**Dopamine and Alcohol Dependence: From Bench to Clinic**

Nitya Jayaram‐Lindström, Mia Ericson, Pia Steensland and Elisabet Jerlhag

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/63144

#### **Abstract**

Alcohol dependence, a chronic relapsing psychiatric disorder, is a major cause of mortality and morbidity. The role of dopamine in alcohol‐induced reward as well in the development of alcohol dependence is reviewed herein. Both preclinical and clinical studies have suggested that alcohol activates the mesolimbic dopamine system (defined as a dopamine projection from the ventral tegmental area (VTA) to the nucleus accumbens (NAc, i.e. ventral striatum)) leading to a euphoric sensation. Alcohol dependence is characterized by a disruption in the reward‐related brain areas including fewer dopamine D2 receptors in ventral striatum. Investigations of the underlying dopaminergic mechanisms involved during the development and maintenance of alcohol dependence could identify novel targets. Human and rodent experimental studies show that dopamine receptor antagonists, agonists and partial agonists as well as dopamine stabilizers influencing dopamine transmission, alter alcohol‐mediated behaviours and thus may be potential treatment targets for alcohol dependence. Although there exists promising preclinical results, the majority of placebo‐controlled randomized clinical trials with traditional dopamine antagonists and agonists have so far have been discouraging. Furthermore, the severe side-effect profiles of many of these compounds may limit their clinical use. Newer dopamine agents, such as partial agonists and dopamine stabilizers, attenuate alcohol‐mediated behaviours in rodents as well as humans. Preclinical as well as clinical studies have shown that substances indirectly targeting the mesolimbic dopamine system may be potential targets for attenuation of alcohol reward. Collectively, the data reviewed herein may contribute to further understanding the complex mechanisms involved in development of alcohol dependence and we suggest that the newer dopamine agents as well as indirect modulators of dopamine signalling deserve to be further evaluated for treatment of alcohol dependence.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**Keywords:** alcohol‐use disorder, mesocorticolimbic dopamine system, nucleus ac‐ cumbens, dopamine stabilizer, antipsychotic drugs

## **1. Introduction**

Alcoholdependence is a chronic relapsing psychiatricdisorder significantly contributing to the global burden of disease [1] and affects about four percent of the world's population over the age of 15 (WHO). In the fifth edition of the diagnostic and statistical manual of mental disor‐ ders (DSM), the term alcohol use disorder was introduced and grossly defined as problem drinking that has become severe. The characteristics ofthis disorderinclude loss of control over alcoholintake,impairedcognitivefunctioning,negativesocialconsequences,physicaltolerance, withdrawal and craving for alcohol. To date, there are three medications approved by both the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) for the treatment of alcohol dependence; disulfiram, naltrexone and acamprosate. The FDA has also approved the use of a long‐acting injectable naltrexone. More recently, the EMA granted authorization also for nalmefene, a compound intended for the reduction of alcohol consump‐ tion in adults with alcohol dependence (EMA 2012). Details regarding the mechanism of action of these compounds are outside the scope of this review. In brief, the pharmacological profile is established for disulfiram (an aldehydedehydrogenase inhibitor), naltrexone (an opioid receptor antagonist) and nalmefene (an opioid receptor modulator), whereas the mechanism of actionoftheanti‐alcoholrelapsedrugacamprosateisnotfullyunderstood.Anindirectactivation of mesolimbic dopamine via accumbal glycine receptors and ventral tegmental nicotinic acetylcholine receptors (nAChRs) appears likely [2, 3], but additional targets has been suggest‐ ed (for review see [4]). Finally, the clinical efficacy of these agents is limited [5], possibly due to the heterogeneous nature of the disorder and the complex neurochemical mechanisms underlying alcohol dependence. Thus, the need for novel and efficacious medications remains.

