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British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 2017 Apr 6;175(14):2809–2824. doi: 10.1111/bph.13757

Oxytocin and opioid addiction revisited: old drug, new applications

Panos Zanos 1,2, Polymnia Georgiou 1,2, Carol Weber 1, Fiona Robinson 4, Christos Kouimtsidis 4, Ramin Niforooshan 4, Alexis Bailey 1,3,✉
PMCID: PMC6016632  PMID: 28378414

Abstract

Opioid addiction has devastating health and socio‐economic consequences, and current pharmacotherapy is limited and often accompanied by side effects, thus novel treatment is warranted. Traditionally, the neurohypophyseal peptide oxytocin (OT) is known for its effects on mediating reward, social affiliation and bonding, stress and learning and memory. There is now strong evidence that OT is a possible candidate for the treatment of drug addiction and depression‐addiction co‐morbidities. This review summarizes and critically discusses the preclinical evidence surrounding the consequences of pharmacological manipulation of the oxytocinergic system on opioid addiction‐related processes, as well as the effects of opioids on the OT system at different stages of the addiction cycle. The mechanisms underlying the effects of OT on opioid addiction, including OT' interaction with the monoaminergic, glutamatergic, opioidergic systems and its effect on the amygdala, the hypothalamic–pituitary–adrenal axis and on memory consolidation of traumatic memories, are also reviewed. We also review clinical evidence on the effects of intranasal OT administration on opioid‐dependent individuals and discuss the therapeutic potential along with the limitations that accompany OT‐based pharmacotherapies. Review of these studies clearly indicates that the OT system is profoundly affected by opioid use and abstinence and points towards the OT system as an important target for developing pharmacotherapies for the treatment of opioid addiction and co‐existing affective disorders, thereby preventing relapse. Therefore, there is a clear need for clinical studies assessing the efficacy of OT‐based pharmacotherapies in opioid addiction.

Linked Articles

This article is part of a themed section on Emerging Areas of Opioid Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.14/issuetoc

Abbreviations

5‐HT

serotonin

ACTH

adenocorticotropic hormone

CPP

conditioned‐place preference

ARC

arcuate nucleus

CRF

corticotropin‐releasing factor

GPCR

G protein‐coupled receptor

HPA

hypothalamic‐pituitary adrenal

i.c.v.

intracerebroventricular

OT

oxytocin

PVN

paraventricular nucleus

SON

supraoptic nucleus

Tables of Links

TARGETS
GPCRs a Ligand‐gated ion channels b
http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=319 http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=416
http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=215
http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=369
http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=366
LIGANDS
http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5 http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=484
http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=912, corticotrophin‐releasing hormone http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2174
http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=940 http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2168
http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1369
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These Tables list key protein targets and ligands in this article which are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Southan et al., 2016), and are permanently archived in the Concise Guide to PHARMACOLOGY 2015/16 (a,bAlexander et al., 2015a,b).

The oxytocin system

Oxytocin (OT), a nine amino acid peptide, was discovered by Sir Henry Dale in 1906 (Dale, 1906) and was the first peptide hormone to be sequenced and synthesized by Du Vigneaud (Du Vigneaud et al., 1953; Tuppy, 1953;Du Vigneaud et al., 1954). OT is synthesized in the supraoptic (SON) and paraventricular (PVN) nuclei of the hypothalamus. Besides the well‐described peripheral function of OT to stimulate uterine contraction and milk ejection, its role as a neurotransmitter and neuromodulator in the brain has recently received increasing attention. OT‐producing neurons located in the hypothalamus innervate brain regions associated with stress, reward, mood, fear, emotionality and drug‐seeking behaviour, such as the amygdala, septum, nucleus accumbens and the bed nucleus of stria terminalis, where OT receptors are expressed (see Gimpl and Fahrenholz, 2001). Following release from nerve terminals, OT binds to OT receptors, but also to vasopressin receptors, as the latter exhibit >85% homology with OT receptors (Busnelli et al., 2013). The OT receptors are G protein‐coupled receptors (GPCRs) (Kimura et al., 1992), but the molecular mechanism(s) of receptor activation and the intracellular signalling events following receptor activation are only partly understood. Activation of the central OT receptors is involved in the modulation of several behaviours including autonomic function, social, sexual, pair‐bonding, maternal, anxiety‐, depressive‐ and psychotic‐like behaviours (see Gimpl and Fahrenholz, 2001; Hashimoto et al., 2012). Recent advances in the field, both from preclinical and clinical studies, have revealed the potential of OT as a possible therapeutic target for the treatment of mental disorders characterized by social dysfunction such as autism, social anxiety disorders, depression, borderline personality disorders and schizophrenia (see Meyer‐Lindenberg et al., 2011).

Based on the key role of OT in social reward and stress regulation, there has been significant interest in the role of OT in addiction. The present review focuses on new and old, preclinical and clinical evidence, suggesting a central involvement of the oxytocinergic system in opioid addiction and addictive‐related behaviours and discusses the potential of OT‐based pharmacotherapies for the treatment of opioid addiction and prevention of relapse. Underlying neurobiological mechanisms and limitations of OT use as a pharmacotherapeutic agent are also discussed.

Oxytocin and the reward system

Increasing interest in the involvement of the oxytocinergic system in drug addiction came from findings suggesting that the brain systems involved in drug reward interact with those involved in natural rewards, such as sexual behaviour and social bonding. Early findings from Carmichael et al. (1987) outlined the ability of sexual self‐stimulation (mediated by the mesolimbic dopaminergic system) to increase plasma OT levels in humans. These findings were recently replicated by de Jong et al. (2015), who showed enhanced salivary OT concentrations due to sexual self‐stimulation. Preclinical findings also showed that partner bonds of prairie voles (a well‐characterized monogamous species) are greatly influenced and regulated by the OT neurotransmission in the brain (Insel and Shapiro, 1992; Insel et al., 1994; Young, 2003). Oxytocinergic interactions with the dopaminergic system in the brain were shown to underlie this pair bonding (Liu and Wang, 2003), indicating possible association between the oxytocinergic and dopaminergic systems to regulate behaviour. Kovacs et al. (1990) showed that both central and peripheral administration of OT acutely increases dopamine utilization within the nucleus accumbens, while chronic systemic administration of OT decreases dopamine utilization within the basal forebrain of mice (Kovacs et al., 1986).

These interactions of the oxytocinergic with the dopaminergic system suggest that OT might have a critical role in the treatment of several dopamine‐related disorders including drug addiction, and its beneficial effects might in fact be mediated by its interactions with several dopaminergic pathways in the brain.

Drug addiction cycle

Addiction is often characterized as a cycle of neurochemical and psychological changes that bring about a shift from an impulsive use of a drug to the compulsive use (see Koob and Le Moal, 2008). Acute administration of drugs of abuse activates the mesolimbic dopaminergic reward pathway in the brain, thus inducing hedonic effects that positively reinforce the user to repeat drug administration. Upon repeated use of the drug, neuroadaptive tolerance to the rewarding effects of the drug is developed and an escalation of the dose is needed in order to achieve the same initial pleasurable effects (see Koob and Le Moal, 2001). During this period, positive reinforcement associated with acute drug administration is gradually replaced with a negative reinforcement, where the drug is taken to prevent the emergence of a negative withdrawal syndrome upon drug cessation. Acute withdrawal from drug use causes aversive drug‐specific physical symptoms that are usually short‐lived, and for some drugs of abuse, including opioids, protracted withdrawal could cause long‐term emotional impairment (see below). In fact, drug users who have abstained from drug administration over a long period of time are still vulnerable to relapse to drug‐seeking, particularly during re‐exposure to the drug itself, to drug‐associated environmental cues or following stress (see Koob and Le Moal, 2008).

Comorbid drug addiction and mood disorders

Chronic exposure to drugs of abuse, as well as prolonged abstinence from these drugs, is associated with lowered mood, increased anxiety, irritability and social withdrawal and isolation. It has been estimated that 45% of the drug‐dependent population has a comorbid psychiatric disorder, compared with 12% of the non‐dependent population (Farrell et al., 2003). More specifically, according to epidemiological studies, there is a marked comorbidity (50–60%) between drug addiction and depression (Guest and Holland, 2011), which is a major issue in psychiatry as it is accompanied by more severe symptoms, longer illness duration, higher service utilization and higher relapse rates (Kosten et al., 1986; Alterman et al., 1996; Brooner et al., 1997). Therefore, considering that antidepressants (see Riggs, 2003) and current addiction pharmacotherapies (see Kampman et al., 2005) have limited efficacy and are frequently accompanied by side effects in people suffering from this comorbidity, understanding the neurobiological mechanisms underlying comorbid depression and addiction disorders will have important therapeutic implications in improving mental health care.

Effects of opioid addiction on the oxytocinergic system

The effects of opioid addiction on the oxytocinergic system and the effect of OT treatment in modulating addiction‐related behaviours are summarized in Tables 1 and 2 respectively.

Table 1.

