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. 2019 Apr 10;177(3):634–641. doi: 10.1111/bph.14634

Histamine, histamine H3 receptor, and alcohol use disorder

Pertti Panula 1,✉
PMCID: PMC7012945  PMID: 30801695

Abstract

Alcohol use disorder is associated with several mental, physical, and social problems. Its treatment is difficult and often requires a combination of pharmacological and behavioural therapy. The brain histaminergic system, one of the wake‐active systems that controls whole‐brain activity, operates through three neuronal GPCRs. The histamine H3 receptor (Hrh3), which is expressed in many brain areas involved in alcohol drinking and alcohol reward, can be targeted with a number of drugs developed initially for cognitive disorders and/or disorders related to sleep, wakefulness, and alertness. In all rodent alcohol drinking models tested so far, H3 receptor antagonists have reduced alcohol drinking and alcohol‐induced place preference and cue‐induced alcohol reinstatement. Several H3 receptor antagonists tested and found to be safe for humans could be subjected to clinical tests to treat alcohol use disorder. Preference should be given to short‐acting drugs to avoid the sleep problems associated with the wake‐maintaining effects of the drugs.

Linked Articles

This article is part of a themed section on New Uses for 21st Century. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.3/issuetoc

Abbreviations

AA

ALKO alcohol (type of alcohol‐preferring rat)

ANA

ALKO non‐alcohol (type of alcohol non‐preferring rat)

AUD

alcohol use disorder

NAcc

nucleus accumbens

RT

randomized treatment

SN

substantia nigra

TMN

tuberomamillary nucleus

VTA

ventral tegmental area

1. ALCOHOL AND BRAIN NEUROTRANSMITTER SYSTEMS

Alcohol use disorder (AUD) is a complex disease, which is despite recent developments still a major health problem (Abrahao, Salinas, & Lovinger, 2017). Drug treatments, based on known targets or circuits, including those tested or already in use (disulphiram, naltrexone, acamprosate, topiramate, baclofen, and gabapentin) all require complementary behavioural therapy, and the results are often still not satisfactory (Abrahao et al., 2017; Korpi et al., 2015; Vuoristo‐Myllys, Lipsanen, Lahti, Kalska, & Alho, 2014).

The brain histaminergic system in mammals comprises cell bodies in the posterior basal hypothalamus in an area named the tuberomamillary nucleus (TMN; Panula, Airaksinen, Pirvola, & Kotilainen, 1990; Panula, Yang, & Costa, 1984; Watanabe et al., 1984), which sends projections to all major parts of the brain (Inagaki et al., 1988; Panula, Pirvola, Auvinen, & Airaksinen, 1989). Alcohol is a simple compound that interacts with target cells mainly through hydrogen bonding and weak hydrophobic interactions (Abrahao et al., 2017) in addition to specific neurotrasnmitter receptors, and thus, high concentrations are needed for reinforcing and sedative effects. Most brain areas are thus affected by systemic intake of alcohol, which affects cells and circuits in many brain areas that receive histaminergic innervation (Inagaki et al., 1988; Panula, Pirvola, Auvinen, & Airaksinen, 1989). Alcohol has well‐characterized effects on GABA and glycine receptors and less well‐understood effects at the glutamate NMDA receptor (Abrahao et al., 2017; Korpi et al., 2015). Since these receptors and some of the signalling pathways also directly affected by alcohol are found in many aminergic neurons, these neurons are among the direct or indirect targets of alcohol.

Initial acute effects of alcohol include increased inhibition through GABAA receptor potentiation, reduced excitation through block of NMDA and AMPA receptors, activation of the mesolimbic system through increased dopamine release, and effects (relaxation, euphoria, and anxiolysis) mediated by neuropeptide systems (Korpi et al., 2015). Withdrawal symptoms are associated with reduced GABAA receptor signalling, increased excitation mediated by NMDA and AMPA receptor activation, and reduced dopamine release in the mesolimbic system. These plastic changes affect a number of brain areas, including the orbitofrontal and prefrontal cortex, dorsomedial, dorsolateral and ventral striatum (nucleus accumbens [Acb]), lateral habenula, amygdala, bed nucleus of the stria terminalis, substantia nigra (SN), ventral tegmentum, and some brainstem areas. Although none of the well‐known behavioural effects of alcohol are directly linked to the histaminergic neuron system, many of these areas express high levels of at least one of the three neuronal G‐protein‐coupled histamine receptors, postsynaptic H1 receptor, H2 receptor, or pre or postsynaptic H3 receptor (Hrh3). In the neurons that express H3 receptors, neurotransmitter release is likely affected by histamine through this receptor or by constitutive activity of the H3 receptor (Panula et al., 2015).

2. GPCRs AS TARGETS FOR AUD

GPCRs are among the most utilized drug targets. Not surprisingly, several GPCRs have been tested in rodents as potential targets to treat AUD. Selective receptor agonists and antagonists and gene‐modified animals have been used in these experiments. Since several methods have been used with variable controls, the results have not always been easy to interpret. Among the most studied receptor are the opioid receptors (Contet, Kieffer, & Befort, 2004; Matthes et al., 1996), dopamine D1 and D2 receptors (Cunningham et al., 2000; El‐Ghundi et al., 1998), 5‐HT receptors (Crabbe et al., 1996; de Bruin et al., 2013), metabotropic glutamate receptors (Zhou et al., 2013), cannabinoid receptors (Hungund, Szakall, Adam, Basavarajappa, & Vadasz, 2003; Naassila, Pierrefiche, Ledent, & Daoust, 2004), and muscarinic receptors (de la Cour et al., 2015). Indeed, repeated alcohol administration increases levels of methionine encephalin‐Arg‐Phe levels in the periaqueductal gray (Lindholm, Ploj, Franck, & Nylander, 2000), and acute moderate doses induce release of methionine‐enkephalin in the NAcc (Marinelli, Bai, Quirion, & Gianoulakis, 2005). Naltrexone, which preferentially blocks opioid μ receptors, is one of the few accepted treatments for AUD. Naltrexone decreases alcohol consumption in rhesus monkeys (Altshuler, Phillips, & Feinhandler, 1980) and rats (Stromberg, Casale, Volpicelli, Volpicelli, & O'Brien, 1998) and is one of the few available drugs currently accepted for treatment of AUD despite challenges met when treating heavy drinkers (Vuoristo‐Myllys, Lahti, Alho, & Julkunen, 2013). The H3 receptor was not initially among the targets predicted to treat AUD, but the findings on a robust reduction in alcohol drinking in both rats (Lintunen et al., 2001) and mice (Nuutinen, Karlstedt, Aitta‐Aho, Korpi, & Panula, 2010) were initially unexpected, but have since been independently verified.

