Dopamine and Alcohol Dependence: From Bench to Clinic

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.

Behavioral Sensitization to the Disinhibition Effect of Ethanol Requires the Dopamine/Ecdysone Receptor in Drosophila

“…These observations indicate that ethanol-induced behaviors in flies and intoxicated humans are similar; thus, the knowledge of their neurobiological basis could help not only uncover evolutionarily conserved vs. distinct neural, cellular and molecular pathways but also gain insight into effective intervention of ethanol abuse and addiction. The biogenic amine dopamine is involved in locomotor stimulating and rewarding effects of ethanol in flies, rodents and humans (Devineni and Heberlein, 2013 ; Abrahao et al, 2014 ; Jayaram-Lindström et al, 2016 ). For example, ethanol intake elevates extracellular dopamine levels in the nucleus accumbens in rodents (Meyer et al, 2009 ; Vena et al, 2016 ).…”

Effects of Long‐Term Alcohol Drinking on the Dopamine D2 Receptor: Gene Expression and Heteroreceptor Complexes in the Striatum in Rats

“…The mesolimbic dopamine system plays a crucial role in alcohol's reinforcing effects, as well as in the development and maintenance of alcohol use disorder (AUD) (Jayaram‐Lindström et al., ). In particular, alcohol activates the projections from the ventral tegmental area to the nucleus accumbens (NAc; i.e., the ventral striatum) and induces striatal dopamine release in rats (Ericson et al., ; Weiss et al., ) and humans (Boileau et al., ; Urban et al., ).…”

“…In particular, alcohol activates the projections from the ventral tegmental area to the nucleus accumbens (NAc; i.e., the ventral striatum) and induces striatal dopamine release in rats (Ericson et al., ; Weiss et al., ) and humans (Boileau et al., ; Urban et al., ). Furthermore, dopamine D2 receptors (D2Rs) in the NAc are crucial for alcohol reinforcement (Hodge et al., ; Jayaram‐Lindström et al., ). Moreover, D2Rs in the dorsolateral striatum are involved in alcohol seeking that after an extended period has become habitual, that is, is independent of alcohol reinforcement (Corbit et al., ), and is mainly influenced by alcohol‐associated cues (Corbit and Janak, ).…”

Stress‐related suppression of peripheral cytokines predicts future relapse in alcohol‐dependent individuals with and without subclinical depression

“…The link between immune suppression in response to stress and motivation for alcohol may reflect allostatic load underlying motivation for alcohol, which has been characterized as sensitization of core stress systems, 65,66 suppressed response to stress [67][68][69][70] and dampened response to reward via downregulation of D2 receptors in the ventral striatum. 71,72 As the function of both the stress and immune systems are intrinsically meshed, dampened immune response to stress during protracted abstinence from alcohol dependence, may also be the result of persistent acute upregulation of stress and immune markers either due to acute withdrawal and/or chronic alcohol intake. More broadly, cytokine suppression in response to stress may reflect an alternative regulatory index of allostatic load arising as an attempt to preserve reward function stability 73 and reflecting the move from positive to negative reinforcement.…”