The mesocorticolimbic dopamine system (or the so‐called brain reward system, **Figure 1**) is one of the established neurobiological systems involved during the development and main‐ tenance of alcohol dependence and thus one potential treatment target. Here, we aim to review the animal and human data describing the role of dopamine and the mesolimbic dopamine system during acute and chronic alcohol exposure. Finally, preclinical and clinical studies evaluating the potential of available dopaminergic agents as well as indirect dopamine modulators as novel medications for alcohol dependence are discussed.

#### **1.1. The brain reward system: the mesocorticolimbic dopamine system**

The mesocorticolimbic dopamine system has an established role in driving the rewarding sensations from natural rewards such as food, sex and exercise, which are important behav‐ iours to ensure our survival [6, 7] as well as among drugs of abuse, including alcohol (for review see [8]). The physiological importance of the mesocorticolimbic dopamine system is highlighted by its evolutionary stability and conservation in primitive invertebrates, such as,

flatworms, all the way up to primates, including humans. It was identified serendipitously in the 1950s when Olds and Milner found that rats self‐administer electrical currents into certain specific brain regions [9]. These findings were later corroborated by studies showing that rats favoured electrical stimulation in the same specific brain regions, over natural rewards [10]. The primary neurotransmitter regulating the rewarding sensation was determined to be dopamine [11]. Furthermore, the specific neuronal circuitries were progressively mapped with major projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAc, i.e. the ventral striatum), the prefrontal cortex (PFC) and amygdala. Collectively, this network of neurons was denominated the mesocorticolimbic dopamine system [12, 13]. The system was later divided into two distinct projections [12], modulating different dopamine‐mediated behavioural effects; the mesolimbic pathway (from the VTA to the NAc) thought to be responsible for the rewarding and pleasurable effects of natural as well as substances of abuse including alcohol (e.g. [14–16]), and the mesocortical pathway (from the VTA to the PFC) believed to be responsible for the motivational and emotional effects [15]. In addition, there are dopamine projections from the VTA to the amygdala and the hippocampus, respectively, involved in reward associative learning and declarative memory formation [15, 17].

**Keywords:** alcohol‐use disorder, mesocorticolimbic dopamine system, nucleus ac‐

Alcoholdependence is a chronic relapsing psychiatricdisorder significantly contributing to the global burden of disease [1] and affects about four percent of the world's population over the age of 15 (WHO). In the fifth edition of the diagnostic and statistical manual of mental disor‐ ders (DSM), the term alcohol use disorder was introduced and grossly defined as problem drinking that has become severe. The characteristics ofthis disorderinclude loss of control over alcoholintake,impairedcognitivefunctioning,negativesocialconsequences,physicaltolerance, withdrawal and craving for alcohol. To date, there are three medications approved by both the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) for the treatment of alcohol dependence; disulfiram, naltrexone and acamprosate. The FDA has also approved the use of a long‐acting injectable naltrexone. More recently, the EMA granted authorization also for nalmefene, a compound intended for the reduction of alcohol consump‐ tion in adults with alcohol dependence (EMA 2012). Details regarding the mechanism of action of these compounds are outside the scope of this review. In brief, the pharmacological profile is established for disulfiram (an aldehydedehydrogenase inhibitor), naltrexone (an opioid receptor antagonist) and nalmefene (an opioid receptor modulator), whereas the mechanism of actionoftheanti‐alcoholrelapsedrugacamprosateisnotfullyunderstood.Anindirectactivation of mesolimbic dopamine via accumbal glycine receptors and ventral tegmental nicotinic acetylcholine receptors (nAChRs) appears likely [2, 3], but additional targets has been suggest‐ ed (for review see [4]). Finally, the clinical efficacy of these agents is limited [5], possibly due to the heterogeneous nature of the disorder and the complex neurochemical mechanisms underlying alcohol dependence. Thus, the need for novel and efficacious medications remains. The mesocorticolimbic dopamine system (or the so‐called brain reward system, **Figure 1**) is one of the established neurobiological systems involved during the development and main‐ tenance of alcohol dependence and thus one potential treatment target. Here, we aim to review the animal and human data describing the role of dopamine and the mesolimbic dopamine system during acute and chronic alcohol exposure. Finally, preclinical and clinical studies evaluating the potential of available dopaminergic agents as well as indirect dopamine

cumbens, dopamine stabilizer, antipsychotic drugs

82 Recent Advances in Drug Addiction Research and Clinical Applications

modulators as novel medications for alcohol dependence are discussed.