Effects of OT on opioid‐induced, addiction‐related, behaviours

Addictive substance Administration paradigm Animal model Oxytocin administration paradigm Effect of oxytocin Reference
Morphine Morphine tolerance: 37.5 mg morphine.HCl pellet, s.c. 48 h−1 Male CFLP mice (25 ± 5 g) housed in groups OT: 50 μg and 100 μg per animal, s.c. (2 h prior to morphine pellet implantation) ↓development of tolerance (Kovacs et al., 1985c)
Morphine tolerance: 30 mg·kg−1 morphine.HCl, s.c. and 5 h later 5 mg·kg−1 morphine.HCl, s.c. Male albino inbred mice (25 ± 5 g) housed in groups OT: 1 μg i.c.v. or intra‐CPu (1 h prior the tolerance‐inducing dose of morphine) ↔ development of tolerance (Sarnyai et al., 1988)
Morphine tolerance: 30 mg·kg−1 morphine.HCl, s.c. and 5 h later 5 mg·kg−1 morphine.HCl, s.c. Male albino inbred mice (25 ± 5 g) housed in groups OT: 1 μg microinjection into: posterior olfactory nucleus, Central nucleus of the amygdala, ventral hipoccampus (1 h prior the tolerance‐inducing dose of morphine) ↓ development of tolerance (Sarnyai et al., 1988)
Morphine tolerance: 60 mg·kg−1 morphine.HCl, s.c. and 5 h later 1 mg·kg−1 morphine.HCl, s.c. Male CFLP mice (25 ± 5 g) housed in groups OT: 2 μg·kg−1, s.c. (1 h prior the tolerance‐inducing dose of morphine) ↓ development of tolerance (Kovacs et al., 1987b)
Morphine tolerance: 100 mg·kg−1 morphine.HCl, s.c. and 5 h later 1 mg·kg−1 morphine. HCl, s.c. Male CFLP mice (25 ± 5 g) in groups OT: 2 μg ·kg−1, s.c. (1 h prior the tolerance‐inducing dose of morphine) ↓ development of tolerance (Kovacs et al., 1987b)
Morphine tolerance: 37.5 mg morphine.HCl pellet, s.c. 48 h−1 then, morphine.HCl (5 mg·kg−1, s.c.) Male CFLP mice, housed in groups OT: 50 μg, s.c. (24 h prior to pellet implantation) ↓ development of tolerance (Kovacs et al., 1984)
Morphine tolerance: 37.5 mg per morphine.HCl pellet, s.c. 48 h−1 then, morphine.HCl (5 mg·kg−1, s.c.) Male CFLP mice, housed in groups OT: 5 ng or 0.5 μg·in 1 μL, i.c.v. (24 h prior to pellet implantation) ↓ development of tolerance (Kovacs et al., 1984)
Morphine tolerance: 37.5 mg morphine.HCl pellet, s.c. 48 h−1 then, morphine.HCl (5 mg·kg−1, s.c.) Male CFLP mice, housed in groups OT: 0.5 ng in 1 μL into the dorsal Hip or the Acb (24 h prior to pellet implantation) ↓ development of tolerance (Kovacs et al., 1984)
Morphine tolerance: 37.5 mg morphine.HCl pellet, s.c. 48 h−1 then, morphine.HCl (5 mg·kg−1, s.c.) Male CFLP mice, housed in groups OT: 0.5 ng in·1 μL, into the CPu, VTA or external cortical surface (24 h prior to pellet implantation) ↔ development of tolerance (Kovacs et al., 1984)
Morphine‐induced conditioned‐place preference: Acquisition: 3 conditioning days (morphine. HCl, 5 mg·kg−1·day−1, s.c.) Male Wistar rats (250–300 g), housed in groups OT: 0.2 μg, i.c.v., 5 min prior to each conditioning session (both prior to morphine and prior to saline injections) ↔ acquisition of morphine CPP (Moaddab et al., 2015)
Morphine‐induced conditioned‐place preference: Expression: 3 conditioning days (morphine. HCl, 5 mg·kg−1·day−1, s.c.) Male Wistar rats (250–300 g), housed in groups OT: 0.2 μg, i.c.v., 5 min prior to the post‐conditioning session ↑ expression of morphine CPP (Moaddab et al., 2015)
Physical signs following precipitated withdrawal: Day 1: 2 x 20 mg·kg−1, i.p. Days 2–4: 2 x 40 mg·kg−1 i.p. (morning and afternoon injections) Naloxone: 4 mg·kg−1, i.p. (1 h after the morning morphine injection daily) Female Wistar rats (130–150 g) housed individually OT: 1.0 μg per animal, s.c. (1 h prior to each morphine injection daily) ↑ physical dependence (decreased body weight) (van Ree and de Wied, 1976)
Naloxone‐precipitated withdrawal: 37.5 mg morphine.HCl pellet, s.c. 74 h−1 Naloxone (74 h after pellet implantation): 1 mg·kg−1, i.p. Male CFLP mice, housed in groups OT: 50 μg, s.c., (24 h prior to pellet implantation) ↑ latency of naloxone‐precipitated withdrawal (Kovacs et al., 1984)
Naloxone‐precipitated withdrawal: 37.5 mg morphine.HCl pellet, s.c. 74 h−1 Naloxone (74 h after pellet implantation): 1 mg·kg−1, i.p. Male CFLP mice, housed in groups OT: 5 ng or 0.5 μg·in 1 μL, i.c.v. (24 h prior to pellet implantation) ↑ latency of naloxone‐precipitated withdrawal (Kovacs et al., 1984)
Naloxone‐precipitated withdrawal: 37.5 mg morphine.HCl pellet, s.c. 74 h−1 Naloxone (74 h after pellet implantation): 1 mg·kg−1, i.p. Male CFLP mice, housed in groups OT: 0.5 ng in·1 μL into the dorsal Hip or the mesolimbic Acb (24 h prior to pellet implantation) ↑ latency of naloxone‐precipitated withdrawal (Kovacs et al., 1984)
Naloxone‐precipitated withdrawal: 37.5 mg morphine.HCl pellet, s.c. 74 h−1 Naloxone (74 h after pellet implantation): 1 mg·kg−1, i.p. Male CFLP mice, housed in groups OT: 0.5 ng·in 1 μL into the CPu, VTA or external cortical surface (24 h prior to pellet implantation) ↔ latency of naloxone‐precipitated withdrawal (Kovacs et al., 1984)
Naloxone‐precipitated withdrawal: 37.5 mg morphine.HCl pellet, s.c. 72 h−1 Naloxone (72 h after pellet implantation): 1 mg·kg−1, i.p. Male CFLP mice (25 ± 5 g) housed in groups OT: 50 μg and 100 μg per animal, s.c. (2 h prior to morphine pellet implantation) ↓ withdrawal symptoms (Kovacs et al., 1985c)
Spontaneous withdrawal: 20–100 mg·kg−1·day−1, for 7 days, i.p. morphine sulphate Withdrawal: 7 days in home cage without injections Male C57BL/6 J mice (20–25 g), housed individually Carbetocin: 6.4 mg·kg−1, i.p. (15 min prior to FST, EPM 5 min−1 prior to 3‐CB test/ ↓ withdrawal‐induced depressive‐, anxiety‐like behaviours, sociability deficits (Zanos et al., 2014a)
Stress‐induced reinstatement morphine CPP: 10 mg·kg−1, s.c., for 4 conditioning days (morphine sulphate in the afternoon) Stress: forced‐swim stress (6‐min total) Male C57BL/6 J mice (20–25 g), housed individually Carbetocin: 6.4 mg·kg−1, i.p. (5 min prior to swim stressor for reinstatement) ↓ stress‐induced reinstatement of morphine conditioned place preference (Zanos et al., 2014a)
Priming‐induced reinstatement of morphine CPP: 10 mg·kg−1, s.c., for 4 conditioning days (morphine sulphate in the afternoon) Priming: 2 mg·kg−1, i.p. (morphine sulphate) Male C57BL/6 J mice (20–25 g), housed individually Carbetocin: 6.4 mg·kg−1, i.p. (5 min prior to morphine priming injection) ↓ morphine‐primed induced reinstatement of morphine conditioned place preference (Georgiou et al., 2015b)
Heroin Self‐administration: 5 days of fixed ratio schedule of reinformcement: 0.25 mL of heroin solution (0.125 mg·mL−1 per infusion), i.v.; experimenter delivered two initial heroin injections by pressing the lever Male Wistar rats (200–230 g) housed individually OT: 1.0 μg per animal, s.c. (1 h prior to experimentation daily) ↑ self‐administration (slightly) (Van Ree and De Wied, 1977)
Self administration: 0.05 mg·kg−1·s−1.c., 2 × daily·4 days−1 +0.4 mg·kg−1, s.c., 2 × daily·3 days−1 Followed by 7 days of progressive ratio schedule of reinforcement: 0.25 mL of heroin solution (0.125 mg·mL−1 per infusion), i.v. Male Wistar rats (200–220 g) housed individually OT: 1.0 μg per animal, s.c. (1 h prior to self‐administration session on the day 7) ↓ self‐administration (Kovacs and Van Ree, 1985)
Development of heroin tolerance (escalating‐dose): 2 x daily i.p. injections (100, 200, 400, 800, 800, 800 μg·kg−1) Self‐administration: On day 7 of heroin injections, rats were placed in self‐administration chambers; fixed‐ratio reinforcement: 50 μL of heroin solution (0.4 g·L−1) – flow rate 5 μL s; schedule terminated upon stable level of responding for 3 consecutive days (usually 7–8 days) Male Sprague–Dawley rats (250 ± 30 g) housed individually OT: intra‐accumbal or injections directly into the ventral Hip; 2 ng; treatment block of saline/OT/saline/OT 1.0 μg per animal, s.c. (1 h prior to self‐administration session daily) ↓ self‐administration (Ibragimov et al., 1987)
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A detailed summary of the effects of OT or OT‐based drugs administration on the behavioural effects of opioids in rodents. ↑ increase; ↓ decrease; ↔ no effect. Acb, nucleus accumbens; CPu, caudate‐putamen; Hip, hippocampus; VTA, ventral tegmental area.

Table 2.