3. HISTAMINE AND H3 RECEPTORS IN BRAIN AREAS RELEVANT FOR AUD

The H3 receptor is widely expressed in the brain of all vertebrates studied (Pillot et al., 2002; Sallmen, Lozada, Anichtchik, Beckman, & Panula, 2003; Sundvik et al., 2011; Tardivel‐Lacombe et al., 2000). In rat brain, the different isoforms show slightly different expression patterns (Drutel et al., 2001), but the significance of this and detailed roles of the isoforms are not known. In general, the H3 receptor is expressed in histaminergic neurons, which is in agreement with its role as an autoreceptor, and in many brain regions. One of the most consistent findings is its abundant expression in telencephalic structures (Figure 1), such as the striatum and cerebral cortex, and dorsal thalamus (Jin, Kalimo, & Panula, 2002; Jin & Panula, 2005; Panula & Nuutinen, 2013; Panula, Sundvik, & Karlstedt, 2014). A comparison of H3 receptor mRNA and receptor radioligand binding studies and the knowledge of neuronal pathways suggests that this receptor is found in several critically important brain structures and pathways related to cognitive functions, motivation, aversion and pleasure, and locomotion, such as the thalamocortical, hypothalamocortical, and striatonigral systems (Panula & Nuutinen, 2013; Figure 2). Both the expression of this receptor and receptor radioligand binding are high in limbic structures such as the hippocampus and amygdala (Haas & Panula, 2003). Interestingly, the tuberomamillary nucleus in which the histaminergic neurons reside receives its heaviest innervation from the infralimbic or medial prefrontal cortex in the rat (Ericson, Blomqvist, & Kohler, 1991), suggesting that the histaminergic neurons get direct inputs from this brain region, which is in a key area for decision making and executive functions. The H3 receptor is highly expressed in this area of the brain.

Figure 1.

Figure 1

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In situ hybridization of rat brain sections with 35S‐labelled oligonucleotide probes for histamine H3 receptor at (a) 2.70, (b) 0.70, and (c) −3.60 mm from bregma shows a clear laminar expression of H3 receptor mRNA in various parts of the cortex (infralimbic cortex [IL], cingulate cortex area 1 [Cg1], frontal cortex, area 1 [Fr1], frontal cortex, area 3 [Fr3], and occipital cortex [Oc]) and high expression throughout the caudate‐putamen (striatum; CPu) and nucleus accumbens (Acb). IL and Cg1 represent parts of rat brain area thought to correspond to parts of prefrontal cortex in humans. BL: basolateral amygdaloid nucleus; CA1: field 1 of cornu ammonis in hippocampus; Cg2: cingulate cortex area 2; VPM: ventral posteromedial thalamic nucleus

Figure 2.

Figure 2

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Dopaminergic (blue) and histaminergic (green) projections target many brain areas essential in alcohol‐related rewarding and drug‐seeking or aversive behaviours. Dopaminergic projections to the prefrontal cortex (PFC), nucleus accumbens (Acb), and amygdala (Am) originate in the ventral tegmental area (VTA); those directed to the caudate‐putamen (CPu) originate in the SN. All histaminergic projections originate in the etuberomamillary nucleus (TMN). 5‐HT‐containing dorsal raphe nucleus (DR; red) and noradrenaline‐containing locus coeruleus (LC; yellow) are also labelled, but their projections are not included. The intensity of the grey scale in target areas lateral habenular nucleus (Lhb), PFC, CPu, Am, and Acb indicates the intensity of the H3 receptor radioligand binding density in autoradiographic films in rat brain. SN: substantia nigra pars compacta

Brain areas important in AUD include the mesocorticotriatal system and extended amygdala including the nucleus of the stria terminalis and habenula (Abrahao et al., 2017; Koob & Volkow, 2016; Korpi et al., 2015; Figure 2). H3 receptor mRNA expression and receptor radioligand binding are high in almost all of these areas (Figures 1 and 2), which render it difficult to identify a sole site of action of H3 receptor antagonists on alcohol drinking or alcohol‐induced place preference. One of the few sites where these drugs affect a significant signalling pathway for these behaviours is the striatum, where an H3 receptor antagonist has been shown to regulate dopaminergic signalling (Nuutinen et al., 2016). In the striatum, dopamine receptor signalling was increased by dopamine receptor agonists quinpirole and SKF38393 in wild type but not in H3 receptor knockout mice (Kononoff Vanhanen, Nuutinen, Tuominen, & Panula, 2016). Even in this location, several H3 receptor expressing pathways merge (Panula & Nuutinen, 2013). Obviously, systemic administration of H3 receptor antagonists, which is also the most appropriate route for evaluating mechanisms intended to be clinically relevant, affects all the circuits in the brain in which the H3 receptor is active. The behavioural consequences of systemic administration naturally represents the sum effect of all these targeted brain areas and circuits. Site targeted administration schedules to study the contribution of distinct H3 receptor‐expressing cell types have not yet been applied to address alcohol‐related behaviours. Since these H3 receptor‐expressing cells release many other neurotransmitters regulated by H3 receptors, the role of H3 receptor antagonists in alcohol‐related behaviours is likely due to circuits involving many of these transmitters.