**1.1. The brain reward system: the mesocorticolimbic dopamine system**

The mesocorticolimbic dopamine system has an established role in driving the rewarding sensations from natural rewards such as food, sex and exercise, which are important behav‐ iours to ensure our survival [6, 7] as well as among drugs of abuse, including alcohol (for review see [8]). The physiological importance of the mesocorticolimbic dopamine system is highlighted by its evolutionary stability and conservation in primitive invertebrates, such as,

**1. Introduction**

In healthy controls, alcohol consumption stimulates dopamine release mediating its reinforc‐ ing effects. Repeated bouts of intoxications will overtime downregulate the dopamine activity in the mesocorticolimbic pathway, leading to an increased risk of developing alcohol depend‐ ence and other impulse control disorders. [18, 13]. It has also been hypothesized that in vulnerable individuals (e.g. those with a family history of alcohol dependence), the proneness

**Figure 1.** Representative illustration of the mesocorticolimbic dopamine system in rat brain.

to develop an addiction is higher since they are born with a reduced number of dopamine D2 receptors in mesocorticolimbic pathway, leading to the alcohol dependence [18, 13]. Further, it has been speculated that this dopamine deficiency is responsible for driving craving and compulsive drinking and contributes to relapse even after a period of protracted abstinence [18, 19]. The preclinical and clinical evidence of the underlying interaction between alcohol and the dopamine D2 receptors within the mesocorticolimbic dopamine system during the acute as well as during chronic intake is reviewed below. The involvement of the dopamine D1, D3, D4 and D5 receptors falls outside the scope of the present review but has previously been reviewed elsewhere [20].

#### **1.2. Interaction between alcohol and the mesocorticolimbic dopamine system**

#### *1.2.1. Preclinical evidence: acute alcohol exposure and dopamine*

Dopamine's importance for alcohol‐induced reward was first identified in studies showing that the catecholamine‐synthesis inhibitor, α‐methyltyrosine (an agent with the ability to inhibit the formation of dopamine in the cytosol of terminals of dopaminergic neurons [21]) blocked alcohol‐induced euphoria, social interaction and talkativeness in humans [22] as well as attenuated alcohol‐induced locomotor activity in rats [23]. *Ex vivo* and *in vivo* voltammetry studies in rats found that alcohol increases the dopamine levels in NAc [24]. In addition, *in vivo* microdialysis studies have since shown that systemic administration of alcohol and other drugs of abuse, including amphetamine, cocaine, opiate and nicotine, increases the accumbal dopamine levels in freely moving rats [25–35], strengthening the hypothesis of an association between the rewarding or euphoric sensation and dopamine release in the NAc. This hypoth‐ esis is further supported by studies showing that drugs that are not rewarding or abused by humans do not modify synaptic accumbal dopamine levels in rat [27]. In addition, voluntary alcohol consumption causes a dose‐dependent [36] release of dopamine in the NAc in rat [37– 39]. Finally, intravenous administration of alcohol, as well as other drugs of abuse, increases the firing rate of dopamine neurons in the VTA in rats [40, 41]. Further support for the role of dopamine D2 receptors in the reinforcing effects of alcohol is given by a study showing that dopamine receptor D2 knockout mice self‐administer less alcohol than the wild‐type mice [42]. In addition to the extensive literature showing a link between accumbal dopamine and alcohol‐ induced reinforcement, it has been shown that the pure anticipation of alcohol (i.e. without alcohol being present) increases the release of dopamine in NAc in rodents trained to self‐ administer alcohol [43–45, 36] and that accumbal dopamine release is associated with asso‐ ciative learning, rather than exposure to the reward itself [46]. Moreover, this anticipation effect is more noticeable in high compared to low‐alcohol‐preferring rats [47]. Studies have also shown that the anticipation of a reward increases the firing of accumbal dopamine neurons [41]. It should, however, be mentioned that results from studies with lesion of the mesocorti‐ colimbic dopamine pathways have shown contradicting results with both decreased [48–50] and unaltered alcohol intake [51–56]. These inconsistent results indicate that the role of accumbal dopamine in reinforcement is complex and highlights that the rewarding properties of alcohol may extend beyond direct or indirect effects on dopamine, involving interactions with several other neurotransmitters including acetylcholine, glutamate, GABA, serotonin (5HT), noradrenaline, taurine and opioids, as well as hormones and peptides [24, 57, 58].