Effects of opioids on the oxytocinergic system

Treatment Addiction phase Administration paradigm Animal model Effect on oxytocin Reference
Morphine Acute 4 μg, i.v. Lactating Wistar rats ↓ hypothalamic OT release (Clarke et al., 1979)
10 mg·kg−1, s.c. Swiss Webster mice between the 11th and 22nd day of lactation ↓ OT release during suckling (Haldar and Sawyer et al. 1978)
5 mg·kg−1, s.c. Male CFLP mice (25 ± 5 g) housed in groups ↑ OT immunoreactivity in Hip, Amy and basal forebrain (Kovacs et al. 1987a)
5 mg·kg−1, i.v. Virgin Sprague–Dawley female rats (~270 g) ↓ spontaneous activity of SON OT neurons
↓ plasma OT levels		 (Pumford et al., 1991)
0.1–1.5 μg·μL−1, i.c.v. Virgin Sprague–Dawley female rats (~300 g) ↓ spontaneous activity of SON OT neurons (Pumford et al., 1991)
Chronic Morphine pellet (37.5 mg morphine.HCl), s.c. Male CFLP mice (25 ± 5 g), housed in groups ↔ OT immunoreactivity in Amy and basal forebrain (Kovacs et al. 1987a)
Osmotic mini‐pump (75 mg), s.c., 1 on day 0, 2 on day 2 and 3 on day 4. On day 8 morphine.HCl (30 mg·kg−1.i.p.) Male Sprague–Dawley rats (230–270 g) housed in groups ↓ OT immunoreactivity in the Hip, SON, ME and ARC
↓ OT peptide levels in SON and ME
↔ OT peptide levels in PVN		 (Laorden et al., 1997; Laorden et al., 1998)
Osmotic mini‐pump, s.c., 10 μg·h−1·40 h−1 then 20 μg h−1·40 h−1 and then 50 μg h−1·40 h−1 Lactating, primiparous Sprague–Dawley female rats (2–4 days post‐partum) ↔ plasma OT levels (Bicknell et al., 1988)
Osmotic mini‐pump, s.c., 10 μg h−1·40 h−1 then 20 μg h−1·40 h−1 and then 50 μg h−1·40 h−1 Virgin Sprague–Dawley female rats (~270 g) ↔ firing rate of active non‐phasic OT neurons (Pumford et al., 1991)
20–100 mg·kg−1·day−1, for 7 days, i.p. morphine sulphate Male C57BL/6 J mice (20–25 g), housed individually ↑ OT receptor levels in the olfactory nuclei, PirCx and Amy
↓ hypothalamic OT levels		 (Zanos et al., 2014a)
Naloxone ‐Precipitated withdrawal Morphine: osmotic mini‐pump, s.c., 10 μg h−1·40 h−1 then 20 μg h−1·40 h−1 and then 50 μg h−1·40 h−1
Naloxone (day 5; following morphine administration):
5 mg·kg−1, i.v.		 Lactating, primiparous Sprague–Dawley female rats ↑ plasma OT levels;
↑ firing rate of OT neurons (SON)		 (Bicknell et al., 1988)
Morphine sulphate (20–40 mg·kg−1) x 5 days, i.c.v (1 μL·h−1)
Naloxone (day 5; after i.c.v. morphine):
5 mg·kg−1, i.v.		 Virgin Sprague–Dawley female rats (243–287 g) housed individually ↑ plasma OT levels;
↑ OT levels in CSF		 (Coombes et al., 1991)
Osmotic mini‐pump (75 mg), s.c., 1 on day 0, 2 on day 2, 3 on day 4.
Naloxone.HCl 1 mg·kg−1, s.c. (on day 7)		 Male Sprague–Dawley rats (200–210 g) housed in groups ↑ OT mRNA levels in the ME and PVN (Laorden et al., 1998)
Morphine: osmotic mini‐pump, s.c., 10 μg h−1·40 h−1, then 20 μg h−1·40 h−1, then 50 μg h−1·40 h−1
Naloxone (day 5; after last morphine infusion):
5 mg·kg−1, i.v.		 Virgin Sprague–Dawley female rats (~250 g) housed individually ↑ plasma OT levels
↑ OT peptide levels in the mediolateral septum
↔ OT levels in the dorsal Hip
↔ OT levels in the nucleus of tractus solitarius		 (Russell et al., 1992)
Morphine: osmotic mini‐pump, s.c., 10 μg h−1·40 h−1, then 20 μg h−1·40 h−1, then 50 μg h−1·40 h−1
Naloxone (day 5 after last morphine infusion):
5 mg·kg−1, i.v.		 Virgin Sprague–Dawley female rats housed individually ↑ OT SON neuron post‐spike excitability in morphine‐dependent rats and to a lesser extend in morphine‐naïve rats (Brown et al., 2005)
Spontaneous withdrawal 20–100 mg·kg−1·day−1, for 7 days, i.p. morphine sulphate
Withdrawal: 7 days in home cage without injections		 Male C57BL/6 J mice (20–25 g), housed individually ↑ OT receptor levels in the olfactory nuclei, MS, VDB, LS, PirCx and Amy (Zanos et al., 2014a)
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A detailed summary of the effects of opioid drugs on the oxytocinergic system. ↑ increase; ↓ decrease; ↔ no effect.

Abbreviations: Amy, amygdala; ARC, arcuate nucleus; Hip, hippocampus; LS, lateral septum; ME, median eminence; MS, medial septum; SON; supraoptic nucleus of the hypothalamus; PirCx, piriform cortex; PVN, paraventricular nucleus of the hypothalamus; VDB, ventral limb of the diagonal band of Broca.

Acute opioid administration

Studies showing a clear role of the oxytocinergic system in the acute reinforcing effects of the opiate morphine were among the first evidence pointing towards the involvement of OT in drug addiction. In particular, acute morphine administration was shown to decrease hypothalamic OT release in female rodents (Clarke et al., 1979; Haldar and Sawyer, 1978). However, Kovacs et al. (1987a) observed increased OT immunoreactivity in extra‐hypothalamic regions including the hippocampus, amygdala and basal forebrain of male mice, suggesting either differential effects of acute opioid administration on OT neurotransmission in different areas of the brain or a sex‐dependent regulation of the oxytocinergic system upon an acute challenge with opioids.

Chronic opioid administration

Chronic administration of morphine induced a significant decrease in OT immunoreactivity in the hippocampus, decreased OT mRNA levels within the SON, median eminence and arcuate nucleus of the hypothalamus (ARC) and reduced brain OT synthesis and plasma OT levels (Kovacs et al., 1987a; Laorden et al., 1998; You et al., 2000; Zanos et al., 2014a). This general down‐regulation of the oxytocinergic system following chronic opioid administration, in comparison with the acute stimulatory effects of opioid administration in different brain regions, may be a result of several neuroadaptive changes in the oxytocinergic system caused by chronic exposure to opioids. We showed that this hypo‐oxytocinergic tone following chronic administration of opioids is linked with a marked increase in OT receptor binding within the olfactory nuclei and amygdala of mice (Zanos et al., 2014a). This effect might comprise a neuroadaptive/compensatory mechanism to counteract the decreased oxytocinergic signalling in the brain. Increased OT receptor binding in the brain following chronic opioid administration might also indicate a hypersensitivity of the oxytocinergic system during this period and should be taken into consideration when choosing the right OT dosing regimen. In fact, while acute administration of low doses of OT lacks deleterious side effects in humans (see MacDonald et al., 2011), there is uncertainty on the effects of chronic administration of OT at both low and higher doses. Importantly, Peters et al. (2014) demonstrated that chronic (15 day) intracerebroventricular (i.c.v.) infusion of OT, at a high dose (10 ng·h−1), induced a paradoxical anxiogenic phenotype in mice. This is particularly important in the case of opioid addiction, where the OT receptor system may be more sensitive based on findings from Zanos et al. (2014a) showing an up‐regulation of OT receptors in an animal model of chronic opioid use. Therefore, high doses of OT could be proven deleterious and even worsen the treatment prognosis in this population. Nonetheless, chronic administration of low doses of OT (1 ng·h−1; 19 days; i.c.v.) prevented psychosocial stress‐induced anxiety (Peters et al., 2014), indicating a dose‐dependent effect of OT. These findings highlight that it may be important for future clinical studies assessing the effects of OT on opioid‐dependent individuals, to use low doses of OT, in order to avoid potential undesirable side effects.

Opioid conditioning/self‐administration

Interestingly and in contrast with the hypothesis that OT might be a potential target for the treatment of drug addiction, central administration of OT did not prevent the acquisition of morphine‐conditioning and it even increased the expression of morphine place‐preference when it was administered prior to the post‐conditioning test in a conditioned place‐preference (CPP) study in rats (Moaddab et al., 2015). In line with this finding, Van Ree and De Wied (1977) showed that peripherally administered OT slightly facilitated heroin self‐administration in rats. These paradoxical effects of OT might be related to the direct actions of OT stimulation on the dopaminergic system (see Section ‘Oxytocin and the reward system’). The fact that activation of the central OT receptors directly increases striatal dopaminergic content (Georgiou et al., 2015b) and OT facilitates the effects of dopamine (Insel, 2003), which is directly involved in the reinforcing properties of the drugs of abuse (Volkow et al., 2006; Wong et al., 2006), indicates that OT administration might cause an enhanced morphine‐induced CPP and/or heroin self‐administration via mimicking and thus augmenting the hedonic effects of morphine. Indeed, similar to morphine (Lintas et al., 2011), OT administration was shown to increase the firing rate of accumbal neurons (Moaddab et al., 2015), indicating that there might be a possible additive effect of morphine and OT on the hyperexcitability of the mesolimbic dopaminergic neurons, which might have driven the enhanced morphine‐induced conditioning. However, the choice of OT dose seems to be critical in determining the beneficial effects of the drug. Indeed, in the morphine CPP study (Moaddab et al., 2015), the authors used a dose of 0.2 μg (i.c.v.), whereas Ibragimov et al. (1987) using a dose of 0.2 ng microinjected into the nucleus accumbens or ventral hippocampus demonstrated that OT was able to abolish heroin self‐administration in heroin‐dependent rats, an effect that was prevented by OT receptor blockade. These controversies highlight the importance for choosing the correct dose for OT to exert its beneficial effect, especially as OT is known to also bind to vasopressin receptors at higher doses (Busnelli et al., 2013), which could cause the exactly opposite behavioural effects (Neumann and Landgraf, 2012). In support of this, Peters et al. (2014) showed dose‐dependent differential effects of chronic central administration of OT on anxiety, stress‐related behaviours and OT receptor binding in different brain regions.

Opioid tolerance

OT was also shown to modulate short‐ and long‐term opioid tolerance. In particular, both peripheral and central OT administration dose‐dependently attenuated the development of analgesic morphine and heroin tolerance in rodents, and a single OT injection also blocked the expression of heroin tolerance following repeated heroin administration (Kovacs et al., 1985b; Kovacs et al., 1984; Kovacs et al., 1998; Kovacs and Telegdy, 1987). These results strongly suggest that OT can rapidly modulate both the early development, as well as the expression of an already developed opioid tolerance. Interestingly, OT treatment reduced heroin self‐administration in heroin‐tolerant (Kovacs et al., 1985a), but not in non‐tolerant rats (Kovacs et al., 1998), although it inhibited the development of tolerance to morphine‐induced hyper‐locomotion in mice (Kovacs and Telegdy, 1987), which might indicate differential effect of OT on the adaptive versus acute opioid tolerance processes. Importantly, the lateral septum was shown to mediate the inhibitory effect of OT on heroin self‐administration as direct microinjection of OT within this brain region abolished heroin self‐administration in heroin‐tolerant rats (Ibragimov and Kovacs, 1987). While the effect of OT on reducing opioid tolerance may be desirable in increasing the therapeutic efficacy of opioid replacement therapy, it may also be dangerous as it could lead to opioid toxicity in patients receiving opioid replacement therapy, especially in cases of accidental opioid overdose. In addition, if tolerance to the respiratory depressant effects of opioids is also reduced by OT, this effect could lead to a higher risk of opioid overdose, which has been also suggested to be the case with the effects of ethanol on tolerance to the respiratory depressant effects of opioids (Hill et al., 2016).