4. ALCOHOL AND HISTAMINE–DOPAMINE INTERACTIONS

The ventral tegmentum, which harbors dopaminergic and GABAergic neurons, is crucial for the development of alcohol‐related behaviours: an injection of the opioid antagonist methylnaloxonium (a non‐selective opioid antagonist) or baclofen (a GABAB receptor agonist) into the ventral tegmental area (VTA) but not into the NAcc decreases alcohol‐induced place preference (Bechtholt & Cunningham, 2005). Wistar rats also self‐administer alcohol into the posterior VTA but not the anterior VTA (Rodd‐Henricks, McKinzie, Crile, Murphy, & McBride, 2000). In the VTA, a single dose of alcohol induces a long‐lasting potentiation of GABAergic synapses in dopaminergic neurons (Melis, Camarini, Ungless, & Bonci, 2002).

Alcohol increases the firing of VTA dopaminergic neurons in both C57BL/6J and DBA/2J mice (Brodie & Appel, 2000). Alcohol also increases postsynaptic GABAA receptor sensitivity and enhances action potential‐independent GABA release onto VTA dopaminergic neurons (Theile, Morikawa, Gonzales, & Morrisett, 2008), which in turn may limit the direct excitation of these neurons. The role of H3 receptors in the regulation of VTA dopaminergic neurons may be complex: Local GABAergic neurons and afferents from the NAcc are potential direct targets of H3 receptor antagonists, since the expression of H3 receptors in NAcc is abundant and VTA GABAergic cells may form the population that expresses H3 receptors. In addition, 5‐HT through 5‐HT2C receptors modulates GABA release on dopaminergic neurons (Theile, Morikawa, Gonzales, & Morrisett, 2009), and H3 receptor agonists inhibit electrically‐evoked 5‐HT release at least in the SN (Threlfell et al., 2004). Although it is possible that one of the key sites of H3 receptor ligands’ action on alcohol‐related behaviours is the VTA, this is unlikely because of the sparsity of H3 receptor radioligand binding and gene expression in this region compared to the SN (Pillot et al., 2002).

During the operant alcohol self‐administration procedure, dopamine release in the NAcc increases in both trained rats and handling controls during placement in the operant chamber, but only in alcohol‐consuming rats during alcohol but not water self‐administration (Doyon et al., 2003). Intraperitoneal alcohol also increases dopamine release in the posterior VTA in rats (Deehan et al., 2016). In mice, alcohol increases dopamine release in the NAcc without affecting histamine release (Nuutinen et al., 2016).

The location of the H3 receptor in many aminergic neurons allows its release from terminals to be directly regulated by histamine and H3 receptor ligands (for a review, see Panula & Nuutinen, 2013). Although in vitro evidence suggests that histamine inhibits the electrically‐evoked release of [3H] dopamine from striatal slices in a manner that is abolished by the H3 receptor antagonist thioperamide and thus may suggest the presence of presynaptic H3 receptors on striatal dopaminergic terminals (Schlicker, Fink, Detzner, & Gothert, 1993), in vivo microdialysis has not revealed an evidence of dopamine release in the striatum by H3 receptor antagonists (Aquino‐Miranda, Escamilla‐Sanchez, Gonzalez‐Pantoja, Bueno‐Nava, & Arias‐Montano, 2016; Nuutinen et al., 2016). The H3 receptor antagonist GSK189254 did not evoke the release of dopamine in the NAcc (Giannoni et al., 2010), and ABT‐239, another H3 receptor antagonist, induced the release of dopamine in the cortex but not the striatum (Fox et al., 2005). Furthermore, the expression of H3 receptor mRNA in the VTA and SN is low in rats and normal humans (Anichtchik, Huotari et al., 2000; Anichtchik, Rinne et al., 2000; Drutel et al., 2001), although H3 receptor radioligand binding is high in the SN (Anichtchik et al., 2001; Anichtchik, Huotari et al., 2000; Pillot et al., 2002). At the cellular level, the expression of H3 receptor mRNA has been reported in the SN, although the transmitter phenotype of the cells was not determined, whereas in the VTA, little if any H3 receptor mRNA was detected (Pillot et al., 2002). Microarray analysis has not verified H3 receptor gene (Hrh3) as one that distinguishes A9 and A10 dopaminergic neurons (Chung et al., 2005), and the gene is not among those which distinguish different clusters of mesencephalic dopaminergic neurons (Poulin et al., 2014).

It is thus unlikely that H3 receptor antagonists would as such be habit‐forming. The histaminergic neuron population may be heterogeneous, since H3 receptor antagonists administered intracerebrally directly to the TMN induce the release of histamine from the prefrontal cortex and nucleus basalis magnocellularis but not from the NAcc or dorsal striatum (Blandina, Munari, Provensi, & Passani, 2012).

5. H3 RECEPTOR, ALCOHOL DRINKING AND CONDITIONED PLACE PREFERENCE

The first report on the possible role of H3 receptors in AUD was the report by Lintunen et al. (2001) on alcohol‐preferring (AA) rats. In this rat line, the levels and turnover of histamine in the brain were significantly higher than those in the Wistar rats or alcohol non‐preferring (ANA) rats, and in the two‐bottle choice self‐administration test, two H3 receptor antagonists, clobenpropit and thioperamide, significantly suppressed alcohol intake, whereas the H1 receptor antagonist mepyramine had no effect on self‐administration. The H3 receptor agonist R‐α‐methylhistamine increased alcohol self‐administration in AA rats, suggesting that H3 receptors regulate this behaviour in a bidirectional manner. This finding was surprising and unexpected and opened up the questions related to the potential mechanisms and clinical use. Interestingly, the AA rats also had higher histamine H3 receptor expression in two relevant brain areas, the primary motor cortex and NAcc, and higher tele‐methylhistamine content in the frontal cortex than that of the ANA rats (Lintunen et al., 2001). Histamine content in AA rat brains was higher than that in ANA rats in the frontal cortex, septum, hippocampus, and mesencephalon (Lintunen et al., 2001). Although the activity of the histaminergic system was clearly higher in AA than in ANA rats, it is not certain that the effect of H3 receptor ligands on alcohol self‐administration is mediated by autoreceptors on projections of TMN histaminergic neurons, because the expression of the H3 receptor is abundant in many different neurons in relevant brain areas (Panula et al., 2015; Panula & Nuutinen, 2013).

