry. Proceedings of the National Academy of Sciences of the United States of America, 108(37), 15037–15042. 10.1073/pnas.1010654108 [DOI] [PMC free article] [PubMed] [Google Scholar]
  139. Volkow, N. D. , Wang, G.‐J. J. , Fowler, J. S. , Logan, J. , Hitzemann, R. , Ding, Y.‐S. S. , Pappas, N. , Shea, C. , & Piscani, K. (1996). Decreases in dopamine receptors but not in dopamine transporters in alcoholics. Alcoholism: Clinical and Experimental Research, 20(9), 1594–1598. 10.1111/j.1530-0277.1996.tb05936.x [DOI] [PubMed] [Google Scholar]
  140. Volkow, N. D. , Wise, R. A. , & Baler, R. (2017). The dopamine motive system: Implications for drug and food addiction. Nature Reviews Neuroscience, 18(12), 741–752. 10.1038/nrn.2017.130 [DOI] [PubMed] [Google Scholar]
  141. Vrang, N. , & Grove, K. (2011). The brainstem preproglucagon system in a non‐human primate (Macaca mulatta). Brain Research, 1397, 28–37. 10.1016/j.brainres.2011.05.002 [DOI] [PubMed] [Google Scholar]
  142. Wang, S. C. , Chen, Y. C. , Lee, C. H. , & Cheng, C. M. (2019). Opioid addiction, genetic susceptibility, and medical treatments: A review. International Journal of Molecular Sciences, 20(17), 4294. 10.3390/ijms20174294 [DOI] [PMC free article] [PubMed] [Google Scholar]
  143. Wang, X. F. , Liu, J. J. , Xia, J. , Liu, J. , Mirabella, V. , & Pang, Z. P. (2015). Endogenous glucagon‐like peptide‐1 suppresses high‐fat food intake by reducing synaptic drive onto mesolimbic dopamine neurons. Cell Reports, 12(5), 726–733. 10.1016/j.celrep.2015.06.062 [DOI] [PMC free article] [PubMed] [Google Scholar]
  144. World Health Organization . (2018). Global status report on alcohol and health 2018. https://www.who.int/publications/i/item/9789241565639 [Google Scholar]
  145. World Health Organization . (2019). WHO global report on trends in prevalence of tobacco use 2000–2025, third edition. https://www.who.int/publications/i/item/who-global-report-on-trends-in-prevalence-of-tobacco-use-2000-2025-third-edition [Google Scholar]
  146. Yammine, L. , Green, C. E. , Kosten, T. R. , de Dios, C. , Suchting, R. , Lane, S. D. , Verrico, C. D. , & Schmitz, J. M. (2021). Exenatide adjunct to nicotine patch facilitates smoking cessation and may reduce post‐cessation weight gain: A pilot randomized controlled trial. Nicotine & Tobacco Research, 23, 1682–1690. 10.1093/ntr/ntab066 [DOI] [PMC free article] [PubMed] [Google Scholar]
  147. You, Z. B. , Wang, B. , Gardner, E. L. , & Wise, R. A. (2019). Cocaine and cocaine expectancy increase growth hormone, ghrelin, GLP‐1, IGF‐1, adiponectin, and corticosterone while decreasing leptin, insulin, GIP, and prolactin. Pharmacology Biochemistry and Behavior, 176(November 2018), 53–56. 10.1016/j.pbb.2018.11.001 [DOI] [PubMed] [Google Scholar]
  148. Zhang, H. , Sturchler, E. , Zhu, J. , Nieto, A. , Cistrone, P. A. , Xie, J. , He, L. L. , Yea, K. , Jones, T. , Turn, R. , di Stefano, P. S. , Griffin, P. R. , Dawson, P. E. , McDonald, P. H. , & Lerner, R. A. (2015). Autocrine selection of a GLP‐1R G‐protein biased agonist with potent antidiabetic effects. Nature Communications, 6(1), 8918–8913. 10.1038/ncomms9918 [DOI] [PMC free article] [PubMed] [Google Scholar]
  149. Zhang, Y. , Kahng, M. W. , Elkind, J. A. , Weir, V. R. , Hernandez, N. S. , Stein, L. M. , & Schmidt, H. D. (2020). Activation of GLP‐1 receptors attenuates oxycodone taking and seeking without compromising the antinociceptive effects of oxycodone in rats. Neuropsychopharmacology, 45(3), 451–461. 10.1038/s41386-019-0531-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
  150. Zorrilla, E. P. , & Koob, G. F. (2019). Impulsivity derived from the dark side: Neurocircuits that contribute to negative urgency. Frontiers in Behavioral Neuroscience, 13(June), 1–15. 10.3389/fnbeh.2019.00136 [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

Data sharing does not apply to this article because no new data were created or analysed in this study.

Articles from British Journal of Pharmacology are provided here courtesy of Wiley

RESOURCES