to develop an addiction is higher since they are born with a reduced number of dopamine D2 receptors in mesocorticolimbic pathway, leading to the alcohol dependence [18, 13]. Further, it has been speculated that this dopamine deficiency is responsible for driving craving and compulsive drinking and contributes to relapse even after a period of protracted abstinence [18, 19]. The preclinical and clinical evidence of the underlying interaction between alcohol and the dopamine D2 receptors within the mesocorticolimbic dopamine system during the acute as well as during chronic intake is reviewed below. The involvement of the dopamine D1, D3, D4 and D5 receptors falls outside the scope of the present review but has previously

Dopamine's importance for alcohol‐induced reward was first identified in studies showing that the catecholamine‐synthesis inhibitor, α‐methyltyrosine (an agent with the ability to inhibit the formation of dopamine in the cytosol of terminals of dopaminergic neurons [21]) blocked alcohol‐induced euphoria, social interaction and talkativeness in humans [22] as well as attenuated alcohol‐induced locomotor activity in rats [23]. *Ex vivo* and *in vivo* voltammetry studies in rats found that alcohol increases the dopamine levels in NAc [24]. In addition, *in vivo* microdialysis studies have since shown that systemic administration of alcohol and other drugs of abuse, including amphetamine, cocaine, opiate and nicotine, increases the accumbal dopamine levels in freely moving rats [25–35], strengthening the hypothesis of an association between the rewarding or euphoric sensation and dopamine release in the NAc. This hypoth‐ esis is further supported by studies showing that drugs that are not rewarding or abused by humans do not modify synaptic accumbal dopamine levels in rat [27]. In addition, voluntary alcohol consumption causes a dose‐dependent [36] release of dopamine in the NAc in rat [37– 39]. Finally, intravenous administration of alcohol, as well as other drugs of abuse, increases the firing rate of dopamine neurons in the VTA in rats [40, 41]. Further support for the role of dopamine D2 receptors in the reinforcing effects of alcohol is given by a study showing that dopamine receptor D2 knockout mice self‐administer less alcohol than the wild‐type mice [42]. In addition to the extensive literature showing a link between accumbal dopamine and alcohol‐ induced reinforcement, it has been shown that the pure anticipation of alcohol (i.e. without alcohol being present) increases the release of dopamine in NAc in rodents trained to self‐ administer alcohol [43–45, 36] and that accumbal dopamine release is associated with asso‐ ciative learning, rather than exposure to the reward itself [46]. Moreover, this anticipation effect is more noticeable in high compared to low‐alcohol‐preferring rats [47]. Studies have also shown that the anticipation of a reward increases the firing of accumbal dopamine neurons [41]. It should, however, be mentioned that results from studies with lesion of the mesocorti‐ colimbic dopamine pathways have shown contradicting results with both decreased [48–50] and unaltered alcohol intake [51–56]. These inconsistent results indicate that the role of accumbal dopamine in reinforcement is complex and highlights that the rewarding properties of alcohol may extend beyond direct or indirect effects on dopamine, involving interactions

**1.2. Interaction between alcohol and the mesocorticolimbic dopamine system**

*1.2.1. Preclinical evidence: acute alcohol exposure and dopamine*

84 Recent Advances in Drug Addiction Research and Clinical Applications

been reviewed elsewhere [20].