The effect of H3 receptor antagonists on alcohol consumption or other AUD‐related behaviours has been reported for a number of H3 receptor antagonists, including thiperamide, clobenpropit, ciproxifan, JNJ‐39220675, JNJ‐10181475, DL77, and ST1283, consisting of both imidazole‐ and non‐imidazole‐based molecules (Bahi, Sadek, Nurulain, Lazewska, & Kiec‐Kononowicz, 2015; Bahi, Sadek, Schwed, Walter, & Stark, 2013; Nuutinen et al., 2011). These studies also utilized a number of different drinking models, suggesting that possible caveats related to a specific method or non‐specific effects of some ligands do not explain the findings.

6. CLINICAL TREATMENT TRIALS WITH H3 RECEPTOR ANTAGONISTS FOR AUD

Since several companies have produced H3 receptor antagonists with high potency, good kinetic properties, and no observed toxicity, two clinical trials have been announced at clinicaltrials.com, but none have yet been initiated or completed. In addition, several companies have developed effective drugs, which have been removed from further development due to adverse side effects or lack of positive effects.

A single centre, randomized, double‐blind, placebo‐controlled parallel group Phase 2 study with bavisant (JNJ 31001074) was announced in 2011 with Janssen Research & Development as sponsor. The intention was to study a primary outcome, the urge to drink. The secondary outcome measures were the number of patients reporting adverse events; abnormal findings from eye examinations were performed as a measure of safety and tolerability, as well as vital signs measurements, electrocardiograms, and clinical laboratory tests. The planned experimental setup included adult (21–62 years) non‐treatment‐seeking currently alcohol‐dependent individuals. In the test setup, the individuals would be shown various computer images and then presented with either a favourite alcohol‐containing drink or water (without drinking the offered drink). Study subjects would have taken one 3 mg tablet of bavisant or matching placebo in the morning of each day. However, the study was withdrawn before enrolment following re‐priorization (Panula et al., 2015).

The outcome of a second trial on pitolisant by Bioprojet were published in 2016. The multisite, double‐blind, placebo‐controlled study, which was withdrawn by the sponsor before recruitment, was planned on male or female moderate or severe Diagnostic and Statistical Manual of Mental Disorders, fifth edition AUD patients 18–65 years of age, who were treatment‐seeking subjects. The planned primary outcome measure was a decrease in the number of monthly heavy drinking days (HDDs). Secondary end‐points included total alcohol consumption from baseline to end of treatment, % of patients without HDDs during the 24 weeks of randomized treatment (RT) phase, % of abstinence days during the RT phase, continuous abstinence duration from baseline during the 24 weeks of RT phase, 4‐week point prevalence abstinence at the end of treatment, improvement in alcohol biomarkers during the 24‐week RT phase, craving during the 24‐week RT phase, Beck depression inventory during the 24‐week RT phase, quality of sleep, % of patients without HDDs during the open label (OL) follow‐up period, quality of life (SF‐12) during the RT phase, and quality of sleep (Pittsburgh Sleep Quality Index) during OL phase. Neither of these prospective clinical trials was cancelled or discontinued because of undesired side effects of lack of efficacy but rather they were withdrawn due to altered company policies.

Based on information on in vivo properties in human subjects available, the most suitable drug for clinical tests in AUD would be AZD5213 developed by Astra‐Zeneca. This compound has shown high occupancy at H3 receptors in human brain, good tolerance after repeated doses (−14 mg·day‐1) and short (about 5 hr) half‐life (Jucaite et al., 2013). The short half‐life is particularly important for an H3 receptor antagonist in clinical use, because drug accumulation in plasma can be significant. The most likely side effects, which include sleep disturbance, may be less prominent than with other H3 receptor drugs.

7. CONCLUDING REMARKS: CURRENT STATE OF RESEARCH AND THE FUTURE

The surprising finding that H3 receptor antagonists can reduce alcohol intake in AA rats has led to a series of rodent studies. These studies have found that several H3 receptor antagonists inhibit alcohol intake in at least three different drinking models and also inhibit alcohol‐induced reward. Similar findings have been obtained in mice lacking H3 receptors. No evidence of habit‐forming properties of H3 receptor antagonists have been reported, although these drugs stimulate the release of several neurotransmitters in different brain regions. Although the H3 receptor is an autoreceptor, which regulates histamine release, its role in regulating several other transmitters including GABA and glutamate renders it possible that histamine itself might not be the key transmitter in th eneuronal circuits involved in AUD. Since the H3 receptor is expressed in many important brain areas, it is not obvious where the effects of H3 receptor antagonists occur that then regulate alcohol‐related behaviours. The most probable site is the cortico‐striato‐mesencephalic system. Alcohol is known to release dopamine in the striatum, and H3 receptor antagonists regulate dopamine signalling in the striatum possibly through receptor oligomers consisting of H3 and dopamine receptors. Experiments on animals in vivo using, for example, optogenetic inhibition or excitation of specific neuronal assemblies in freely behaving animals would be needed to address the potential involvement of these and other areas, for example, the habenula and amygdala. Drug companies have produced potentially useful and safe H3 receptor antagonists for clinical testing. Two clinical trials have been planned to test the use of these drugs to treat AUD. Both have been withdrawn before starting due to company policy reasons. The clinical potential of these drugs is thus still not tested. Such trials would be the obvious next step to open a new area of application.

7.1. Nomenclature of targets and ligands

Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Harding et al., 2018), and are permanently archived in the Concise Guide to PHARMACOLOGY 2017/18 (Alexander, Christopoulos et al., 2017; Alexander, Peters et al., 2017).

CONFLICT OF INTEREST

The author declares no conflicts of interest.

ACKNOWLEDGEMENTS

This research was supported by grants from the Academy of Finland, Sigrid Juselius Foundation, Finnish Fund for Alcohol Research, and Finska Läkaresällskapet.

