**2. The dopamine system: a potential treatment target for alcohol dependence**

#### **2.1. Dopamine D2 receptor antagonists**

Traditional dopamine D2 receptor antagonists (so‐called neuroleptics, first‐generation antipsychotic drugs or typical antipsychotic drugs) are primary used for the treatment of psychosis, schizophrenia and bipolar disorder [11] based on their ability to counteract a heightened dopamine activity in the brain. It should also be mentioned that these typical antipsychotic agents might have effects on other receptors including dopamine D1, 5HT2 and alpha1 receptors. As reviewed above, the acute reinforcing effects of addictive drugs, including alcohol, could be mediated by increased dopamine release in the NAc, activating dopamine D2 receptors [71, 27, 30]. Thus, traditional dopamine D2 receptor antagonists have been evaluated as potential treatment targets for alcohol dependence based on the hypothesis that they are expected to block the rewarding effects of alcohol.

#### *2.1.1. Preclinical evidence for the use of dopamine D2 receptor antagonists to attenuate alcohol‐mediated behaviours*

The hypothesis that dopamine D2 receptor antagonists have the ability to attenuate alcohol‐ mediated behaviours is supported by rodent studies showing that both haloperidol and pimozide attenuate alcohol‐induced locomotor stimulation [129] and that these compounds as well as fluphenazine, decrease alcohol‐seeking behaviour and operant self‐administration [130–132]. These findings are further substantiated by the data showing that peripheral administration of the dopamine D2 receptor antagonist fluphenazine decreased responding for alcohol, without affecting responses for water in rats [133]. In addition, haloperiodol dose‐ dependently reduced operant self‐administration of alcohol in rats [134] as well as decreased alcohol presentations in the self‐administration model [132]. Supportively, low doses of dopamine D2 receptor antagonists inhibit the rewarding properties of other drugs of abuse in rats [135, 42, 136]. It should be noted that some studies have shown contradicting effects [137– 139], indicating that the role of dopamine in alcohol‐mediated behaviours in complex.

1990s, a polymorphism in the dopamine D2 receptor gene was found to be associated with alcohol dependence [119]. Several studies have since then tried to replicate this association, but the outcome has been inconsistent (for review, see [120]). Although associations have been found between polymorphism of the dopamine D4 gene and alcohol craving, binge drinking as well as novelty seeking (which is a known personality trait important for drinking behaviour in patients with alcohol dependence) [121–123], no positive associations between dopamine D4 receptor genes and alcohol dependence *per se* have been established (for review, see [120]).

Released dopamine into the synaptic cleft is eliminated by catechol‐O‐methyltransferase (COMT) metabolism as well as reuptake by dopamine transporter (DAT). Studies have shown that DAT polymorphism is associated with alcohol withdrawal symptoms as well as with paternal history of alcohol dependence rather than alcohol dependence *per se* [124, 125]. The risk of developing late onset alcohol dependence (especially in males) as well as the co‐ dependence of alcohol and nicotine is associated with polymorphism in COMT [126–128]. Albeit cumulative evidence shows association between polymorphisms in various dopamine‐ related genes and behaviours associated with alcohol dependence, the findings are inconclu‐ sive and therefore, the conclusions from these human genetic studies are limited and remain

**2. The dopamine system: a potential treatment target for alcohol**

Traditional dopamine D2 receptor antagonists (so‐called neuroleptics, first‐generation antipsychotic drugs or typical antipsychotic drugs) are primary used for the treatment of psychosis, schizophrenia and bipolar disorder [11] based on their ability to counteract a heightened dopamine activity in the brain. It should also be mentioned that these typical antipsychotic agents might have effects on other receptors including dopamine D1, 5HT2 and alpha1 receptors. As reviewed above, the acute reinforcing effects of addictive drugs, including alcohol, could be mediated by increased dopamine release in the NAc, activating dopamine D2 receptors [71, 27, 30]. Thus, traditional dopamine D2 receptor antagonists have been evaluated as potential treatment targets for alcohol dependence based on the hypothesis that

*2.1.1. Preclinical evidence for the use of dopamine D2 receptor antagonists to attenuate alcohol‐mediated*

The hypothesis that dopamine D2 receptor antagonists have the ability to attenuate alcohol‐ mediated behaviours is supported by rodent studies showing that both haloperidol and pimozide attenuate alcohol‐induced locomotor stimulation [129] and that these compounds as well as fluphenazine, decrease alcohol‐seeking behaviour and operant self‐administration [130–132]. These findings are further substantiated by the data showing that peripheral

controversial.

**dependence**

*behaviours*

**2.1. Dopamine D2 receptor antagonists**

88 Recent Advances in Drug Addiction Research and Clinical Applications

they are expected to block the rewarding effects of alcohol.