To further elucidate the role of the NAc and the VTA in alcohol‐mediated dopamine regulation, extensive rodent studies, with for example intra‐cranial alcohol infusions and electrophysio‐ logical techniques, have been conducted. With regards to the NAc, rodent studies confirm that intra‐NAc alcohol perfusions increase the release of dopamine in the same brain region (e.g. [59, 38, 60–62]). An effect that is suggested to be regulated via a neuronal circuitry involving glycine receptors in the NAc as well as anterior ventral tegmental nAChR [59, 63, 64]. Inter‐ estingly, the NAc is a heterogeneous region most often divided into two distinct anatomically and functionally different regions, that is the central core and the surrounding shell compart‐ ment [65–69] and it has been suggested that dopaminergic innervation of the NAc core is associated with the nigrostriatal system, while that of the NAc shell is related to the mesolimbic system [70]. Alcohol has been shown to increase the release of dopamine in NAc shell, but not in the core [71–73]. Studies are also emerging suggesting the need for further division of this brain region since it was demonstrated that a borderline region between the core and shell of the NAc is the region most responsive to alcohol [74].

With regards to the VTA, both *in vitro* and *in vivo* studies show that alcohol increases the firing of dopamine neurons in the VTA projecting to NAc [75–79, 40]. Similarly, in a situation of synaptic transmission blockade, alcohol has been found to increase the firing of dissociated VTA dopamine neurons [76, 77] implying that alcohol activates ventral tegmental dopamine neurons independent of afferent signalling. Furthermore, studies with intra‐VTA alcohol infusions highlight that different subregions within the heterogeneous VTA might have different ability to modulate the alcohol‐induced dopamine response. Specifically, rats voluntarily self‐administer alcohol, as well as acetaldehyde (an alcohol metabolite) into the posterior, but not anterior, part of the VTA [80–85], indicating that alcohol is reinforcing only within the posterior VTA. The suggestion is further supported by a study showing that intra‐ cranial infusions into the posterior VTA of the D2 agonist quinpirole (in doses that activate local D2 autoreceptors, thereby reducing the firing rate of VTA dopamine neurons [86, 87]), attenuates alcohol self‐administration, which can be restored when the D2 agonist is removed or blocked with administration of a D2 antagonist [84]. In corroboration are the findings that the sensitivity of the posterior VTA to the reinforcing effects of alcohol is enhanced in alcohol‐ preferring rats [88]. There are, however, some contradicting results indicating that these subregion‐specific effects might be related to the administered dose of alcohol, the use of various methods, the rat strains across the studies as well as differences in coordinates used for local injections (within the anterior VTA). For example, it has been demonstrated that perfusion of a low, but not a high dose of alcohol into the anterior, but not posterior part of the VTA increased accumbal dopamine in rats [89], and a recent study indicates that additional VTA subregions might be involved as alcohol increases the firing frequency of a subset of dopamine neurons in the medial, but not lateral, part of the VTA [90]. It should also be noted that in both outbreed as well as alcohol‐preferring rats, there are studies showing no influence on the accumbal dopamine levels regardless of dose of alcohol or location in the VTA [59, 91]. Collectively, these data suggest that VTA is a heterogeneous area that differs in morphology and topography (for review, see [92]), and the anterior/posterior and lateral/medial part have different functions regarding alcohol and its activation of the mesolimbic dopamine system.

#### *1.2.2. Clinical evidence: acute alcohol consumption and dopamine*

The development of positron imaging technique (PET) and the radiotracer 11C‐raclopride in the 1990s made it possible to study *in vivo* dopamine function in humans. A series of human imaging studies over the last decade have demonstrated that alcohol [93, 94] as well as other drugs of abuse [95] increase striatal dopamine release. This is further corroborated by the findings that self‐reported behavioural measures of stimulation, euphoria or drug wanting by alcohol correlates with the magnitude and rate of ventral striatum dopamine release [96–98, 94, 99, 100]. These studies clearly substantiated the involvement of dopamine in the reinforcing effects of alcohol and closely mimicked the findings of the preclinical studies.