Panula P. Histamine, histamine H3 receptor, and alcohol use disorder. Br J Pharmacol. 2020;177:634–641. 10.1111/bph.14634

REFERENCES

  1. Abrahao, K. P. , Salinas, A. G. , & Lovinger, D. M. (2017). Alcohol and the brain: Neuronal molecular targets, synapses, and circuits. Neuron, 96, 1223–1238. 10.1016/j.neuron.2017.10.032 [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Alexander, S. P. H. , Christopoulos, A. , Davenport, A. P. , Kelly, E. , Marrion, N. V. , Peters, J. A. , … CGTP Collaborators . (2017). The Concise Guide to pharmacology 2017/18: G protein‐coupled receptors. British Journal of Pharmacology, 174, S17–S129. 10.1111/bph.13878 [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Alexander, S. P. H. , Peters, J. A. , Kelly, E. , Marrion, N. V. , Faccenda, E. , Harding, S. D. , … CGTP Collaborators . (2017). The Concise Guide to PHARMACOLOGY 2017/18: Ligand‐gated ion channels. British Journal of Pharmacology, 174(S1), S130–S159. 10.1111/bph.13879 [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Altshuler, H. L. , Phillips, P. E. , & Feinhandler, D. A. (1980). Alteration of ethanol self‐administration by naltrexone. Life Sciences, 26, 679–688. 10.1016/0024-3205(80)90257-X [DOI] [PubMed] [Google Scholar]
  5. Anichtchik, O. V. , Huotari, M. , Peitsaro, N. , Haycock, J. W. , Mannisto, P. T. , & Panula, P. (2000). Modulation of histamine H‐3 receptors in the brain of 6‐hydroxydopamine‐lesioned rats. European Journal of Neuroscience, 12, 3823–3832. 10.1046/j.1460-9568.2000.00267.x [DOI] [PubMed] [Google Scholar]
  6. Anichtchik, O. V. , Peitsaro, N. , Rinne, J. O. , Kalimo, H. , & Panula, P. (2001). Distribution and modulation of histamine H3 receptors in basal ganglia and frontal cortex of healthy controls and patients with Parkinson's disease. Neurobiology of disease, 8, 707–716. 10.1006/nbdi.2001.0413 [DOI] [PubMed] [Google Scholar]
  7. Anichtchik, O. V. , Rinne, J. O. , Kalimo, H. , & Panula, P. (2000). An altered histaminergic innervation of the substantia nigra in Parkinson's disease. Experimental Neurology, 163, 20–30. 10.1006/exnr.2000.7362 [DOI] [PubMed] [Google Scholar]
  8. Aquino‐Miranda, G. , Escamilla‐Sanchez, J. , Gonzalez‐Pantoja, R. , Bueno‐Nava, A. , & Arias‐Montano, J. A. (2016). Histamine H3 receptor activation inhibits dopamine synthesis but not release or uptake in rat nucleus accumbens. Neuropharmacology, 106, 91–101. 10.1016/j.neuropharm.2015.07.006 [DOI] [PubMed] [Google Scholar]
  9. Bahi, A. , Sadek, B. , Nurulain, S. M. , Lazewska, D. , & Kiec‐Kononowicz, K. (2015). The novel non‐imidazole histamine H3 receptor antagonist DL77 reduces voluntary alcohol intake and ethanol‐induced conditioned place preference in mice. Physiology & Behavior, 151, 189–197. 10.1016/j.physbeh.2015.07.012 [DOI] [PubMed] [Google Scholar]
  10. Bahi, A. , Sadek, B. , Schwed, S. J. , Walter, M. , & Stark, H. (2013). Influence of the novel histamine H(3) receptor antagonist ST1283 on voluntary alcohol consumption and ethanol‐induced place preference in mice. Psychopharmacology, 228, 85–95. 10.1007/s00213-013-3019-7 [DOI] [PubMed] [Google Scholar]
  11. Bechtholt, A. J. , & Cunningham, C. L. (2005). Ethanol‐induced conditioned place preference is expressed through a ventral tegmental area dependent mechanism. Behavioral Neuroscience, 119, 213–223. 10.1037/0735-7044.119.1.213 [DOI] [PubMed] [Google Scholar]
  12. Blandina, P. , Munari, L. , Provensi, G. , & Passani, M. B. (2012). Histamine neurons in the tuberomamillary nucleus: A whole center or distinct subpopulations? Frontiers in Systems Neuroscience, 6, 33. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Brodie, M. S. , & Appel, S. B. (2000). Dopaminergic neurons in the ventral tegmental area of C57BL/6J and DBA/2J mice differ in sensitivity to ethanol excitation. Alcoholism, Clinical and Experimental Research, 24, 1120–1124. 10.1111/j.1530-0277.2000.tb04658.x [DOI] [PubMed] [Google Scholar]
  14. Chung, C. Y. , Seo, H. , Sonntag, K. C. , Brooks, A. , Lin, L. , & Isacson, O. (2005). Cell type‐specific gene expression of midbrain dopaminergic neurons reveals molecules involved in their vulnerability and protection. Human Molecular Genetics, 14, 1709–1725. 10.1093/hmg/ddi178 [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Contet, C. , Kieffer, B. L. , & Befort, K. (2004). Mu opioid receptor: A gateway to drug addiction. Current Opinion in Neurobiology, 14, 370–378. 10.1016/j.conb.2004.05.005 [DOI] [PubMed] [Google Scholar]
  16. Crabbe, J. C. , Phillips, T. J. , Feller, D. J. , Hen, R. , Wenger, C. D. , Lessov, C. N. , & Schafer, G. L. (1996). Elevated alcohol consumption in null mutant mice lacking 5‐HT1B serotonin receptors. Nature Genetics, 14, 98–101. [DOI] [PubMed] [Google Scholar]
  17. Cunningham, C. L. , Howard, M. A. , Gill, S. J. , Rubinstein, M. , Low, M. J. , & Grandy, D. K. (2000). Ethanol‐conditioned place preference is reduced in dopamine D2 receptor‐deficient mice. Pharmacology, Biochemistry, and Behavior, 67, 693–699. 10.1016/S0091-3057(00)00414-7 [DOI] [PubMed] [Google Scholar]