Studies elucidating the underlying mechanism of action of the complex dopamine–alcohol interaction have been conducted. Experiments exploring the role of accumbal dopamine receptors in alcohol‐mediated behaviours showed that intra‐NAc administration of first‐ generation antipsychotic drugs including fluphenazine or raclopride decreased alcohol self‐ administration in rats [133] as well as the total responding for alcohol [140] and reduced the total responding by decreasing time course and response rate for alcohol self‐administration in rats [141]. On the other hand, local administration of the dopamine D2 receptor antagonist, sulpiride, into the anterior VTA did not alter alcohol nor sucrose intake in high‐alcohol‐ preferring rats [142]. It should also be mentioned that accumbal dopamine D1 receptor might regulate alcohol‐induced reward. Indeed, intra‐NAc infusion of a dopamine D1 receptor antagonist (SCH23390 or ecopipam) decreased alcohol‐mediated behaviours in rats [141, 143]. Collectively, these data indicate that the dopamine D2 as well as D1 receptors within the NAc regulate alcohol reinforcement.

#### *2.1.2. Clinical evidence for the use of dopamine D2 antagonists for the treatment of alcohol dependence*

Based on the preclinical evidence of a reduction in alcohol consumption via blockade of dopamine D2 receptors, the potential of dopamine D2 antagonists as a pharmacotherapy for alcohol dependence has been investigated in clinical populations.

Dopamine D2 receptor antagonists have been studied in human laboratory studies involving alcohol administration in dependent individuals and found to be effective in reducing craving. In a laboratory study involving 16 individuals with alcohol abuse and/or dependence, the D2 antagonist haloperidol was compared to placebo. The results of this small study demonstrated that haloperidol significantly decreased measures of craving, reduced impulsivity, and the amounts of alcohol ingested [144]. The dopamine D2 antagonist flupenthixol has also been evaluated in a clinical study of 281 recently detoxified alcohol‐dependent patients [145]. The results demonstrated that treatment with the depot formulation of flupenthixol led to a significant increase in rates of relapse (85.2% on active treatment compared with 62.5% on placebo). A major concern with flupenthixol is results from studies demonstrating an increase in the risk of relapse in rodents as well as humans [146], an effect preferentially observed in males [147]. Overall, the clinical utility of atypical antipsychotics has shown to be of some benefit in patients suffering from alcohol dependence and a concomitant psychiatric diagnosis including schizophrenia [148, 149]. A major challenge, however, with the first‐generation antipsychotic drugs is their severe side effect profile including extrapyramidal symptoms, sedation, cognitive impairment, neuroleptic malignant syndrome, which have limited their use in research and in turn its clinical utility in treating alcohol dependence [150, 151].

#### **2.2. Atypical dopamine D2 receptor antagonists**

The newer generations of dopamine D2 receptor antagonists (so‐called atypical antipsychotics or second generation antipsychotic drugs) have a broader pharmacological profile since they target several dopamine receptors, including D1, D3, D4 and D5, as well as various other neurotransmitter systems including 5‐HT, muscarinic acetylcholine and histamine receptors. These atypical antipsychotics have a significantly improved side effect profile compared to the traditional first generation of dopamine D2 antagonists. Thus, there has been a renewed interest in evaluating these medications as potential treatment for alcohol dependence with the assumption that the atypical antipsychotics might reduce craving and consumption of alcohol without the substantial adverse effect profile [152]. Furthermore, they are clinically used for alcohol‐dependent patients during the acute detoxification phase to prevent agitation, hallucinations and delirium tremens [153].

#### *2.2.1. Preclinical evidence for the use of atypical dopamine D2 receptor antagonists (i.e. atypical antipsychotics) to attenuate alcohol‐mediated behaviours*

The hypothesis that atypical antipsychotics may decrease alcohol intake are supported by two separate studies with risperidone and olanzapine in high‐alcohol‐preferring rats [154, 155]. Furthermore, remoxipride decreases the number of alcohol presentations per session in rats by inducing an early termination of the alcohol‐drinking bout during the self‐administration session [132] and repeated systemic administration of paliperidone decreased the acquisition of alcohol consumption in high‐alcohol‐preferring P rats [156]. In addition, a recent study, comparing the effect of the atypical antipsychotic drug clozapine to that of the traditional dopamine D2 receptor antagonist haloperidol, showed that clozapine but not haloperidol attenuated the initiation of alcohol drinking and development of alcohol preference in high‐ alcohol‐preferring rats [157]. Neither compound had an effect on maintenance of chronic alcohol drinking [157], which is in line with a study showing that clozapine did not reduce alcohol consumption in alcohol‐preferring rats [155].