Opioid withdrawal/relapse

The first evidence for a role of OT on the regulation of opioid withdrawal came from Kovacs et al. (1985c) who showed that peripheral OT administration decreases naloxone‐precipitated morphine withdrawal symptoms in rodents. To unravel the mechanism underlying the inhibitory effect of OT on opioid withdrawal symptoms, later studies investigated the effect of pharmacologically induced opioid withdrawal on OT neurotransmission. In particular, Bicknell et al. (1988) demonstrated that naloxone‐precipitated morphine withdrawal, a protocol that is widely used to precipitate acute physical opioid withdrawal symptoms, increases plasma OT levels, as well as the firing rate of oxytocinergic neurons in the SON of chronically morphine‐treated, lactating rats. Additionally, naloxone administration also produced a large increase in OT levels within the CSF of opioid‐dependent rats (Coombes et al., 1991). Finally, naloxone‐precipitated morphine withdrawal increased expression of Fos protein within the SON (Murphy et al., 1997; Johnstone et al., 2000) and OT mRNA levels within the median eminence and PVN (Laorden et al., 1998), which may illustrate an increase in the biosynthesis of OT. These findings are somewhat unexpected as OT treatment prevents naloxone‐precipitated withdrawal symptoms at a time when OT neurotransmission is already enhanced. Taken together, these results might indicate a possible OT receptor‐independent mechanism of action of exogenously administered OT on the regulation of opioid withdrawal physical symptoms. Indeed, it has been demonstrated that OT might exert an OT receptor‐independent action at GABAA receptor δ subunits, to regulated addiction‐related processes (Bowen et al., 2015).

In contrast to the pharmacologically induced morphine withdrawal findings, recent studies have demonstrated a differential regulation of the oxytocinergic system following non‐precipitated, long‐term spontaneous withdrawal from opioid treatment in mice. Zanos et al. (2014a) found decreased hypothalamic OT levels and increased OT receptor binding in the olfactory nuclei, piriform cortex, septum and amygdala following spontaneous (non‐precipitated) withdrawal from chronic escalating‐dose morphine administration in mice. These neuroadaptive alterations of the oxytocinergic system were concomitant with the emergence of emotional deficits including depressive‐, anxiety‐like behaviours and social impairment, at least in an animal model. We also demonstrated that carbetocin, an OT analogue, was able to prevent morphine withdrawal‐induced emotional impairment, as well as stress‐ and priming‐induced reinstatement of morphine conditioned preference in mice (Zanos et al., 2014a; Georgiou et al., 2015b). These findings demonstrate the ability of OT treatment to reduce the physical and emotional symptoms of opioid abstinence, suggesting a promising pharmacotherapy for comorbid mood and substance abuse disorders, as well as relapse prevention, thus warranting a clinical investigation in opioid abusers and abstinent individuals undergoing detoxification.

Mechanisms underlying the effect of OT on opioid addiction

The mechanism/s by which OT exerts its effect on drug‐related behaviours are complex and not fully understood. Here, we outline some of the main suggested mechanisms based on preclinical and clinical evidence.

Interactions with the monoaminergic system

Dopamine

The most characterized link between the oxytocinergic and the dopaminergic systems stems from the fact that OT‐mediated social affiliative behaviours are also linked to key alterations in the dopaminergic reward system (Young and Wang, 2004; Skuse and Gallagher, 2009). OT is known to modulate dopamine turnover, and OT receptors have been shown to functionally interact with the dopamine D2 receptors in the nucleus accumbens (Romero‐Fernandez et al., 2012). Thus, it is perhaps not surprising that the dopaminergic system is involved in the mechanism(s) underlying the effect of OT in modulating addictive‐related behaviours. For instance, Qi et al. (2008) demonstrated that OT administration prevents methamphetamine‐induced hyperlocomotion via decreasing methamphetamine‐associated reduction on dopamine turnover in the mesolimbic system of the brain. In addition, intra‐prefrontal cortex administration of OT prevented amphetamine‐induced impairment of pair‐bond formation, via blocking amphetamine‐induced increases in dopamine levels in the nucleus accumbens (Young et al., 2014). With regards to opioid addiction, Georgiou et al. (2015b) showed that administration of the OT analogue carbetocin increases dopamine turnover in the striatum of mice, which was associated with the ability of the drug to prevent both priming‐ and stress‐induced reinstatement to opioid CPP.

Noradrenaline

Some preliminary evidence for an interaction between the oxytocinergic and noradrenergic systems exists. OT administration enhances http://topics.sciencedirect.com/topics/page/Norepinephrine release in the http://topics.sciencedirect.com/topics/page/Supraoptic_nucleus of the hypothalamus, which then activates http://topics.sciencedirect.com/topics/page/Hypothalamus OT neurons (Onaka et al., 2003). Importantly, we have recently shown that the prevention of morphine primed‐reinstatement of opioid‐seeking behaviour following administration of OT is directly associated with the ability of OT to suppress striatal noradrenaline turnover in mice (Georgiou et al., 2015b), thus suggesting the presence of a noradrenergic mechanism underlying the beneficial effect of OT on opioid relapse prevention. Nonetheless, this was not the case with stress‐induced reinstatement indicating differential regulation of OT‐noradrenaline interactions in mediating diverse reinstatement triggers.

5‐HT (serotonin)

Preliminary data suggest possible interactions between the oxytocinergic and serotonergic systems, which might be implicated in the modulation of several neuropsychiatric disorders. For example, http://topics.sciencedirect.com/topics/page/Serotonergic terminals originating from the dorsal and median http://topics.sciencedirect.com/topics/page/Raphe_nuclei were shown to project to the PVN magnocellular neurons (Sawchenko et al., 1983; Larsen et al., 1996), where they possibly regulate OT release via an interaction with the 5‐HT receptors (Jorgensen et al., 2003; Ho et al., 2007). In addition, administration of a 5‐HT receptor http://topics.sciencedirect.com/topics/page/Agonist to healthy individuals increased plasma OT levels (Lee et al., 2003). Although the involvement of the serotonergic system in the mechanisms underlying the effects of OT on opioid addiction‐related behaviours has not been investigated to date, it is important to pursue research aiming to understand whether OT‐based pharmacotherapies, via interacting with the serotonergic system, are effective in treating opioid addiction‐mood disorder comorbidities, considering the evidence that serotonin reuptake inhibitor antidepressant drugs, such as citalopram and fluvoxamine, may exert their antidepressant effects partly via interacting with the oxytocinergic system (Uvnas‐Moberg et al., 1999; Swaab et al., 2000; de Jong et al., 2007).

Interactions with the glutamatergic system

While the role of glutamatergic neurotransmission in opioid addiction has not yet been identified, there is evidence to suggest a key involvement of the glutamatergic system in the pharmacological effects of OT on modulating addictive‐related behaviours. In particular, Qi et al. (2009) showed that OT treatment abolished stress‐induced, but not methamphetamine‐priming, increases in glutamate levels in the medial prefrontal cortex of mice undergoing reinstatement of methamphetamine CPP. Interestingly, this effect was associated with the ability of OT to prevent stress‐induced, but not drug‐primed, reinstatement to methamphetamine place‐preference.

Role of the amygdala

Intranasal OT has been shown to decrease anxiety via reducing amygdala reactivity in response to threat (Kirsch et al., 2005; Domes et al., 2007; Baumgartner et al., 2008; Labuschagne et al., 2010). As there is high comorbidity between drug addiction and anxiety disorders, it is plausible that OT may act within this precise brain network to induce its restorative effect on recovering emotional impairment in drug‐dependent individuals. Indeed, we have shown that chronic administration of morphine (Zanos et al., 2014a), cocaine (Georgiou et al., 2015a; Georgiou et al., 2016b), methamphetamine (Zanos et al., 2014b; Georgiou et al., 2016a) and nicotine (Zanos et al., 2015) induces an up‐regulation of the OT receptor binding in the amygdala of mice, indicating a possible common neuroadaptation of the oxytocinergic system in response to different classes of drugs of abuse. Although the exact mechanisms underlying these neuroadaptations need further investigation, it is likely that these changes of the OT receptor system in the amygdala are involved in the modulation of drug/emotional impairment comorbidity. Given the anxiolytic, antidepressant and social‐enhancing effects of OT administration on humans when administered via an intranasal spray (Kirsch et al., 2005; Baumgartner et al., 2008; Di Simplicio et al., 2009) or on animal models when administered centrally or peripherally (Windle et al., 2004; Dabrowska et al., 2011), this dysregulation (up‐regulation) of the OT receptor system in the amygdala may constitute a common neurobiological mechanism to counteract the negative emotional state induced by chronic drug administration. Therefore, the use of an OT‐based pharmacotherapy to preferably jump‐start the amygdala to attenuate emotional distress, including anxiety, and activate stress‐coping mechanisms could be an important area for research and further our understanding of the role of the oxytocinergic system in the amygdala, in controlling substance abuse.

Hypothalamic–pituitary–adrenal (HPA) axis activity

There is evidence to support a regulatory role of the HPA axis on the anxiolytic and antidepressant effects of OT. Specifically, i.c.v. administration of OT decreased stress‐induced corticosterone release in rats (Windle et al., 1997). Moreover, intra‐PVN administration of an OT receptor http://topics.sciencedirect.com/topics/page/Receptor_antagonists increased basal adenocorticotropic hormone (ACTH) levels, while it reduced ACTH release in response to a forced‐swim stress in male rats (Neumann et al., 2000a, b). These findings indicate a possible tonic inhibition of the HPA axis by OT and an enhancing action under stress conditions. With regards to opioid addiction, we have shown that the effect of carbetocin on preventing stress‐ (Zanos et al., 2014a) and priming‐induced (Georgiou et al., 2015b) reinstatement of morphine‐seeking does not depend on changes in activity of the HPA axis, as we did not observe any effects of carbetocin on plasma corticosterone levels following either priming‐ or stress‐induced reinstatement in mice. However, the effects of OT or OT‐based drug administration on the central corticotropin‐releasing factor (CRF) system cannot be precluded since there is evidence for a direct regulation of the CRF neurotransmission by OT (Bulbul et al., 2011; Jurek et al., 2015; Pati et al., 2015).