  18. de Bruin, N. M. , McCreary, A. C. , van Loevezijn, A. , de Vries, T. J. , Venhorst, J. , van Drimmelen, M. , & Kruse, C. G. (2013). A novel highly selective 5‐HT6 receptor antagonist attenuates ethanol and nicotine seeking but does not affect inhibitory response control in Wistar rats. Behavioural Brain Research, 236, 157–165. 10.1016/j.bbr.2012.08.048 [DOI] [PubMed] [Google Scholar]
  19. de la Cour, C. , Sorensen, G. , Wortwein, G. , Weikop, P. , Dencker, D. , Fink‐Jensen, A. , & Molander, A. (2015). Enhanced self‐administration of alcohol in muscarinic acetylcholine M4 receptor knockout mice. European Journal of Pharmacology, 746, 1–5. 10.1016/j.ejphar.2014.10.050 [DOI] [PubMed] [Google Scholar]
  20. Deehan, G. A. Jr. , Knight, C. P. , Waeiss, R. A. , Engleman, E. A. , Toalston, J. E. , McBride, W. J. , … Rodd, Z. A. (2016). Peripheral administration of ethanol results in a correlated increase in dopamine and serotonin within the posterior ventral tegmental area. Alcohol and Alcoholism, 51, 535–540. 10.1093/alcalc/agw037 [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Doyon, W. M. , York, J. L. , Diaz, L. M. , Samson, H. H. , Czachowski, C. L. , & Gonzales, R. A. (2003). Dopamine activity in the nucleus accumbens during consummatory phases of oral ethanol self‐administration. Alcoholism, Clinical and Experimental Research, 27, 1573–1582. 10.1097/01.ALC.0000089959.66222.B8 [DOI] [PubMed] [Google Scholar]
  22. Drutel, G. , Peitsaro, N. , Karlstedt, K. , Wieland, K. , Smit, M. J. , Timmerman, H. , … Leurs, R. (2001). Identification of rat H3 receptor isoforms with different brain expression and signaling properties. Molecular Pharmacology, 59, 1–8. [PubMed] [Google Scholar]
  23. El‐Ghundi, M. , George, S. R. , Drago, J. , Fletcher, P. J. , Fan, T. , Nguyen, T. , … O'Dowd, B. F. (1998). Disruption of dopamine D1 receptor gene expression attenuates alcohol‐seeking behavior. European Journal of Pharmacology, 353, 149–158. 10.1016/S0014-2999(98)00414-2 [DOI] [PubMed] [Google Scholar]
  24. Ericson, H. , Blomqvist, A. , & Kohler, C. (1991). Origin of neuronal inputs to the region of the tuberomammillary nucleus of the rat brain. The Journal of Comparative Neurology, 311, 45–64. 10.1002/cne.903110105 [DOI] [PubMed] [Google Scholar]
  25. Fox, G. B. , Esbenshade, T. A. , Pan, J. B. , Browman, K. E. , Zhang, M. , Ballard, M. E. , … Hancock, A. A. (2005). Selective H3 receptor (H3R) blockade: Broad efficacy in cognition and schizophrenia. Inflammation Research, 54(Suppl 1), S23–S24. [DOI] [PubMed] [Google Scholar]
  26. Giannoni, P. , Medhurst, A. D. , Passani, M. B. , Giovannini, M. G. , Ballini, C. , Corte, L. D. , & Blandina, P. (2010). Regional differential effects of the novel histamine H3 receptor antagonist 6‐[(3‐cyclobutyl‐2,3,4,5‐tetrahydro‐1H‐3‐benzazepin‐7‐yl)oxy]‐N‐methyl‐3‐pyridine carboxamide hydrochloride (GSK189254) on histamine release in the central nervous system of freely moving rats. The Journal of Pharmacology and Experimental Therapeutics, 332, 164–172. 10.1124/jpet.109.158444 [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Haas, H. , & Panula, P. (2003). The role of histamine and the tuberomamillary nucleus in the nervous system. Nature Reviews Neuroscience, 4, 121–130. 10.1038/nrn1034 [DOI] [PubMed] [Google Scholar]
  28. Harding, S. D. , Sharman, J. L. , Faccenda, E. , Southan, C. , Pawson, A. J. , Ireland, S. , … NC‐IUPHAR (2018). The IUPHAR/BPS Guide to PHARMACOLOGY in 2018: Updates and expansion to encompass the new guide to IMMUNOPHARMACOLOGY. Nucleic Acids Research, 46, D1091–D1106. 10.1093/nar/gkx1121 [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Hungund, B. L. , Szakall, I. , Adam, A. , Basavarajappa, B. S. , & Vadasz, C. (2003). Cannabinoid CB1 receptor knockout mice exhibit markedly reduced voluntary alcohol consumption and lack alcohol‐induced dopamine release in the nucleus accumbens. Journal of Neurochemistry, 84, 698–704. 10.1046/j.1471-4159.2003.01576.x [DOI] [PubMed] [Google Scholar]
  30. Inagaki, N. , Yamatodani, A. , Ando‐Yamamoto, M. , Tohyama, M. , Watanabe, T. , & Wada, H. (1988). Organization of histaminergic fibers in the rat brain. The Journal of Comparative Neurology, 273, 283–300. 10.1002/cne.902730302 [DOI] [PubMed] [Google Scholar]
  31. Jin, C. Y. , Kalimo, H. , & Panula, P. (2002). The histaminergic system in human thalamus: Correlation of innervation to receptor expression. European Journal of Neuroscience, 15, 1125–1138. 10.1046/j.1460-9568.2002.01951.x [DOI] [PubMed] [Google Scholar]
  32. Jin, C. Y. , & Panula, P. (2005). The laminar histamine receptor system in human prefrontal cortex suggests multiple levels of histaminergic regulation. Neuroscience, 132, 137–149. 10.1016/j.neuroscience.2004.12.017 [DOI] [PubMed] [Google Scholar]