#### *2.2.2. Clinical evidence for the use of atypical dopamine D2 antagonists for the treatment of alcohol dependence*

The atypical antipsychotic tiapride has been found to be efficacious in reducing alcohol drinking two placebo‐controlled clinical trials [158, 159]. A small study in twenty alcohol‐ dependent individuals, with significant levels of anxiety or depression, showed that tiapride treatment causes a reduced alcohol intake as well as prolonged periods of abstinence [158]. In the largest of the studies [159], 100 recently abstinent alcohol‐dependent patients were randomized to 300 mg of tiapride or placebo for a 3‐month treatment period. This study showed that patients receiving medication had higher rates of abstinence and improved on an array of health care outcomes.

Another atypical antipsychotic drug, quetiapine, has been evaluated in a case study [160] and an open‐label study [161] in patients with alcohol dependence and comorbid psychiatric diagnosis. Both studies demonstrated that quetiapine was well tolerated and in the latter study, the medication not only reduced alcohol consumption and overall psychiatric symptom intensity but also significantly reduced craving. A double‐blind placebo‐controlled study by Kampman and colleagues evaluated the effect of quetiapine and found that the medication was well tolerated and clinically effective in reducing drinking [162]. The effect of medication was found to be stronger in individuals with a more severe disease phenotype. It should, however, be noted that more recent clinical trials using the extended release formulation of quetiapine [163, 164] failed to replicate the clinical findings of the previous studies.

In a retrospective study of 151 schizophrenic patients with alcohol dependence, 36 patients received the atypical antipsychotic medication clozapine. At the 6‐month follow‐up, 79% of the patients on clozapine were in remission from a diagnosis of alcohol dependence, while approximately 33% of those not taking clozapine were in remission [148].

Olanzapine, another example of a second generation of antipsychotics, has been evaluated in a human cue‐craving study, where the compound reduced the urge to drink post‐exposure to alcohol cues, without affecting the rewarding effects of alcohol following the consumption of a priming dose of alcohol [152]. Based on this clinical finding and the knowledge that olanza‐ pine also has a high affinity for the D4 receptors, it was hypothesized whether the dopamine receptor D4 gene maybe involved in meditating its clinical effects. In a subsequent pharma‐ cogenetic, 12‐weeks placebo‐controlled trial in heavy social drinker olanzapine was evaluated in 67 individuals [165] showing that those individuals with the dopamine D4 receptor 7 repeat allele (a polymorphism of the dopamine D4 receptor gene) reported a greater reduction in cue‐ induced craving and alcohol consumption compared to individuals with the short allele. These data are supported by the findings that olanzapine reduces craving for alcohol at baseline for both individuals with the DRD4 shorter and longer allele, but only reduces craving after exposure to alcohol cues and after a priming dose of alcohol for individuals with the DRD4 longer allele [166]. Overall, the results from studies evaluating olanzapine as a potential medication for alcohol dependence have provided evidence of a marginal effect restricted to a sub population of patients (with the longer dopamine D4 receptor allele).

In conclusion, although some clinical trials with atypical antipsychotics in alcohol‐dependent patients show promising results, a recent systemic review of atypical antipsychotics, a heterogeneous class of drugs [167] has demonstrated inconsistent clinical response across studies on these compounds effects on alcohol‐related parameters. The clinical use of atypical antipyschotics for treatment of alcohol dependence might also be limited by their side effects profile, even though it is substantially improved compared to the typical antipsychotics (for review see [168]).

#### **2.3. Dopamine D2 agonists**

**2.2. Atypical dopamine D2 receptor antagonists**

90 Recent Advances in Drug Addiction Research and Clinical Applications

hallucinations and delirium tremens [153].

*antipsychotics) to attenuate alcohol‐mediated behaviours*

alcohol consumption in alcohol‐preferring rats [155].

*dependence*

array of health care outcomes.

The newer generations of dopamine D2 receptor antagonists (so‐called atypical antipsychotics or second generation antipsychotic drugs) have a broader pharmacological profile since they target several dopamine receptors, including D1, D3, D4 and D5, as well as various other neurotransmitter systems including 5‐HT, muscarinic acetylcholine and histamine receptors. These atypical antipsychotics have a significantly improved side effect profile compared to the traditional first generation of dopamine D2 antagonists. Thus, there has been a renewed interest in evaluating these medications as potential treatment for alcohol dependence with the assumption that the atypical antipsychotics might reduce craving and consumption of alcohol without the substantial adverse effect profile [152]. Furthermore, they are clinically used for alcohol‐dependent patients during the acute detoxification phase to prevent agitation,

*2.2.1. Preclinical evidence for the use of atypical dopamine D2 receptor antagonists (i.e. atypical*