Extinction of traumatic memories

Although not tested in the context of drug addiction, there is compelling evidence to suggest that OT facilitates extinction of memories associated with fear. For instance, i.c.v. administration of OT prior to fear conditioning does not appear to have any effect on fear learning; however, later fear extinction is facilitated by OT, while OT receptor antagonists administration impairs extinction learning and retrieval (Singewald et al., 2015). Therefore, it is conceivable that OT may be able to alleviate the affective emotional consequences of drug addiction and prevent relapse by interfering with the consolidation of fear memories, making these memories weaker and more susceptible to extinction (Singewald et al., 2015). This hypothesis warrants further exploration.

Interactions with the endogenous opioid system

Opioid peptide regulation of the OT system has been suggested to at least partly underlie the effects of opioid drugs on the OT system. In fact, opioid peptide neuronal fibres and terminals are located in close proximity with OT neurons within the hypothalamus (Bicknell et al., 1988). Moreover, μ‐opioid receptors are highly expressed in the hypothalamus, and particularly within the SON and PVN nuclei, where oxytocinergic neurons project from (Atweh and Kuhar, 1983). These studies indicate possible interactions between the opioid and oxytocinergic systems. Indeed, it was recently demonstrated with the use of receptor autoradiographic binding in μ receptor knockout mice, the presence of brain region‐specific interactions between the μ receptor and OT receptor systems (Gigliucci et al., 2014; Georgiou et al., 2015b), which may be involved in the effects of OT on the modulation of opioid‐associated behaviours discussed in this review. Furthermore, a remarkable decrease in OT gene expression was observed in the nucleus accumbens of mice lacking the μ receptor gene (Becker et al., 2014), further supporting a close interaction between the opioidergic and oxytocinergic systems.

OT as a potential pharmacotherapy for opioid addiction: from bench to bedside

Clinical studies

There is currently a limited number of clinical trials investigating the efficacy of OT in the treatment of drug addiction. With regards to opioid addiction, there have been only two clinical studies to‐date that assessed the effects of intranasal OT on opioid‐dependent patients (Stauffer et al., 2016; Woolley et al., 2016). The main outcome of both studies demonstrates a safe and good tolerability profile of OT administration in opioid‐dependent individuals, even after repeated administration for 2 weeks. In a randomized, double‐blind, placebo‐controlled, crossover study, Woolley et al. (2016) reported that intranasal OT administration (40 IU) did not improve cue‐induced craving in opioid‐dependent subjects receiving opioid replacement therapy. In contrast, in a placebo‐controlled trial of individuals undergoing methadone replacement treatment for opioid and co‐occurring cocaine use disorder, placebo‐treated patients reported an increase for heroin craving, while individuals who received intranasal OT treatment (40 IU; two times daily × 2 weeks) did not exhibit increased craving response (Stauffer et al., 2016), providing some promise for the treatment of this population. No evidence of a reduction of opioid tolerance following OT administration was observed in these trials. This is especially important considering the findings of OT‐induced opioid tolerance observed in animals, which could have potentially led to fatal overdose

Therapeutic potential of OT in opioid addiction treatment and addiction‐emotional impairment comorbidities

In light of the literature reviewed here, OT has unambiguously a key role in mediating several opioid addiction‐related behavioural and neurochemical processes and can be considered a promising target for the treatment of opioid dependence and emotional impairment comorbidity. One important factor that distinguishes OT from currently available medications is that it does not show abuse or addiction potential. In fact, the doses used in the preclinical studies, which revealed that OT induces CPP, are much higher than the doses used in the clinical trials (Liberzon et al., 1997). Evidence also suggests that patients treated with OT could not discriminate between placebo or the actual drug (MacDonald et al., 2011), further supporting the lack of rewarding properties of OT at least at doses ranging from 18 ‐ 40 IU. However, future studies should assess the possibility of any rewarding effects following chronic administration of OT in humans.

Another unique property of OT that is particularly important for the treatment of opioid addiction and/or comorbid mood disorders is related to its prosocial effects (Churchland and Winkielman, 2012). Prolonged use of drugs of abuse results in disintegration of the social lives of drug addicts and may lead to social isolation and poor decision‐making in their social domain at the expense of compulsive pre‐occupation with the drug and its related cues (Dawe et al., 2009; Volkow et al., 2011). Impaired social behaviours have been linked with the propensity of addicts to relapse after long‐term abstinence (Tokar et al., 1975). Therefore, considering the therapeutic effects of social support programs (e.g. Alcoholics Anonymous, Narcotics Anonymous) and the benefits of social rehabilitation and social reintegration in keeping addicts abstinent from the drug (Koerner, 2010; McGregor and Bowen, 2012), the current findings for the pro‐social effects of OT may suggest its use as an adjunct to cognitive behavioural therapy as a novel effective ‘psycho‐biological therapy’ for the prevention of relapse to drug‐seeking. In support of this, OT and social support have been shown to interact and exert a stress‐buffering effect following a psychosocial stress challenge in humans (Heinrichs et al., 2003). Moreover, there is clinical evidence for a beneficial role of OT in the treatment of other disorders characterized by social cognitive impairment including autistic spectrum disorders and schizophrenia (Carter, 2007; Heinrichs and Gaab, 2007).

Limitations

One concern for studies looking at effects of exogenously administered OT is that it has a very short plasma (3–5 min) and central (30 min) half‐life (Uvnas‐Moberg, 1998; Ludwig and Leng, 2006). However, intranasal administration of OT has been shown to induce more prolonged release of at least 80 min (Burri et al., 2008) and has extended biological (endocrine and sexual) activity, even after a single dose in humans (Uvanas‐Moberg et al., 2005). Intranasally administered OT has been shown to cross the blood‐brain barrier and to exert central effects (Born et al., 2002; Chang et al., 2012; Pedersen et al., 2013). Nonetheless, the development of smaller non‐peptide OT agonists with high specificity for central OT receptors is undoubtedly desirable.

Although the outcome from the many clinical trials using intranasal OT treatment points towards a safe profile of the drug (MacDonald et al., 2011), there are some unanswered questions related to its safety following chronic use in drug‐dependent individuals. In fact, high doses of intravenous OT have been associated with cardiovascular side effects including hypotension and myocardial ischaemia (Dyer et al., 2011) or electrolyte imbalances due to its structural similarity to arginine vasopressin and its effects on the kidneys (Rasmussen et al., 2004). Importantly, OT administration at high doses could also activate the vasopressin V1A receptors in the brain, which may actually lead to opposing behavioural responses (Neumann and Landgraf, 2012). Concerns also include the safety of OT administration in females at different reproductive phases due to the peripheral effects of OT (i.e. milk ejection, labour induction), as well as the regulation of OT by the gonadal hormones (Zhang et al., 1991; McCarthy, 1995).

Moreover, caution needs to be applied when choosing the dose of OT for chronic intranasal administration. Peters et al. (2014) showed that chronic i.c.v. infusion of OT (15 days) at a high dose (10 ng·h−1) induced an anxiogenic phenotype whereas low doses of OT(1 ng·h−1 for 19 days) prevented psychological stress‐induced hyper‐anxiety in rats. These findings highlight the need for a deeper understanding of chronic treatment and dose‐dependent effects of OT before we consider OT for long‐term therapeutic use for the treatment of psychiatric conditions such as addiction.

Concluding remarks

Preclinical and clinical evidence clearly indicates the potential of OT as an effective next‐generation treatment (possibly as an ad hoc medication) for opioid addiction and comorbid mood disorders, as well as prevention of relapse. Therefore, there is a need for future clinical studies to directly assess the effect of OT‐based pharmacotherapies on the different stages of opioid addiction and to determine doses that would avoid any detrimental side effects.

Conflict of interest

The authors declare no conflicts of interest.

Zanos P., Georgiou P., Weber C., Robinson F., Kouimtsidis C., Niforooshan R., and Bailey A. (2018) Oxytocin and opioid addiction revisited: old drug, new applications, British Journal of Pharmacology, 175: 2809–2824, https://doi.org/10.1111/bph.13757.