#### *1.2.3. Preclinical evidence: chronic alcohol exposure and dopamine*

As mentioned above, it has been hypothesized that the chronic intake of alcohol induces a dopamine deficit state in the brain reward system and that this dysfunction may drive craving and relapse to drinking [101, 18, 19]. In outbred rodents, however, the effects on the mesolimbic dopamine system following chronic alcohol treatment are inconsistent [102]. One possible explanation for these discrepancies may be that most preclinical studies to‐date have used forced alcohol administration which introduces an element of stress and artefact into the experiment, casting doubt on the applicability to our understanding of human alcohol dependence. In this review, we will therefore focus on studies with clear face validity to the human condition, that is those using voluntary self‐administration.

The dopamine deficiency hypothesis is supported by a study showing decreased dopamine receptor gene expression after several months of voluntary alcohol drinking [103]. In addition, microdialysis studies in freely moving outbred rats show a decreased dopamine output in the NAc, compared to age‐matched alcohol‐naïve controls, following 7 weeks [104] and 10 months [29] of voluntary alcohol consumption. Furthermore, after 10 months of drinking, a blunted dopamine response following a systemic alcohol challenge has been found in long‐term drinking, compared to alcohol‐naïve rats [29]. These results indicate that long‐term drinking attenuates the responsiveness of the system to external dopamine stimulation, in addition to decreasing baseline levels of dopamine. It should, however, be noted that acute administration of alcohol induces a twofold increase in dopamine output in the NAc shell in high compared to low‐alcohol‐preferring rats [105], indicating that there might be a difference in these aspects between outbred standard laboratory rats and inbred alcohol‐preferring rats.

The selectively inbred alcohol‐preferring and non‐alcohol‐preferring rat strains have been extensively used to investigate the neurochemical mechanisms underlying alcohol depend‐ ence. In line with the dopamine deficiency hypothesis, the baseline accumbal dopamine levels appear to be lower [105] and the dopamine D2 receptors in NAc are fewer [106] in high‐ preferring compared to low‐preferring rats. In fact, neurochemical data show that high‐ alcohol‐seeking behaviour is associated with 10–15% lower accumbal dopamine content compared with low‐alcohol‐seeking rats [107]. In addition, overexpression of accumbal dopamine D2 receptors reduces alcohol in non‐preferring as well as high‐preferring rats [108, 109]. These results highlight that not only chronic alcohol consumption, but also genetic factors, influence the dopaminergic response to alcohol. Furthermore, it has been suggested that more dorsal parts of the striatum is recruited once the dependence develops [110, 111] although until now this has been investigated only in other drugs of abuse than alcohol.

#### *1.2.4. Clinical evidence: alcohol dependence and dopamine*

and topography (for review, see [92]), and the anterior/posterior and lateral/medial part have different functions regarding alcohol and its activation of the mesolimbic dopamine system.

The development of positron imaging technique (PET) and the radiotracer 11C‐raclopride in the 1990s made it possible to study *in vivo* dopamine function in humans. A series of human imaging studies over the last decade have demonstrated that alcohol [93, 94] as well as other drugs of abuse [95] increase striatal dopamine release. This is further corroborated by the findings that self‐reported behavioural measures of stimulation, euphoria or drug wanting by alcohol correlates with the magnitude and rate of ventral striatum dopamine release [96–98, 94, 99, 100]. These studies clearly substantiated the involvement of dopamine in the reinforcing

As mentioned above, it has been hypothesized that the chronic intake of alcohol induces a dopamine deficit state in the brain reward system and that this dysfunction may drive craving and relapse to drinking [101, 18, 19]. In outbred rodents, however, the effects on the mesolimbic dopamine system following chronic alcohol treatment are inconsistent [102]. One possible explanation for these discrepancies may be that most preclinical studies to‐date have used forced alcohol administration which introduces an element of stress and artefact into the experiment, casting doubt on the applicability to our understanding of human alcohol dependence. In this review, we will therefore focus on studies with clear face validity to the