The hypothesis that atypical antipsychotics may decrease alcohol intake are supported by two separate studies with risperidone and olanzapine in high‐alcohol‐preferring rats [154, 155]. Furthermore, remoxipride decreases the number of alcohol presentations per session in rats by inducing an early termination of the alcohol‐drinking bout during the self‐administration session [132] and repeated systemic administration of paliperidone decreased the acquisition of alcohol consumption in high‐alcohol‐preferring P rats [156]. In addition, a recent study, comparing the effect of the atypical antipsychotic drug clozapine to that of the traditional dopamine D2 receptor antagonist haloperidol, showed that clozapine but not haloperidol attenuated the initiation of alcohol drinking and development of alcohol preference in high‐ alcohol‐preferring rats [157]. Neither compound had an effect on maintenance of chronic alcohol drinking [157], which is in line with a study showing that clozapine did not reduce

*2.2.2. Clinical evidence for the use of atypical dopamine D2 antagonists for the treatment of alcohol*

The atypical antipsychotic tiapride has been found to be efficacious in reducing alcohol drinking two placebo‐controlled clinical trials [158, 159]. A small study in twenty alcohol‐ dependent individuals, with significant levels of anxiety or depression, showed that tiapride treatment causes a reduced alcohol intake as well as prolonged periods of abstinence [158]. In the largest of the studies [159], 100 recently abstinent alcohol‐dependent patients were randomized to 300 mg of tiapride or placebo for a 3‐month treatment period. This study showed that patients receiving medication had higher rates of abstinence and improved on an

Another atypical antipsychotic drug, quetiapine, has been evaluated in a case study [160] and an open‐label study [161] in patients with alcohol dependence and comorbid psychiatric diagnosis. Both studies demonstrated that quetiapine was well tolerated and in the latter study, the medication not only reduced alcohol consumption and overall psychiatric symptom

As described previously, in vivo microdialysis studies rodent and imaging studies in individ‐ uals with alcohol dependence have demonstrated that chronic exposure to alcohol induce a dopamine deficit state. Thus, it is logical to hypothesize that a dopamine agonist would substitute for this dopaminergic dysfunction during alcohol dependence and alleviate the associated depression‐like symptoms and craving for alcohol.

#### *2.3.1. Preclinical evidence for the use of dopamine agonists to attenuate alcohol‐mediated behaviours*

The potential of dopamine D2 agonists to regulate alcohol‐mediated behaviours is support‐ ed by a study showing that apomorphine, dose‐dependently reduces operant self‐adminis‐ tration as well as decreases momentary response rates for alcohol in rats [134] and that SDZ‐ 205‐152, a synthetic‐mixed D1/D2 dopamine receptor agonist dose‐dependently reduces self‐ administration of alcohol, but not water, in rats [169]. Moreover, cabergoline, a dopamine D2 receptor agonist, decreased alcohol intake, relapse drinking as well as alcohol‐seeking behaviour in rodents [170]. In addition, low doses of bromocriptine produced a significant, dose‐dependent shift in decreasing the preference for alcohol while enhancing water consumption [171], indicating that the compound at lower doses preferentially augment autoreceptor function, leading to decreased dopamine turnover with a blunted response to the rewarding effects of alcohol as a result. Studies with intra‐NAc administration of quinpirole, further indicating that D2 receptors are involved in a biphasic effect on alcohol self‐administration, by showing that low doses of the agonist increase, whereas higher doses decrease, self‐administration of alcohol [141] (but see also [140]). A study has also investi‐ gated the effect of dopamine D2 receptor agonist administration into VTA on alcohol intake. This study showed that microinjection of either quinpirole or quinelorane, into the anterior part of the VTA dose‐dependently decreased alcohol, but not sucrose, intake in alcohol‐ preferring rats [142]. In support are the data showing that local administration of cabergo‐ line into the VTA reduced alcohol‐seeking behaviour in rats [170]. These data are contradictory to the findings showing that the dopamine D2 receptor antagonist into the anterior VTA did not alter alcohol intake in high‐alcohol‐preferring rats [142]. Therefore, mechanisms regulating alcohol reinforcement might be different in selectively breed high alcohol‐consuming rats compared to outbreed rats, and this should be investigated in more detail. It should also be mentioned that infusion of the dopamine D1‐like agonist SKF 38393 into NAc had no effect on alcohol self‐administration in rats [141]. Albeit the data are somewhat contradictory, it might be hypothesized that accumbal as well as ventral tegmen‐ tal dopamine D2 receptors may regulate alcohol reinforcement in rodents.

