Available online 13 March 2024

Author links open overlay panel, Abstract

The mesolimbic dopamine pathway plays a major role in drug reinforcement and is likely involved also in the development of drug addiction. Ethanol, like most addictive drugs, acutely activates the mesolimbic dopamine system and releases dopamine, and ethanol-associated stimuli also appear to trigger dopamine release. In addition, chronic exposure to ethanol reduces the baseline function of the mesolimbic dopamine system. The molecular mechanisms underlying ethanol´s interaction with this system remain, however, to be unveiled. Here research on the actions of ethanol in the mesolimbic dopamine system, focusing on the involvement of cystein-loop ligand-gated ion channels, opiate receptors, gastric peptides and acetaldehyde is briefly reviewed. In summary, a great complexity as regards ethanol´s mechanism(s) of action along the mesolimbic dopamine system has been revealed. Consequently, several new targets and possibilities for pharmacotherapies for alcohol use disorder have emerged.

Section snippetsBrain dopamine systems

In 1957, Carlsson and co-workers proposed that dopamine serves as a brain neurotransmitter (Carlsson et al., 1957, Carlsson et al., 1958). Later, Dahlström and Fuxe (1964) visualized dopamine neurons by histochemical techniques and revealed the presence of four major dopamine systems, (1) the nigrostriatal dopamine system originating in the substantia nigra in the mesencephalon and projecting to the dorsal striatum (caudate-putamen), (2) the mesolimbic dopamine system originating in the ventral

Ethanol and brain dopamine systems

In the 60s and 70s, ethanol and other drugs of abuse were shown to activate brain catecholamine systems (Carlsson and Lindqvist, 1973, Corrodi et al., 1966), an effect that was associated with enhanced locomotor stimulation in experimental animals (Carlsson, Engel, & Svensson, 1972) and in talkativeness, social interaction etc. in man (Ahlenius, Carlsson, Engel, Svensson, & Sodersten, 1973). In the late seventies Engel and Carlsson suggested that these psychomotor stimulatory effects contribute

Ethanol, acetaldehyde and the mesolimbic dopamine system

The first metabolite of ethanol, acetaldehyde, is a well-known mediator of aversive effects of alcohol, likely explaining why genetic studies suggest that polymorphisms producing increased blood acetaldehyde levels after ethanol intake are associated with a reduced risk of developing alcoholism (Edenberg, 2007). However, evidence obtained in experimental animals also suggests that acetaldehyde is involved in the rewarding, motivational and addictive properties of alcohol (Foddai et al., 2004,

Ethanol and cystein-loop ligand-gated ion channels

The cysteine-loop ligand-gated ion channels are composed of five subunit proteins forming an ion-channel passing through the neuronal cell membrane. The subunits appear in many forms and show different degrees of homology, which sorts them into different subgroups of subunits and receptors. Nicotinic acetylcholine receptors (nAChRs), GlyRs, GABAA receptors and 5-HT3 receptors all are cysteine-loop ion-channels. Ethanol has clearly been demonstrated both in vitro and in vivo to functionally

Ethanol, nAChR and the mesolimbic dopamine system

Nicotinic acetylcholine receptors are present on the cell bodies and the neuronal terminals of the mesolimbic dopamine system (Jensen, Frolund, Liljefors, & Krogsgaard-Larsen, 2005). The first indication of a possible involvement of nAChRs in ethanol’s dopamine elevating effect was obtained in mice, where the dopamine turnover and locomotor stimulating effects of ethanol were partly blocked by systemic administration of the tertiary nAChR antagonist mecamylamine but not by the quaternary

Ethanol, GlyR and the mesolimbic dopamine system

Until recently interest concerning GlyRs was focused on their role in the spinal cord, whereas they were not believed to serve any major function in the forebrain. However, it is now clear that the GlyR is present and functionally active also in the forebrain, in e.g. the nAc. Thus, experiments using rt-PCR and Western blot have revealed the presence of GlyRs in the nAc (e.g. Jonsson et al., 2009; Jonsson et al., 2012; Molander & Söderpalm, 2005a), and electrophysiological studies have