  33. Jucaite, A. , Takano, A. , Bostrom, E. , Jostell, K. G. , Stenkrona, P. , Halldin, C. , … Nyberg, S. (2013). AZD5213: a novel histamine H3 receptor antagonist permitting high daytime and low nocturnal H3 receptor occupancy, a PET study in human subjects. The International Journal of Neuropsychopharmacology, 16, 1231–1239. 10.1017/S1461145712001411 [DOI] [PubMed] [Google Scholar]
  34. Kononoff Vanhanen, J. , Nuutinen, S. , Tuominen, M. , & Panula, P. (2016). Histamine H3 receptor regulates sensorimotor gating and dopaminergic signaling in the striatum. The Journal of Pharmacology and Experimental Therapeutics, 357, 264–272. 10.1124/jpet.115.230771 [DOI] [PubMed] [Google Scholar]
  35. Koob, G. F. , & Volkow, N. D. (2016). Neurobiology of addiction: A neurocircuitry analysis. Lancet Psychiatry, 3, 760–773. 10.1016/S2215-0366(16)00104-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Korpi, E. R. , den Hollander, B. , Farooq, U. , Vashchinkina, E. , Rajkumar, R. , Nutt, D. J. , … Dawe, G. S. (2015). Mechanisms of action and persistent neuroplasticity by drugs of abuse. Pharmacological Reviews, 67, 872–1004. 10.1124/pr.115.010967 [DOI] [PubMed] [Google Scholar]
  37. Lindholm, S. , Ploj, K. , Franck, J. , & Nylander, I. (2000). Repeated ethanol administration induces short‐ and long‐term changes in enkephalin and dynorphin tissue concentrations in rat brain. Alcohol, 22, 165–171. 10.1016/S0741-8329(00)00118-X [DOI] [PubMed] [Google Scholar]
  38. Lintunen, M. , Hyytia, P. , Sallmen, T. , Karlstedt, K. , Tuomisto, L. , Leurs, R. , … Panula, P. (2001). Increased brain histamine in an alcohol‐preferring rat line and modulation of ethanol consumption by H(3) receptor mechanisms. The FASEB Journal, 15, 1074–1076. 10.1096/fj.00-0545fje [DOI] [PubMed] [Google Scholar]
  39. Marinelli, P. W. , Bai, L. , Quirion, R. , & Gianoulakis, C. (2005). A microdialysis profile of Met‐enkephalin release in the rat nucleus accumbens following alcohol administration. Alcoholism, Clinical and Experimental Research, 29, 1821–1828. 10.1097/01.alc.0000183008.62955.2e [DOI] [PubMed] [Google Scholar]
  40. Matthes, H. W. , Maldonado, R. , Simonin, F. , Valverde, O. , Slowe, S. , Kitchen, I. , … Kieffer, B. L. (1996). Loss of morphine‐induced analgesia, reward effect and withdrawal symptoms in mice lacking the mu‐opioid‐receptor gene. Nature, 383, 819–823. 10.1038/383819a0 [DOI] [PubMed] [Google Scholar]
  41. Melis, M. , Camarini, R. , Ungless, M. A. , & Bonci, A. (2002). Long‐lasting potentiation of GABAergic synapses in dopamine neurons after a single in vivo ethanol exposure. The Journal of Neuroscience, 22, 2074–2082. 10.1523/JNEUROSCI.22-06-02074.2002 [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Naassila, M. , Pierrefiche, O. , Ledent, C. , & Daoust, M. (2004). Decreased alcohol self‐administration and increased alcohol sensitivity and withdrawal in CB1 receptor knockout mice. Neuropharmacology, 46, 243–253. 10.1016/j.neuropharm.2003.09.002 [DOI] [PubMed] [Google Scholar]
  43. Nuutinen, S. , Karlstedt, K. , Aitta‐Aho, T. , Korpi, E. R. , & Panula, P. (2010). Histamine and H3 receptor‐dependent mechanisms regulate ethanol stimulation and conditioned place preference in mice. Psychopharmacology, 208, 75–86. 10.1007/s00213-009-1710-5 [DOI] [PubMed] [Google Scholar]
  44. Nuutinen, S. , Lintunen, M. , Vanhanen, J. , Ojala, T. , Rozov, S. , & Panula, P. (2011). Evidence for the role of histamine H3 receptor in alcohol consumption and alcohol reward in mice. Neuropsychopharmacology, 36, 2030–2040. 10.1038/npp.2011.90 [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Nuutinen, S. , Maki, T. , Rozov, S. , Backstrom, P. , Hyytia, P. , Piepponen, P. , & Panula, P. (2016). Histamine H3 receptor antagonist decreases cue‐induced alcohol reinstatement in mice. Neuropharmacology, 106, 156–163. 10.1016/j.neuropharm.2015.06.006 [DOI] [PubMed] [Google Scholar]
  46. Panula, P. , Airaksinen, M. S. , Pirvola, U. , & Kotilainen, E. (1990). A histamine‐containing neuronal system in human brain. Neuroscience, 34, 127–132. 10.1016/0306-4522(90)90307-P [DOI] [PubMed] [Google Scholar]
  47. Panula, P. , Chazot, P. L. , Cowart, M. , Gutzmer, R. , Leurs, R. , Liu, W. L. , … Haas, H. L. (2015). International Union of Basic and Clinical Pharmacology. XCVIII. Histamine receptors. Pharmacological Reviews, 67, 601–655. 10.1124/pr.114.010249 [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Panula, P. , & Nuutinen, S. (2013). The histaminergic network in the brain: Basic organization and role in disease. Nature Reviews. Neuroscience, 14, 472–487. 10.1038/nrn3526 [DOI] [PubMed] [Google Scholar]
  49. Panula, P. , Pirvola, U. , Auvinen, S. , & Airaksinen, M. S. (1989). Histamine‐immunoreactive nerve fibers in the rat brain. Neuroscience, 28, 585–610. 10.1016/0306-4522(89)90007-9 [DOI] [PubMed] [Google Scholar]
  50. Panula, P. , Sundvik, M. , & Karlstedt, K. (2014). Developmental roles of brain histamine. Trends in Neurosciences, 37, 159–168. 10.1016/j.tins.2014.01.001 [DOI] [PubMed] [Google Scholar]