References

  1. Alexander SPH, Davenport AP, Kelly E, Marrion N, Peters JA, Benson HE et al. (2015a). The Concise Guide to PHARMACOLOGY 2015/16: G protein‐coupled receptors. Br J Pharmacol 172: 5744–5869. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Alexander SPH, Peters JA, Kelly E, Marrion N, Benson HE, Faccenda E et al. (2015b). The Concise Guide to PHARMACOLOGY 2015/16: Ligand‐gated ion channels. Br J Pharmacol 172: 5870–5903. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Alterman AI, McKay JR, Mulvaney FD, McLellan AT (1996). Prediction of attrition from day hospital treatment in lower socioeconomic cocaine‐dependent men. Drug Alcohol Depend 40: 227–233. [DOI] [PubMed] [Google Scholar]
  4. Atweh SF, Kuhar MJ (1983). Distribution and physiological significance of opioid receptors in the brain. Br Med Bull 39: 47–52. [DOI] [PubMed] [Google Scholar]
  5. Baumgartner T, Heinrichs M, Vonlanthen A, Fischbacher U, Fehr E (2008). Oxytocin shapes the neural circuitry of trust and trust adaptation in humans. Neuron 58: 639–650. [DOI] [PubMed] [Google Scholar]
  6. Becker JAJ, Clesse D, Spiegelhalter C, Schwab Y, Le Merrer J, Kieffer BL (2014). Autistic‐like syndrome in mu opioid receptor null mice is relieved by facilitated mGluR4 activity. Neuropsychopharmacology 39: 2049–2060. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bicknell RJ, Leng G, Lincoln DW, Russell JA (1988). Naloxone excites oxytocin neurones in the supraoptic nucleus of lactating rats after chronic morphine treatment. J Physiol 396: 297–317. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Born J, Lange T, Kern W, McGregor GP, Bickel U, Fehm HL (2002). Sniffing neuropeptides: a transnasal approach to the human brain. Nat Neurosci 5: 514–516. [DOI] [PubMed] [Google Scholar]
  9. Bowen MT, Peters ST, Absalom N, Chebib M, Neumann ID, McGregor IS (2015). Oxytocin prevents ethanol actions at delta subunit‐containing GABAA receptors and attenuates ethanol‐induced motor impairment in rats. Proc Natl Acad Sci U S A 112: 3104–3109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Brooner RK, King VL, Kidorf M, Schmidt CW Jr, Bigelow GE (1997). Psychiatric and substance use comorbidity among treatment‐seeking opioid abusers. Arch Gen Psychiatry 54: 71–80. [DOI] [PubMed] [Google Scholar]
  11. Brown CH, Stern JE, Jackson KL, Bull PM, Leng G, Russell JA (2005). Morphine withdrawal increases intrinsic excitability of oxytocin neurons in morphine‐dependent rats. Eur J Neurosci 21: 501–512. [DOI] [PubMed] [Google Scholar]
  12. Bulbul M, Babygirija R, Cerjak D, Yoshimoto S, Ludwig K, Takahashi T (2011). Hypothalamic oxytocin attenuates CRF expression via GABA(A) receptors in rats. Brain Res 1387: 39–45. [DOI] [PubMed] [Google Scholar]
  13. Burri A, Heinrichs M, Schedlowski M, Kruger TH (2008). The acute effects of intranasal oxytocin administration on endocrine and sexual function in males. Psychoneuroendocrinology 33: 591–600. [DOI] [PubMed] [Google Scholar]
  14. Busnelli M, Bulgheroni E, Manning M, Kleinau G, Chini B (2013). Selective and potent agonists and antagonists for investigating the role of mouse oxytocin receptors. J Pharmacol Exp Ther 346: 318–327. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Carmichael MS, Humbert R, Dixen J, Palmisano G, Greenleaf W, Davidson JM (1987). Plasma oxytocin increases in the human sexual response. J Clin Endocrinol Metab 64: 27–31. [DOI] [PubMed] [Google Scholar]
  16. Carter CS (2007). Sex differences in oxytocin and vasopressin: implications for autism spectrum disorders? Behav Brain Res 176: 170–186. [DOI] [PubMed] [Google Scholar]
  17. Chang SW, Barter JW, Ebitz RB, Watson KK, Platt ML (2012). Inhaled oxytocin amplifies both vicarious reinforcement and self reinforcement in rhesus macaques (Macaca mulatta). Proc Natl Acad Sci U S A 109: 959–964. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Churchland PS, Winkielman P (2012). Modulating social behavior with oxytocin: how does it work? What does it mean? Horm Behav 61: 392–399. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Clarke G, Wood P, Merrick L, Lincoln DW (1979). Opiate inhibition of peptide release from the neurohumoral terminals of hypothalamic neurones. Nature 282: 746–748. [DOI] [PubMed] [Google Scholar]
  20. Coombes JE, Robinson IC, Antoni FA, Russell JA (1991). Release of oxytocin into blood and into cerebrospinal fluid induced by naloxone in anaesthetized morphine‐dependent rats: the role of the paraventricular nucleus. J Neuroendocrinol 3: 551–561. [DOI] [PubMed] [Google Scholar]
  21. Dabrowska J, Hazra R, Ahern TH, Guo JD, McDonald AJ, Mascagni F et al. (2011). Neuroanatomical evidence for reciprocal regulation of the corticotrophin‐releasing factor and oxytocin systems in the hypothalamus and the bed nucleus of the stria terminalis of the rat: implications for balancing stress and affect. Psychoneuroendocrinology 36: 1312–1326. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Dale HH (1906). On some physiological actions of ergot. J Physiol 34: 163–206. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Dawe S, Davis P, Lapworth K, McKetin R (2009). Mechanisms underlying aggressive and hostile behavior in amphetamine users. Curr Opin Psychiatry 22: 269–273. [DOI] [PubMed] [Google Scholar]
  24. de Jong TR, Veening JG, Olivier B, Waldinger MD (2007). Oxytocin involvement in SSRI‐induced delayed ejaculation: a review of animal studies. J Sex Med 4: 14–28. [DOI] [PubMed] [Google Scholar]
  25. Di Simplicio M, Massey‐Chase R, Cowen PJ, Harmer CJ (2009). Oxytocin enhances processing of positive versus negative emotional information in healthy male volunteers. J Psychopharmacol 23: 241–248. [DOI] [PubMed] [Google Scholar]
  26. Domes G, Heinrichs M, Glascher J, Buchel C, Braus DF, Herpertz SC (2007). Oxytocin attenuates amygdala responses to emotional faces regardless of valence. Biol Psychiatry 62: 1187–1190. [DOI] [PubMed] [Google Scholar]
  27. du Vigneaud V, Ressler C, Swan JM, Roberts CW, Katsoyannis PG (1954). The synthesis of oxytocin1. J Am Chem Soc 76: 3115–3121. [Google Scholar]
  28. du Vigneaud V, Ressler C, Trippett S (1953). The sequence of amino acids in oxytocin, with a proposal for the structure of oxytocin. J Biol Chem 205: 949–957. [PubMed] [Google Scholar]
  29. Dyer RA, Butwick AJ, Carvalho B (2011). Oxytocin for labour and caesarean delivery: implications for the anaesthesiologist. Curr Opin Anaesthesiol 24: 255–261. [DOI] [PubMed] [Google Scholar]
  30. Farrell M, Howes S, Bebbington P, Brugha T, Jenkins R, Lewis G et al. (2003). Nicotine, alcohol and drug dependence, and psychiatric comorbidity – results of a national household survey. Int Rev Psychiatry 15: 50–56. [DOI] [PubMed] [Google Scholar]
  31. Georgiou P, Zanos P, Ehteramyan M, Hourani S, Kitchen I, Maldonado R et al. (2015a). Differential regulation of mGlu5 R and MuOPr by priming‐ and cue‐induced reinstatement of cocaine‐seeking behaviour in mice. Addict Biol 20: 902–912. [DOI] [PubMed] [Google Scholar]
  32. Georgiou P, Zanos P, Garcia‐Carmona JA, Hourani S, Kitchen I, Kieffer BL et al. (2015b). The oxytocin analogue carbetocin prevents priming‐induced reinstatement of morphine‐seeking: involvement of dopaminergic, noradrenergic and MOPr systems. Eur Neuropsychopharmacol 25: 2459–2464. [DOI] [PubMed] [Google Scholar]
  33. Georgiou P, Zanos P, Garcia‐Carmona JA, Hourani S, Kitchen I, Laorden ML et al. (2016a). Methamphetamine abstinence induces changes in mu‐opioid receptor, oxytocin and CRF systems: association with an anxiogenic phenotype. Neuropharmacology 105: 520–532. [DOI] [PubMed] [Google Scholar]
  34. Georgiou P, Zanos P, Hourani S, Kitchen I, Bailey A (2016b). Cocaine abstinence induces emotional impairment and brain region‐specific upregulation of the oxytocin receptor binding. Eur J Neurosci 44: 2446–2454. [DOI] [PubMed] [Google Scholar]
  35. Gigliucci V, Leonzino M, Busnelli M, Luchetti A, Palladino VS, D'Amato FR et al. (2014). Region specific up‐regulation of oxytocin receptors in the opioid oprm1(−/−) mouse model of autism. Front Pediatr 2: 91. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Gimpl G, Fahrenholz F (2001). The oxytocin receptor system: structure, function, and regulation. Physiol Rev 81: 629–683. [DOI] [PubMed] [Google Scholar]
  37. Guest C, Holland M (2011). Co‐existing mental health and substance use and alcohol difficulties – why do we persist with the term “dual diagnosis” within mental health services? Adv Dual Diagn 4: 162–172. [Google Scholar]
  38. Haldar J, Sawyer WH (1978). Inhibition of oxytocin release by morphine and its analogs. Proc Soc Exp Biol Med 157: 476–480. [DOI] [PubMed] [Google Scholar]
  39. Hashimoto H, Uezono Y, Ueta Y (2012). Pathophysiological function of oxytocin secreted by neuropeptides: a mini review. Pathophysiology 19: 283–298. [DOI] [PubMed] [Google Scholar]
  40. Heinrichs M, Baumgartner T, Kirschbaum C, Ehlert U (2003). Social support and oxytocin interact to suppress cortisol and subjective responses to psychosocial stress. Biol Psychiatry 54: 1389–1398. [DOI] [PubMed] [Google Scholar]
  41. Heinrichs M, Gaab J (2007). Neuroendocrine mechanisms of stress and social interaction: implications for mental disorders. Curr Opin Psychiatry 20: 158–162. [DOI] [PubMed] [Google Scholar]
  42. Hill R, Lyndon A, Withey S, Roberts J, Kershaw Y, MacLachlan J et al. (2016). Ethanol reversal of tolerance to the respiratory depressant effects of morphine. Neuropsychopharmacology 41: 762–773. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Ho SS, Chow BK, Yung WH (2007). Serotonin increases the excitability of the hypothalamic paraventricular nucleus magnocellular neurons. Eur J Neurosci 25: 2991–3000. [DOI] [PubMed] [Google Scholar]