Ethanol, 5-HT3 receptors the mesolimbic dopamine system

5-HT3 receptors are present in the nAc and their activation facilitates accumbal dopamine release, although they do not appear to be tonically activated by serotonin (Chen et al., 1991, Jiang et al., 1990, Parsons and Justice, 1993). Several reports using in vivo voltammetry or in vivo microdialysis have shown that the increased dopamine output produced by ethanol in the nAc can be prevented by local or systemic administration of drugs antagonizing brain 5-HT3 receptors (Campbell and McBride,

Ethanol, GABAA receptors and the mesolimbic dopamine system

GABAA receptors are abundant along the mesolimbic dopamine system, and interference with these either in the VTA or in the nAc will influence dopamine output in the nAc. Indeed, perfusion of the GABAA channel antagonist picrotoxin in the nAc increases extracellular dopamine levels. Thus, GABAA receptors in this area most likely tonically reduce dopamine output. In consonance with these findings local administration of GABAA agonists reduces extracellular dopamine levels in the nAc (Ferraro et

Ethanol, glutamate receptors and the mesolimbic dopamine system

The relationship between the glutamate system and mesolimbic dopamine activity is complicated. Glutamatergic neurons project both from the prefrontal cortex and from deeper brain regions, e.g. the amygdala, hippocampus and the lateral hypothalamus, to both the VTA and the nAc, and various glutamatergic receptors, both ionotropic and metabotropic, are present in these areas. Several studies using various in vivo techniques have been performed to establish whether glutamatergic receptors control

Ethanol, opioid receptors and the mesolimbic dopamine system

The beneficial effect of opioid antagonists on excessive alcohol consumption has been a subject of interest within the research society for a long time (Altshuler, 1979). The endogenous opioid system is highly present within the brain reward system and participates in the modulation of reward circuits (Mansour et al., 1995, Trigo et al., 2010). Modulation of opioid receptors, using µ- and δ-receptor antagonists as well as β-endorphin knockout mouse models, was found to alter the ethanol-induced

Ghrelin

Ghrelin, a gastric peptide important in regulating hunger and appetite, has in a line of studies been implicated in the reinforcing properties of alcohol. Human studies found that plasma levels of ghrelin are higher in abstinent alcoholic individuals as compared to controls (Kim et al., 2005, Kraus et al., 2005), whereas acute alcohol consumption suppresses plasma levels of the hormone (Calissendorff, Danielsson, Brismar, & Röjdmark, 2005). In addition, the elevated levels of ghrelin in

Glucagon-like peptide-1 (GLP-1)

Glucagon-like peptide 1 is released from the gut but is also present in the brain, i.a. along the mesolimbic dopamine system. This peptide regulates food intake and glucose homeostasis. Lately, numerous studies have indicated that GLP-1 agonists may also regulate various aspects of reward and among them also alcohol reward and reinforcement (Egecioglu et al., 2013, Shirazi et al., 2013). Exendin-4, liraglutide and semaglutide have all to varying extents been shown to reduce alcohol consumption,

Disulfiram

The oldest pharmacological treatment for alcoholism, disulfiram, inhibits aldehyde dehydrogenase, thus producing aversive side effects of alcohol consumption due to accumulation of acetaldehyde. However, even though this is probably the main action of the drug, disulfiram may also influence dopamine activity, since it decreases noradrenaline and increases dopamine levels due to inhibition of dopamine-β-hydroxylase (Bourdélat-Parks et al., 2005, Karamanakos et al., 2001). Moreover, inhibition of

Summary and implications

Both animal and human studies demonstrate that ethanol releases dopamine in the ventral striatum, an essential part of the brain reward system. This dopamine release and consequences thereof are likely involved in the initial positive reinforcing effects of ethanol and at later stages probably both in the positive and negative reinforcing effects of the drug. The latter may be inferred from findings in rats that ethanol’s dopamine elevating effect is preserved after subchronic and chronic

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