The dopamine deficiency hypothesis is supported by a study showing decreased dopamine receptor gene expression after several months of voluntary alcohol drinking [103]. In addition, microdialysis studies in freely moving outbred rats show a decreased dopamine output in the NAc, compared to age‐matched alcohol‐naïve controls, following 7 weeks [104] and 10 months [29] of voluntary alcohol consumption. Furthermore, after 10 months of drinking, a blunted dopamine response following a systemic alcohol challenge has been found in long‐term drinking, compared to alcohol‐naïve rats [29]. These results indicate that long‐term drinking attenuates the responsiveness of the system to external dopamine stimulation, in addition to decreasing baseline levels of dopamine. It should, however, be noted that acute administration of alcohol induces a twofold increase in dopamine output in the NAc shell in high compared to low‐alcohol‐preferring rats [105], indicating that there might be a difference in these aspects

The selectively inbred alcohol‐preferring and non‐alcohol‐preferring rat strains have been extensively used to investigate the neurochemical mechanisms underlying alcohol depend‐ ence. In line with the dopamine deficiency hypothesis, the baseline accumbal dopamine levels appear to be lower [105] and the dopamine D2 receptors in NAc are fewer [106] in high‐ preferring compared to low‐preferring rats. In fact, neurochemical data show that high‐ alcohol‐seeking behaviour is associated with 10–15% lower accumbal dopamine content

effects of alcohol and closely mimicked the findings of the preclinical studies.

*1.2.2. Clinical evidence: acute alcohol consumption and dopamine*

86 Recent Advances in Drug Addiction Research and Clinical Applications

*1.2.3. Preclinical evidence: chronic alcohol exposure and dopamine*

human condition, that is those using voluntary self‐administration.

between outbred standard laboratory rats and inbred alcohol‐preferring rats.

As mentioned earlier, in vulnerable individuals (related to genetic and environmental factors) as well as healthy individuals, repeated administration of alcohol can lead to perturbations in the dopamine‐regulated circuitry, leading to the development of alcohol dependence. For instance, a human laboratory study has demonstrated that intravenous administration of alcohol causes an increase in dopamine in the ventral striatum in non‐treatment‐seeking alcohol‐dependent individuals [112]. Further, imaging studies have shown that the number of dopamine D2 receptors is lower in individuals with alcohol or drug dependence, compared to healthy controls [113, 114] and there is considerable evidence that the low levels of D2 receptors levels contribute to the excessive urges/craving for alcohol and subsequently to relapse [115]. In addition, decreased dopamine transmission in the mesolimbic regions, such as the ventral striatum, likely contributes to anhedonia and decreased reward sensitivity in alcohol‐dependent individuals. Further, in abstinent high‐risk drinkers as well as alcohol‐ dependent individuals, alcohol‐associated cues activate the ventral striatum, which further contribute to the high risk of relapse in these individuals [116, 117].

A recent PET study [118] demonstrated for the first time that, in addition to the ventral striatum, the long‐term consumption of alcohol leads to lowered dopamine levels also in prefrontal cortical structures. These findings support the extensive clinical findings demon‐ strating that alcohol‐dependent individuals have significant impairments in executive functions such as working memory, impulsivity and decision‐making; functions governed by the cortical brain structures. The fact that there is also less dopamine in the prefrontal cortex, governing these executive functions, is of significance as it could impair the alcohol‐dependent individual's capacity to utilize behavioural treatment strategies, which are critical to relapse prevention.

Collectively, these data indicate that dopamine plays a central role in reward, motivation and planning. Given the relevance of dopamine in the chronic phase of alcohol use and in the development of alcohol dependence, there is considerable interest in evaluating medications that can specifically modify dopamine, thereby serving as potential pharmacotherapies to treat alcohol dependence.

#### *1.2.5. Human genetic evidence: alcohol dependence and dopamine*

The preclinical and clinical evidence presented above suggest that dopamine regulates alcohol‐ mediated behaviours. Numerous human genetic studies have therefore investigated associa‐ tions between alcohol dependence and genes related to dopamine function. As early as the 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 controversial.