  44. Ibragimov R, Kovacs G (1987). [Effect of oxytocin microinjections into the lateral septal nucleus on intravenous heroin self‐administration in heroin‐tolerant rats]Fiziol Zh SSSR Im I M Sechenova 73: 1625–1629. [PubMed] [Google Scholar]
  45. Ibragimov R, Kovacs GL, Szabo G, Telegdy G (1987). Microinjection of oxytocin into limbic‐mesolimbic brain structures disrupts heroin self‐administration behavior: a receptor‐mediated event? Life Sci 41: 1265–1271. [DOI] [PubMed] [Google Scholar]
  46. Insel TR (2003). Is social attachment an addictive disorder? Physiol Behav 79: 351–357. [DOI] [PubMed] [Google Scholar]
  47. Insel TR, Shapiro LE (1992). Oxytocin receptor distribution reflects social organization in monogamous and polygamous voles. Proc Natl Acad Sci U S A 89: 5981–5985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Insel TR, Wang ZX, Ferris CF (1994). Patterns of brain vasopressin receptor distribution associated with social organization in microtine rodents. J Neurosci 14: 5381–5392. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Johnstone LE, Brown CH, Meeren HK, Vuijst CL, Brooks PJ, Leng G et al. (2000). Local morphine withdrawal increases c‐fos gene, Fos protein, and oxytocin gene expression in hypothalamic magnocellular neurosecretory cells. J Neurosci 20: 1272–1280. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Jong TR, Menon R, Bludau A, Grund T, Biermeier V, Klampfl SM et al. (2015). Salivary oxytocin concentrations in response to running, sexual self‐stimulation, breastfeeding and the TSST: the regensburg oxytocin challenge (ROC) study. Psychoneuroendocrinology 62: 381–388.26385109 [Google Scholar]
  51. Jorgensen H, Riis M, Knigge U, Kjaer A, Warberg J (2003). Serotonin receptors involved in vasopressin and oxytocin secretion. J Neuroendocrinol 15: 242–249. [DOI] [PubMed] [Google Scholar]
  52. Jurek B, Slattery DA, Hiraoka Y, Liu Y, Nishimori K, Aguilera G et al. (2015). Oxytocin regulates stress‐induced Crf gene transcription through CREB‐regulated transcription coactivator 3. J Neurosci 35: 12248–12260. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Kampman KM, Leiderman D, Holmes T, LoCastro J, Bloch DA, Reid MS et al. (2005). Cocaine rapid efficacy screening trials (CREST): lessons learned. Addiction 100 (Suppl 1): 102–110. [DOI] [PubMed] [Google Scholar]
  54. Kimura T, Tanizawa O, Mori K, Brownstein MJ, Okayama H (1992). Structure and expression of a human oxytocin receptor. Nature 356: 526–529. [DOI] [PubMed] [Google Scholar]
  55. Kirsch P, Esslinger C, Chen Q, Mier D, Lis S, Siddhanti S et al. (2005). Oxytocin modulates neural circuitry for social cognition and fear in humans. J Neurosci 25: 11489–11493. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Koerner (2010). Secret of AA: after 75 years, we don't know how it works. Wired . Available at: http://www.wired.com/magazine/2010/06/ff_alcoholics_anonymous/ (accessed 3rd March 2013).
  57. Koob GF, Le Moal M (2008). Addiction and the brain antireward system. Annu Rev Psychol 59: 29–53. [DOI] [PubMed] [Google Scholar]
  58. Koob GF, Le Moal M (2001). Drug addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology 24: 97–129. [DOI] [PubMed] [Google Scholar]
  59. Kosten TR, Rounsaville BJ, Kleber HD (1986). A 2.5‐year follow‐up of depression, life crises, and treatment effects on abstinence among opioid addicts. Arch Gen Psychiatry 43: 733–738. [DOI] [PubMed] [Google Scholar]
  60. Kovacs CL, Van Ree JM (1985). Behaviorally active oxytocin fragments simultaneously attenuate heroin self‐administration and tolerance in rats. Life Sci 37: 1895–1900. [DOI] [PubMed] [Google Scholar]
  61. Kovacs GL, Borthaiser Z, Telegdy G (1985a). Oxytocin reduces intravenous heroin self‐administration in heroin‐tolerant rats. Life Sci 37: 17–26. [DOI] [PubMed] [Google Scholar]
  62. Kovacs GL, Faludi M, Falkay G, Telegdy G (1986). Peripheral oxytocin treatment modulates central dopamine transmission in the mouse limbic structures. Neurochem Int 9: 481–485. [DOI] [PubMed] [Google Scholar]
  63. Kovacs GL, Faludi M, Telegdy G (1985b). Oxytocin diminishes heroin tolerance in mice. Psychopharmacology (Berl) 86: 377–379. [DOI] [PubMed] [Google Scholar]
  64. Kovacs GL, Horvath Z, Sarnyai Z, Faludi M, Telegdy G (1985c). Oxytocin and a C‐terminal derivative (Z‐prolyl‐D‐leucine) attenuate tolerance to and dependence on morphine and interact with dopaminergic neurotransmission in the mouse brain. Neuropharmacology 24: 413–419. [DOI] [PubMed] [Google Scholar]
  65. Kovacs GL, Izbeki F, Horvath Z, Telegdy G (1984). Effects of oxytocin and a derivative (Z‐prolyl‐D‐leucine) on morphine tolerance/withdrawal are mediated by the limbic system. Behav Brain Res 14: 1–8. [DOI] [PubMed] [Google Scholar]
  66. Kovacs GL, Laczi F, Vecsernyes M, Hodi K, Telegdy G, Laszlo FA (1987a). Limbic oxytocin and arginine 8‐vasopressin in morphine tolerance and dependence. Exp Brain Res 65: 307–311. [DOI] [PubMed] [Google Scholar]
  67. Kovacs GL, Sarnyai Z, Barbarczi E, Szabo G, Telegdy G (1990). The role of oxytocin‐dopamine interactions in cocaine‐induced locomotor hyperactivity. Neuropharmacology 29: 365–368. [DOI] [PubMed] [Google Scholar]
  68. Kovacs GL, Sarnyai Z, Izbeki F, Szabo G, Telegdy G, Barth T et al. (1987b). Effects of oxytocin‐related peptides on acute morphine tolerance: opposite actions by oxytocin and its receptor antagonists. J Pharmacol Exp Ther 241: 569–574. [PubMed] [Google Scholar]
  69. Kovacs GL, Sarnyai Z, Szabo G (1998). Oxytocin and addiction: a review. Psychoneuroendocrinology 23: 945–962. [DOI] [PubMed] [Google Scholar]
  70. Kovacs GL, Telegdy G (1987). Beta‐endorphin tolerance is inhibited by oxytocin. Pharmacol Biochem Behav 26: 57–60. [DOI] [PubMed] [Google Scholar]
  71. Labuschagne I, Phan KL, Wood A, Angstadt M, Chua P, Heinrichs M et al. (2010). Oxytocin attenuates amygdala reactivity to fear in generalized social anxiety disorder. Neuropsychopharmacology 35: 2403–2413. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. Laorden ML, Milanes MV, Chapleur‐Chateau M, Burlet A (1997). Changes in hypothalamic oxytocin levels during morphine tolerance. Neuropeptides 31: 143–146. [DOI] [PubMed] [Google Scholar]
  73. Laorden ML, Milanes MV, Chapleur‐Chateau M, Burlet A (1998). Changes in oxytocin content in rat brain during morphine withdrawal. Neuropeptides 32: 67–71. [DOI] [PubMed] [Google Scholar]
  74. Larsen PJ, Hay‐Schmidt A, Vrang N, Mikkelsen JD (1996). Origin of projections from the midbrain raphe nuclei to the hypothalamic paraventricular nucleus in the rat: a combined retrograde and anterograde tracing study. Neuroscience 70: 963–988. [DOI] [PubMed] [Google Scholar]
  75. Lee R, Garcia F, van de Kar LD, Hauger RD, Coccaro EF (2003). Plasma oxytocin in response to pharmaco‐challenge to D‐fenfluramine and placebo in healthy men. Psychiatry Res 118: 129–136. [DOI] [PubMed] [Google Scholar]
  76. Liberzon I, Trujillo KA, Akil H, Young EA (1997). Motivational properties of oxytocin in the conditioned place preference paradigm. Neuropsychopharmacology 17: 353–359. [DOI] [PubMed] [Google Scholar]
  77. Lintas A, Chi N, Lauzon NM, Bishop SF, Gholizadeh S, Sun N et al. (2011). Identification of a dopamine receptor‐mediated opiate reward memory switch in the basolateral amygdala‐nucleus accumbens circuit. J Neurosci 31: 11172–11183. [DOI] [PMC free article] [PubMed] [Google Scholar]
  78. Liu Y, Wang ZX (2003). Nucleus accumbens oxytocin and dopamine interact to regulate pair bond formation in female prairie voles. Neuroscience 121: 537–544. [DOI] [PubMed] [Google Scholar]
  79. Ludwig M, Leng G (2006). Dendritic peptide release and peptide‐dependent behaviours. Nature reviews . Neuroscience 7: 126–136. [DOI] [PubMed] [Google Scholar]
  80. MacDonald E, Dadds MR, Brennan JL, Williams K, Levy F, Cauchi AJ (2011). A review of safety, side‐effects and subjective reactions to intranasal oxytocin in human research. Psychoneuroendocrinology 36: 1114–1126. [DOI] [PubMed] [Google Scholar]
  81. McCarthy MM (1995). Estrogen modulation of oxytocin and its relation to behavior. Adv Exp Med Biol 395: 235–245. [PubMed] [Google Scholar]
  82. McGregor IS, Bowen MT (2012). Breaking the loop: oxytocin as a potential treatment for drug addiction. Horm Behav 61: 331–339. [DOI] [PubMed] [Google Scholar]
  83. Meyer‐Lindenberg A, Domes G, Kirsch P, Heinrichs M (2011). Oxytocin and vasopressin in the human brain: social neuropeptides for translational medicine. Nat Rev Neurosci 12: 524–538. [DOI] [PubMed] [Google Scholar]
  84. Moaddab M, Hyland BI, Brown CH (2015). Oxytocin enhances the expression of morphine‐induced conditioned place preference in rats. Psychoneuroendocrinology 53: 159–169. [DOI] [PubMed] [Google Scholar]
  85. Murphy NP, Onaka T, Brown CH, Leng G (1997). The role of afferent inputs to supraoptic nucleus oxytocin neurons during naloxone‐precipitated morphine withdrawal in the rat. Neuroscience 80: 567–577. [DOI] [PubMed] [Google Scholar]
  86. Neumann ID, Kromer SA, Toschi N, Ebner K (2000a). Brain oxytocin inhibits the (re)activity of the hypothalamo‐pituitary‐adrenal axis in male rats: involvement of hypothalamic and limbic brain regions. Regul Pept 96: 31–38. [DOI] [PubMed] [Google Scholar]
  87. Neumann ID, Landgraf R (2012). Balance of brain oxytocin and vasopressin: implications for anxiety, depression, and social behaviors. Trends Neurosci 35: 649–659. [DOI] [PubMed] [Google Scholar]