#### *2.3.2. Clinical evidence for the use of dopamine agonists for the treatment of alcohol dependence*

Bromocriptine, a dopamine agonist has been used clinically for Parkinson's disease. At low doses, bromocriptine can reduce alcohol consumption in animals [171]; it is possible that low‐ dose dopamine agonists preferentially augment autoreceptor function, thereby decreasing dopamine turnover and blunting the rewarding effects of alcohol. An early double‐blinded study [172] reported that bromocriptine reduced alcohol craving in alcohol‐dependent patients with a specific genotype of the dopamine D2 receptor gene (i.e. the A1/A1 and A1/A2 geno‐ types). However, subsequent double‐blind placebo‐controlled trials found no effect on relapse or related behaviours [173, 174]. Currently, due to the knowledge of the addictive potential of dopamine agonists, combined with the lack of consistent findings from clinical studies, it is suggested that dopamine receptor agonists do not hold promise as a treatment for alcohol dependence.

#### **2.4. Partial dopamine agonists**

*2.3.1. Preclinical evidence for the use of dopamine agonists to attenuate alcohol‐mediated behaviours*

92 Recent Advances in Drug Addiction Research and Clinical Applications

The potential of dopamine D2 agonists to regulate alcohol‐mediated behaviours is support‐ ed by a study showing that apomorphine, dose‐dependently reduces operant self‐adminis‐ tration as well as decreases momentary response rates for alcohol in rats [134] and that SDZ‐ 205‐152, a synthetic‐mixed D1/D2 dopamine receptor agonist dose‐dependently reduces self‐ administration of alcohol, but not water, in rats [169]. Moreover, cabergoline, a dopamine D2 receptor agonist, decreased alcohol intake, relapse drinking as well as alcohol‐seeking behaviour in rodents [170]. In addition, low doses of bromocriptine produced a significant, dose‐dependent shift in decreasing the preference for alcohol while enhancing water consumption [171], indicating that the compound at lower doses preferentially augment autoreceptor function, leading to decreased dopamine turnover with a blunted response to the rewarding effects of alcohol as a result. Studies with intra‐NAc administration of quinpirole, further indicating that D2 receptors are involved in a biphasic effect on alcohol self‐administration, by showing that low doses of the agonist increase, whereas higher doses decrease, self‐administration of alcohol [141] (but see also [140]). A study has also investi‐ gated the effect of dopamine D2 receptor agonist administration into VTA on alcohol intake. This study showed that microinjection of either quinpirole or quinelorane, into the anterior part of the VTA dose‐dependently decreased alcohol, but not sucrose, intake in alcohol‐ preferring rats [142]. In support are the data showing that local administration of cabergo‐ line into the VTA reduced alcohol‐seeking behaviour in rats [170]. These data are contradictory to the findings showing that the dopamine D2 receptor antagonist into the anterior VTA did not alter alcohol intake in high‐alcohol‐preferring rats [142]. Therefore, mechanisms regulating alcohol reinforcement might be different in selectively breed high alcohol‐consuming rats compared to outbreed rats, and this should be investigated in more detail. It should also be mentioned that infusion of the dopamine D1‐like agonist SKF 38393 into NAc had no effect on alcohol self‐administration in rats [141]. Albeit the data are somewhat contradictory, it might be hypothesized that accumbal as well as ventral tegmen‐

tal dopamine D2 receptors may regulate alcohol reinforcement in rodents.

dependence.

*2.3.2. Clinical evidence for the use of dopamine agonists for the treatment of alcohol dependence*

Bromocriptine, a dopamine agonist has been used clinically for Parkinson's disease. At low doses, bromocriptine can reduce alcohol consumption in animals [171]; it is possible that low‐ dose dopamine agonists preferentially augment autoreceptor function, thereby decreasing dopamine turnover and blunting the rewarding effects of alcohol. An early double‐blinded study [172] reported that bromocriptine reduced alcohol craving in alcohol‐dependent patients with a specific genotype of the dopamine D2 receptor gene (i.e. the A1/A1 and A1/A2 geno‐ types). However, subsequent double‐blind placebo‐controlled trials found no effect on relapse or related behaviours [173, 174]. Currently, due to the knowledge of the addictive potential of dopamine agonists, combined with the lack of consistent findings from clinical studies, it is suggested that dopamine receptor agonists do not hold promise as a treatment for alcohol Based on the knowledge that alcohol can both stimulate dopamine activity as well as induce a hypo‐dopaminergic state, it has been suggested that partial agonists might have potential as novel medications for alcohol dependence. A partial agonist, such as aripiprazole, has a lower intrinsic activity at the receptor than a full agonist (e.g. dopamine), meaning that when it binds to the receptor, it will activate the receptor but produce a less potent biological response than the full agonist [175–177]. In the presence of high levels of the full agonist, a partial agonist will have functional antagonistic activity by binding to the receptor and preventing the response from the full agonist. Partial dopamine D2 agonists, therefore, offer the opportunity to treat the dysregulated dopamine activity during acute alcohol consumption as well as alcohol dependence.