  51. Panula, P. , Yang, H. Y. , & Costa, E. (1984). Histamine‐containing neurons in the rat hypothalamus. Proceedings of the National Academy of Sciences of the United States of America, 81, 2572–2576. 10.1073/pnas.81.8.2572 [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Pillot, C. , Heron, A. , Cochois, V. , Tardivel‐Lacombe, J. , Ligneau, X. , Schwartz, J. C. , & Arrang, J. M. (2002). A detailed mapping of the histamine H(3) receptor and its gene transcripts in rat brain. Neuroscience, 114, 173–193. 10.1016/S0306-4522(02)00135-5 [DOI] [PubMed] [Google Scholar]
  53. Poulin, J. F. , Zou, J. , Drouin‐Ouellet, J. , Kim, K. Y. , Cicchetti, F. , & Awatramani, R. B. (2014). Defining midbrain dopaminergic neuron diversity by single‐cell gene expression profiling. Cell Reports, 9, 930–943. 10.1016/j.celrep.2014.10.008 [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Rodd‐Henricks, Z. A. , McKinzie, D. L. , Crile, R. S. , Murphy, J. M. , & McBride, W. J. (2000). Regional heterogeneity for the intracranial self‐administration of ethanol within the ventral tegmental area of female Wistar rats. Psychopharmacology, 149, 217–224. 10.1007/s002139900347 [DOI] [PubMed] [Google Scholar]
  55. Sallmen, T. , Lozada, A. F. , Anichtchik, O. V. , Beckman, A. L. , & Panula, P. (2003). Increased brain histamine H3 receptor expression during hibernation in golden‐mantled ground squirrels. BMC Neuroscience, 4, 24 10.1186/1471-2202-4-24 [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Schlicker, E. , Fink, K. , Detzner, M. , & Gothert, M. (1993). Histamine inhibits dopamine release in the mouse striatum via presynaptic H3 receptors. Journal of Neural Transmission. General Section, 93, 1–10. [DOI] [PubMed] [Google Scholar]
  57. Stromberg, M. F. , Casale, M. , Volpicelli, L. , Volpicelli, J. R. , & O'Brien, C. P. (1998). A comparison of the effects of the opioid antagonists naltrexone, naltrindole, and beta‐funaltrexamine on ethanol consumption in the rat. Alcohol, 15, 281–289. 10.1016/S0741-8329(97)00131-6 [DOI] [PubMed] [Google Scholar]
  58. Sundvik, M. , Kudo, H. , Toivonen, P. , Rozov, S. , Chen, Y. C. , & Panula, P. (2011). The histaminergic system regulates wakefulness and orexin/hypocretin neuron development via histamine receptor H1 in zebrafish. The FASEB Journal, 25, 4338–4347. 10.1096/fj.11-188268 [DOI] [PubMed] [Google Scholar]
  59. Tardivel‐Lacombe, J. , Rouleau, A. , Heron, A. , Morisset, S. , Pillot, C. , Cochois, V. , … Arrang, J. M. (2000). Cloning and cerebral expression of the guinea pig histamine H3 receptor: Evidence for two isoforms. NeuroReport, 11, 755–759. 10.1097/00001756-200003200-00020 [DOI] [PubMed] [Google Scholar]
  60. Theile, J. W. , Morikawa, H. , Gonzales, R. A. , & Morrisett, R. A. (2008). Ethanol enhances GABAergic transmission onto dopamine neurons in the ventral tegmental area of the rat. Alcoholism, Clinical and Experimental Research, 32, 1040–1048. 10.1111/j.1530-0277.2008.00665.x [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Theile, J. W. , Morikawa, H. , Gonzales, R. A. , & Morrisett, R. A. (2009). Role of 5‐hydroxytryptamine2C receptors in Ca2+‐dependent ethanol potentiation of GABA release onto ventral tegmental area dopamine neurons. The Journal of Pharmacology and Experimental Therapeutics, 329, 625–633. 10.1124/jpet.108.147793 [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Threlfell, S. , Cragg, S. J. , Kallo, I. , Turi, G. F. , Coen, C. W. , & Greenfield, S. A. (2004). Histamine H3 receptors inhibit serotonin release in substantia nigra pars reticulata. The Journal of Neuroscience, 24, 8704–8710. 10.1523/JNEUROSCI.2690-04.2004 [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Vuoristo‐Myllys, S. , Lahti, J. , Alho, H. , & Julkunen, J. (2013). Predictors of dropout in an outpatient treatment for problem drinkers including cognitive‐behavioral therapy and the opioid antagonist naltrexone. Journal of Studies on Alcohol and Drugs, 74, 894–901. 10.15288/jsad.2013.74.894 [DOI] [PubMed] [Google Scholar]
  64. Vuoristo‐Myllys, S. , Lipsanen, J. , Lahti, J. , Kalska, H. , & Alho, H. (2014). Outcome predictors for problem drinkers treated with combined cognitive behavioral therapy and naltrexone. The American Journal of Drug and Alcohol Abuse, 40, 103–110. 10.3109/00952990.2013.853074 [DOI] [PubMed] [Google Scholar]
  65. Watanabe, T. , Taguchi, Y. , Shiosaka, S. , Tanaka, J. , Kubota, H. , Terano, Y. , … Wada, H. (1984). Distribution of the histaminergic neuron system in the central nervous system of rats; A fluorescent immunohistochemical analysis with histidine decarboxylase as a marker. Brain Research, 295, 13–25. 10.1016/0006-8993(84)90811-4 [DOI] [PubMed] [Google Scholar]
  66. Zhou, Z. , Karlsson, C. , Liang, T. , Xiong, W. , Kimura, M. , Tapocik, J. D. , … Goldman, D. (2013). Loss of metabotropic glutamate receptor 2 escalates alcohol consumption. Proceedings of the National Academy of Sciences of the United States of America, 110, 16963–16968. 10.1073/pnas.1309839110 [DOI] [PMC free article] [PubMed] [Google Scholar]

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