  88. Neumann ID, Torner L, Wigger A (2000b). Brain oxytocin: differential inhibition of neuroendocrine stress responses and anxiety‐related behaviour in virgin, pregnant and lactating rats. Neuroscience 95: 567–575. [DOI] [PubMed] [Google Scholar]
  89. Onaka T, Ikeda K, Yamashita T, Honda K (2003). Facilitative role of endogenous oxytocin in noradrenaline release in the rat supraoptic nucleus. Eur J Neurosci 18: 3018–3026. [DOI] [PubMed] [Google Scholar]
  90. Pati D, Smith J, de Kloet A, Krause E, Frazier C (2015). Tonic modulation of central CRF circuits by oxytocin in response to peripheral salt loading. FASEB J 29 (1 Supplement 836.2). [Google Scholar]
  91. Pedersen CA, Smedley KL, Leserman J, Jarskog LF, Rau SW, Kampov‐Polevoi A et al. (2013). Intranasal oxytocin blocks alcohol withdrawal in human subjects. Alcohol Clin Exp Res 37: 484–489. [DOI] [PMC free article] [PubMed] [Google Scholar]
  92. Peters S, Slattery DA, Uschold‐Schmidt N, Reber SO, Neumann ID (2014). Dose‐dependent effects of chronic central infusion of oxytocin on anxiety, oxytocin receptor binding and stress‐related parameters in mice. Psychoneuroendocrinology 42: 225–236. [DOI] [PubMed] [Google Scholar]
  93. Pumford KM, Leng G, Russell JA (1991). Morphine actions on supraoptic oxytocin neurones in anaesthetized rats: tolerance after i.c.v. morphine infusion. J Physiol 440: 437–454. [DOI] [PMC free article] [PubMed] [Google Scholar]
  94. Qi J, Yang J‐Y, Wang F, Zhao Y‐N, Song M, Wu C‐F (2009). Effects of oxytocin on methamphetamine‐induced conditioned place preference and the possible role of glutamatergic neurotransmission in the medial prefrontal cortex of mice in reinstatement. Neuropharmacology 56: 856–865. [DOI] [PubMed] [Google Scholar]
  95. Qi J, Yang JY, Song M, Li Y, Wang F, Wu CF (2008). Inhibition by oxytocin of methamphetamine‐induced hyperactivity related to dopamine turnover in the mesolimbic region in mice. Naunyn Schmiedebergs Arch Pharmacol 376: 441–448. [DOI] [PubMed] [Google Scholar]
  96. Rasmussen MS, Simonsen JA, Sandgaard NC, Hoilund‐Carlsen PF, Bie P (2004). Effects of oxytocin in normal man during low and high sodium diets. Acta Physiol Scand 181: 247–257. [DOI] [PubMed] [Google Scholar]
  97. Riggs PD (2003). Treating adolescents for substance abuse and comorbid psychiatric disorders. Sci Pract Perspect 2: 18–29. [DOI] [PMC free article] [PubMed] [Google Scholar]
  98. Romero‐Fernandez W, Borroto‐Escuela DO, Agnati LF, Fuxe K (2012). Evidence for the existence of dopamine d2‐oxytocin receptor heteromers in the ventral and dorsal striatum with facilitatory receptor‐receptor interactions. Mol Psychiatr 18: 849–850. [DOI] [PubMed] [Google Scholar]
  99. Russell JA, Neumann I, Landgraf R (1992). Oxytocin and vasopressin release in discrete brain areas after naloxone in morphine‐tolerant and ‐dependent anesthetized rats: push‐pull perfusion study. J Neurosci 12: 1024–1032. [DOI] [PMC free article] [PubMed] [Google Scholar]
  100. Sarnyai Z, Viski S, Krivan M, Szabo G, Kovacs GL, Telegdy G (1988). Endogenous oxytocin inhibits morphine tolerance through limbic forebrain oxytocin receptors. Brain Res 463: 284–288. [DOI] [PubMed] [Google Scholar]
  101. Sawchenko PE, Swanson LW, Steinbusch HW, Verhofstad AA (1983). The distribution and cells of origin of serotonergic inputs to the paraventricular and supraoptic nuclei of the rat. Brain Res 277: 355–360. [DOI] [PubMed] [Google Scholar]
  102. Singewald N, Schmuckermair C, Whittle N, Holmes A, Ressler KJ (2015). Pharmacology of cognitive enhancers for exposure‐based therapy of fear, anxiety and trauma‐related disorders. Pharmacol Ther 149: 150–190. [DOI] [PMC free article] [PubMed] [Google Scholar]
  103. Skuse DH, Gallagher L (2009). Dopaminergic‐neuropeptide interactions in the social brain. Trends Cogn Sci 13: 27–35. [DOI] [PubMed] [Google Scholar]
  104. Southan C, Sharman JL, Benson HE, Faccenda E, Pawson AJ, Alexander SPH et al. (2016). The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. Nucl Acids Res 44 (Database Issue): D1054–D1068. [DOI] [PMC free article] [PubMed] [Google Scholar]
  105. Stauffer CS, Musinipally V, Suen A, Lynch KL, Shapiro B, Woolley JD (2016). A two‐week pilot study of intranasal oxytocin for cocaine‐dependent individuals receiving methadone maintenance treatment for opioid use disorder. Addiction Res Theor 24: 490–498. [DOI] [PMC free article] [PubMed] [Google Scholar]
  106. Swaab DF, Fliers E, Hoogendijk WJ, Veltman DJ, Zhou JN (2000). Interaction of prefrontal cortical and hypothalamic systems in the pathogenesis of depression. Prog Brain Res 126: 369–396. [DOI] [PubMed] [Google Scholar]
  107. Tokar JT, Brunse AJ, Stefflre VJ, Sodergren JA, Napior DA (1975). Determining what heroin means to heroin addicts. Dis Nerv Syst 36: 77–81. [PubMed] [Google Scholar]
  108. Tuppy H (1953). The amino‐acid sequence in oxytocin. Biochim Biophys Acta 11: 449–450. [DOI] [PubMed] [Google Scholar]
  109. Uvanas‐Moberg K, Arn I, Magnusson D (2005). The psychobiology of emotion: the role of the oxytocinergic system. Int J Behav Med 12: 59–65. [DOI] [PubMed] [Google Scholar]
  110. Uvnas‐Moberg K (1998). Oxytocin may mediate the benefits of positive social interaction and emotions. Psychoneuroendocrinology 23: 819–835. [DOI] [PubMed] [Google Scholar]
  111. Uvnas‐Moberg K, Bjokstrand E, Hillegaart V, Ahlenius S (1999). Oxytocin as a possible mediator of SSRI‐induced antidepressant effects. Psychopharmacology (Berl) 142: 95–101. [DOI] [PubMed] [Google Scholar]
  112. Van Ree JM, De Wied D (1977). Modulation of heroin self‐administration by neurohypophyseal principles. Eur J Pharmacol 43: 199–202. [DOI] [PubMed] [Google Scholar]
  113. van Ree JM, de Wied D (1976). Prolyl‐leucyl‐glycinamide (PLG) facilitates morphine dependence. Life Sci 19: 1331–1339. [DOI] [PubMed] [Google Scholar]
  114. Volkow ND, Baler RD, Goldstein RZ (2011). Addiction: pulling at the neural threads of social behaviors. Neuron 69: 599–602. [DOI] [PMC free article] [PubMed] [Google Scholar]
  115. Volkow ND, Wang GJ, Telang F, Fowler JS, Logan J, Childress AR et al. (2006). Cocaine cues and dopamine in dorsal striatum: mechanism of craving in cocaine addiction. J Neurosci 26: 6583–6588. [DOI] [PMC free article] [PubMed] [Google Scholar]
  116. Windle RJ, Kershaw YM, Shanks N, Wood SA, Lightman SL, Ingram CD (2004). Oxytocin attenuates stress‐induced c‐fos mRNA expression in specific forebrain regions associated with modulation of hypothalamo‐pituitary‐adrenal activity. J Neurosci 24: 2974–2982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  117. Windle RJ, Shanks N, Lightman SL, Ingram CD (1997). Central oxytocin administration reduces stress‐induced corticosterone release and anxiety behavior in rats. Endocrinology 138: 2829–2834. [DOI] [PubMed] [Google Scholar]
  118. Wong DF, Kuwabara H, Schretlen DJ, Bonson KR, Zhou Y, Nandi A et al. (2006). Increased occupancy of dopamine receptors in human striatum during cue‐elicited cocaine craving. Neuropsychopharmacology 31: 2716–2727. [DOI] [PubMed] [Google Scholar]
  119. Woolley JD, Arcuni PA, Stauffer CS, Fulford D, Carson DS, Batki S et al. (2016). The effects of intranasal oxytocin in opioid‐dependent individuals and healthy control subjects: a pilot study. Psychopharmacology (Berl) 233: 2571–2580. [DOI] [PMC free article] [PubMed] [Google Scholar]
  120. You ZD, Li JH, Song CY, Wang CH, Lu CL (2000). Chronic morphine treatment inhibits oxytocin synthesis in rats. Neuroreport 11: 3113–3116. [DOI] [PubMed] [Google Scholar]
  121. Young KA, Liu Y, Gobrogge KL, Wang H, Wang Z (2014). Oxytocin reverses amphetamine‐induced deficits in social bonding: evidence for an interaction with nucleus accumbens dopamine. J Neurosci 34: 8499–8506. [DOI] [PMC free article] [PubMed] [Google Scholar]
  122. Young L (2003). The neural basis of pair bonding in a monogamous species: a model for understanding the biological basis of human behavior. National Research Council (US) Panel for the Workshop on the Biodemography of Fertility and Family Behavior Panel for the Workshop on the Biodemography of Fertility and Family Behavior: National Academies Press
  123. Young LJ, Wang Z (2004). The neurobiology of pair bonding. Nat Neurosci 7: 1048–1054. [DOI] [PubMed] [Google Scholar]
  124. Zanos P, Georgiou P, Metaxas A, Kitchen I, Winsky‐Sommerer R, Bailey A (2015). Region‐specific up‐regulation of oxytocin receptor binding in the brain of mice following chronic nicotine administration. Neurosci Lett 600: 33–37. [DOI] [PubMed] [Google Scholar]
  125. Zanos P, Georgiou P, Wright SR, Hourani SM, Kitchen I, Winsky‐Sommerer R et al. (2014a). The oxytocin analogue carbetocin prevents emotional impairment and stress‐induced reinstatement of opioid‐seeking in morphine‐abstinent mice. Neuropsychopharmacology 39: 855–865. [DOI] [PMC free article] [PubMed] [Google Scholar]
  126. Zanos P, Wright SR, Georgiou P, Yoo JH, Ledent C, Hourani SM et al. (2014b). Chronic methamphetamine treatment induces oxytocin receptor up‐regulation in the amygdala and hypothalamus via an adenosine A2A receptor‐independent mechanism. Pharmacol Biochem Behav 119: 72–79. [DOI] [PubMed] [Google Scholar]
  127. Zhang J, Weston PG, Hixon JE (1991). Influence of estradiol on the secretion of oxytocin and prostaglandin F2 alpha during luteolysis in the ewe. Biol Reprod 45: 395–403. [DOI] [PubMed] [Google Scholar]

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