#### *2.4.1. Preclinical evidence for the use of partial dopamine agonists to attenuate alcohol‐mediated behaviours*

In line with the hypothesis that a partial dopamine D2 agonist would block the reinforcing effects of alcohol, aripiprazole attenuates alcohol's ability to increase the locomotor activity in mice [178, 179](an indirect measure of activation of the mesolimbic dopamine system). On the other hand, aripiprazole did not interfere with the alcohol‐induced impairment in motor balance as measured by rotarod test [179]. Furthermore, repeated systemic aripiprazole administration decreases alcohol intake in alcohol‐preferring rats [180], while single oral administration dose‐dependently decreases alcohol self‐administration in outbred rats [181]. In addition, aripiprazole has been shown to reverse alcohol‐induced place preference and anxiety‐like behaviour in mice [182].

#### *2.4.2. Clinical evidence for the use of dopamine partial agonists for the treatment of alcohol dependence*

Clinically, the partial dopamine D2 agonist aripiprazole has been evaluated in a few random‐ ized placebo‐controlled trials and human laboratory studies. A pilot study showed that aripiprazole reduces the rate of relapse and craving in patients with alcohol dependence [183]. In a subsequent larger 12‐weeks, double‐blind, placebo‐controlled study of 295 alcohol‐ dependent patients aripiprazole was initiated at 2 mg/day, titrated to a maximum dose of 20  mg/day [184]. This study showed that aripiprazole decreased heavy drinking days compared to placebo during week four and eight; however, the effect was lost by the maximum dose at week twelve [184]. The effects of aripiprazole were also evaluated in a human laboratory study in non‐treatment seeking alcohol‐dependent individuals (n = 30), showing that the compound was well‐tolerated and reduced drinking, especially in impulsive individuals [185]. Voronin and colleagues also showed that aripiprazole decreased the number of drinks in a bar–lab environment after consumption of a priming drink, as well as weakened the association between the priming‐induced stimulation and further drinking. In another double‐blind comparison trial, aripiprazole was shown to reduce craving [186] but to a lesser extent than the FDA‐approved medication naltrexone [187]. Finally, a brain imaging study demonstrated that aripiprazole attenuated cue‐induced activation as evidenced by a reduced activation of the right ventral striatum with a corresponding reduction in drinking in individuals with alcohol dependence [188]. Thus far, early results with aripiprazole appear promising, although whether this or similar compounds might be useful to treat alcohol dependence or be posi‐ tioned as a medication with a specific profile, that is as targeted intervention in more impulsive alcohol‐dependent individuals needs to be evaluated further.

#### **2.5. Dopamine stabilizers**

As a further development of the partial agonist concept, Nobel Laureate Arvid Carlsson and co‐workers, developed a novel family of compounds based on their ability to stabilize, that is to stimulate, suppress or show no effect on the dopamine activity depending on the prevailing dopaminergic tone [189]. This stabilizing concept was postulated based on a PET study in rhesus monkeys where infusions with the compound (‐)‐OSU6162 (OSU6162) induced a dopaminergic tone‐dependent effect with a reduction in the striatal L‐[11C]DOPA influx rate in monkeys with high baseline values and an increased striatal L‐[11C]DOPA influx rate in animals with low baseline values [190]. The mechanism of action is, however, not completely understood, and although *in vitro* studies indicate that OSU6162, like aripiprazole, acts as a partial agonist at D2 receptors [191, 192], behavioural studies have failed to demonstrate any intrinsic activity of the compound ([195]). Instead it has been suggested that OSU6162 produces functionally opposite effects by acting as an antagonist at both presynaptic autoreceptors and postsynaptic D2 receptors [189, 193–195]. Based on the hypothesis that OSU6162 can counteract both hyper‐ and hypo‐dopaminergic states, the compound has recently been evaluated in both animal models modulating alcohol‐mediated behaviours as well as in a placebo‐controlled human laboratory study in alcohol‐dependent patients.

#### *2.5.1. Preclinical evidence for the use of dopamine stabilizers to attenuate alcohol‐mediated behaviours*

A series of experiments in outbred rats show that the dopamine stabilizer OSU6162 attenuates several alcohol‐mediated behaviours including voluntary alcohol intake, alcohol withdrawal symptoms and cue/priming‐induced reinstatement of alcohol seeking in long‐term drinking rats [196]. Furthermore, OSU6162 blunted alcohol‐induced dopamine output in the NAc of alcohol‐naïve rats [196], indicating that OSU6162 has the ability to attenuate the rewarding effects of alcohol. In contrast, a more recent microdialysis study conducted in long‐term drinking rats, showed that OSU6162, compared to vehicle‐pretreatment, had no significant effect on the alcohol‐induced dopamine peak [29]. The contrasting microdialysis results in alcohol‐drinking versus alcohol‐naïve rats highlight OSU6162´s ability to modulate the dopamine output dependent on the prevailing dopaminergic tone. Furthermore, these results indicate that OSU6162 might have the ability to attenuate alcohol‐mediated behaviours by counteracting the hypo‐dopaminergic state induced by long‐term drinking. Collectively, together with the finding that OSU6162 did not induce conditioned place preference [29] (an indication that the compound has no rewarding properties of its own), these results indicate that OSU6162 has many of the favourable characteristics of a potential medication for alcohol dependence.

#### *2.5.2. Clinical evidence for the use of a dopamine stabilizer for the treatment of alcohol dependence*

alcohol dependence [188]. Thus far, early results with aripiprazole appear promising, although whether this or similar compounds might be useful to treat alcohol dependence or be posi‐ tioned as a medication with a specific profile, that is as targeted intervention in more impulsive

As a further development of the partial agonist concept, Nobel Laureate Arvid Carlsson and co‐workers, developed a novel family of compounds based on their ability to stabilize, that is to stimulate, suppress or show no effect on the dopamine activity depending on the prevailing dopaminergic tone [189]. This stabilizing concept was postulated based on a PET study in rhesus monkeys where infusions with the compound (‐)‐OSU6162 (OSU6162) induced a dopaminergic tone‐dependent effect with a reduction in the striatal L‐[11C]DOPA influx rate in monkeys with high baseline values and an increased striatal L‐[11C]DOPA influx rate in animals with low baseline values [190]. The mechanism of action is, however, not completely understood, and although *in vitro* studies indicate that OSU6162, like aripiprazole, acts as a partial agonist at D2 receptors [191, 192], behavioural studies have failed to demonstrate any intrinsic activity of the compound ([195]). Instead it has been suggested that OSU6162 produces functionally opposite effects by acting as an antagonist at both presynaptic autoreceptors and postsynaptic D2 receptors [189, 193–195]. Based on the hypothesis that OSU6162 can counteract both hyper‐ and hypo‐dopaminergic states, the compound has recently been evaluated in both animal models modulating alcohol‐mediated behaviours as well as in a placebo‐controlled

*2.5.1. Preclinical evidence for the use of dopamine stabilizers to attenuate alcohol‐mediated behaviours*

A series of experiments in outbred rats show that the dopamine stabilizer OSU6162 attenuates several alcohol‐mediated behaviours including voluntary alcohol intake, alcohol withdrawal symptoms and cue/priming‐induced reinstatement of alcohol seeking in long‐term drinking rats [196]. Furthermore, OSU6162 blunted alcohol‐induced dopamine output in the NAc of alcohol‐naïve rats [196], indicating that OSU6162 has the ability to attenuate the rewarding effects of alcohol. In contrast, a more recent microdialysis study conducted in long‐term drinking rats, showed that OSU6162, compared to vehicle‐pretreatment, had no significant effect on the alcohol‐induced dopamine peak [29]. The contrasting microdialysis results in alcohol‐drinking versus alcohol‐naïve rats highlight OSU6162´s ability to modulate the dopamine output dependent on the prevailing dopaminergic tone. Furthermore, these results indicate that OSU6162 might have the ability to attenuate alcohol‐mediated behaviours by counteracting the hypo‐dopaminergic state induced by long‐term drinking. Collectively, together with the finding that OSU6162 did not induce conditioned place preference [29] (an indication that the compound has no rewarding properties of its own), these results indicate that OSU6162 has many of the favourable characteristics of a potential medication for alcohol

alcohol‐dependent individuals needs to be evaluated further.

94 Recent Advances in Drug Addiction Research and Clinical Applications

human laboratory study in alcohol‐dependent patients.

**2.5. Dopamine stabilizers**

dependence.

The dopamine stabilizer OSU6162 was recently evaluated in a placebo‐controlled human laboratory alcohol craving study in 56 alcohol dependent individuals [197]. Two weeks of OSU6162 treatment significantly attenuated priming‐induced craving and induced signifi‐ cantly lower subjective "liking" of the consumed alcohol, compared to placebo. Interestingly, the treatment effects of OSU6162 were driven by those individuals with high level of baseline impulsivity, corroborating previous results with the partial dopamine D2 agonist aripiprazole [185]. These results suggest that pharmacological stabilization of the dopamine system might prove as an effective target for alleviating some of the reward driven behaviours during alcohol dependence. Together with OSU6162's favourable side effect profile [198, 197, 199], these results render support for a larger placebo‐controlled efficacy trial in alcohol‐dependent patients to evaluate OSU6162's effect on drinking outcomes.

#### **2.6. Pharmacological agents inducing indirect modulation of dopamine**

As mentioned previously, in addition the affecting the dopamine system directly, alcohol interacts with the mesolimbic dopamine system indirectly via several other neurotransmitters. There is a wide range of such compounds, and here, we will only mention a few, specifically targeting glycine receptors and nAChRs, with a clear interaction with dopamine transmission in the mesolimbic dopamine system [64].

#### *2.6.1. Preclinical evidence for the use of compounds that indirectly targets dopamine to attenuate alcohol‐ mediated behaviours*

Rodent studies exploring the potential of targeting the glycine system as a medication for alcohol dependence showed that systemic administration of the glycine transporter‐1 inhibitor Org25935 increased extracellular glycine in the NAc, which prevented alcohol‐induced dopamine release [200, 201] as well as decreased alcohol intake and prevented relapse drinking [202, 203]. These results provided rational for a randomized placebo‐controlled clinical trial in alcohol‐dependent individuals.

Emerging data suggests that the activity of dopamine neurons in the VTA projecting to the NAc is regulated by several afferents, such as, for example the cholinergic neurons projecting from the laterodorsal tegmental nucleus (LDTg) (for review see [204]). Although alcohol's direct interaction with this cholinergic‐dopaminergic reward link remains to be fully eluci‐ dated, a study show that voluntary alcohol intake in high‐alcohol‐consuming rats causes a concomitant release of ventral tegmental acetylcholine and accumbal dopamine [39]. Several rodent studies with nAChR antagonists such as mecamylamine or selective nAChRs antago‐ nists such as alpha‐conotoxin MII highlight the potential of nAChRs as novel medications for alcohol dependence by showing that these compounds prevent alcohol from increasing dopamine and reduce alcohol consumption behaviour [28, 38, 32, 34, 35]. These nAChR antagonists are limited in a clinical setting due to low blood–brain barrier permeability and an unfavourable side effect profile. The potential of nAChR's as novel treatment target was revived with the marketing of the partial nAChR agonist varenicline as a smoking cessation agent. It has been shown that varenicline reduce alcohol intake and alcohol‐seeking behaviour in long‐term drinking rats [205] and modulate NAc dopamine after systemic administrations of alcohol alone and in combination with nicotine [206].

#### *2.6.2. Clinical evidence for the use of indirect modulation of dopamine for the treatment of alcohol dependence*

Albeit the preclinical data look promising regarding the glycine transporter‐1 inhibitor Org25935, the multicenter randomized clinical trial produced a negative outcome on alcohol intake, but did not discard the potential importance of the mechanism [207]. More promis‐ ing clinical studies with varenicline show that this agent decreased alcohol consumption and craving in an experimental setting in heavy‐drinking smokers [208–210]. Moreover, data from a randomized clinical trial in alcohol‐dependent individuals show that the smoking cessa‐ tion agent reduced the weekly percent heavy drinking days drinks, decreased the drinks per drinking day as well as prevented alcohol craving [211]. It should, however, be noted that recent clinical trials in alcohol‐dependent individuals were unable to find a beneficial effect of varenicline based on self‐reported alcohol consumption [212, 213]. Nevertheless, when also monitoring the selective alcohol biomarker phosphatidylethanol (PEth) in the blood of the subjects in the above‐mentioned clinical trial [212], it was found that varenicline indeed had effect on this objective measure of alcohol consumption [214] strengthening the potential of varenicline as potential novel medication for alcohol dependence. Besides glycine receptors and nAChR, there are various signalling systems indirectly targeting the mesolimbic dopamine system with promising preclinical findings on alcohol‐mediated behaviours. Collectively, these data indicate that indirect modulation of dopamine signalling might be a potential target for novel treatment strategies for alcohol dependence and that these targets should be investigated in more detail in human laboratory studies as well as randomized clinical trials.

#### **3. Conclusion**

Extensive preclinical and clinical research support the hypothesis that alcohol's acute rein‐ forcing effects are mediated through a dopamine surge in the mesocorticolimbic dopamine system and that the chronic and excessive alcohol consumption, in contrast, induces a dopamine deficient state driving the processes of craving and relapse. In addition, it is well substantiated that alcohol affects dopamine directly via the NAc and VTA as well as through indirect activation of the mesolimbic pathway via interaction with other reward‐related brain regions and neurotransmitters. These complex relationships need to be investigated further. Given dopamine's pivotal role in the development and maintenance of alcohol dependence, medications targeting dopamine does constitute an important area of research. Although promising preclinical results, the majority of results from the clinical studies with dopamine‐ acting medications have thus far been discouraging. The side effects profile of many of the evaluated compounds, including typical antipsychotic drugs, render them clinically unfav‐ ourable. On the other hand, newer dopamine agents, without complete antagonism or agonism, especially the dopamine stabilizers show promise and deserve further investigation in alcohol‐dependent patients.
