Abstract
Dopamine and serotonin (5-HT) in the nucleus accumbens (ACC) and ventral tegmental area of the mesoaccumbens reward pathways have been implicated in the mechanisms underlying development of alcohol dependence. We used a C57BL/6J mouse model with increased voluntary alcohol-drinking behavior by exposing the mice to alcohol vapor for 20 consecutive days. In the alcohol-exposed mice, the expression of 5-HT2C receptor mRNA increased in the ACC, caudate nucleus and putamen, dorsal raphe nucleus (DRN), hippocampus and lateral hypothalamus, while the protein level of 5-HT2C receptor significantly increased in the ACC. The expression of 5-HT7 receptor mRNA increased in the ACC and DRN. Contents of 5-HT decreased in the ACC shell (ACCS) and DRN of the alcohol-exposed mice. The basal extracellular releases of dopamine (DA) and 5-HT in the ACCS increased more in the alcohol-exposed mice than in alcohol-naïve mice. The magnitude of the alcohol-induced ACCS DA and 5-HT release in the alcohol-exposed mice was increased compared with the control mice. Intraperitoneal (i.p.) administration or local injection into ACCS of the 5-HT2C receptor antagonist, SB-242084, suppressed voluntary alcohol-drinking behavior in the alcohol-exposed mice. But the i.p. administration of the 5-HT7 receptor antagonist, SB-258719, did not have significant effects on alcohol-drinking behavior in the alcohol-exposed mice. The effects of the 5-HT2C receptor antagonist were not observed in the air-exposed control mice. These results suggest that adaptations of the 5-HT system, especially the upregulation of 5-HT2C receptors in the ACCS, are involved in the development of enhanced voluntary alcohol-drinking behavior.
Highlights
It is generally thought that alcohol is consumed for its positive reinforcing effects, and that chronic exposure to alcohol results in adaptations with abnormal drinking patterns (Clapp et al, 2008; Koob & Volkow, 2010)
The mice exposed to alcohol vapor showed an increase in alcohol consumption as a percentage of total fluid intake (Fig. 1G), because there was no significant difference in water intake of the two groups of mice in the alcohol consumption test (Fig. 1F)
To examine adaptive and compensatory processes in the mesoaccumbens reward pathway that mediate the development from occasional drinking to active and compulsive drinking that leads to excessive alcohol consumption, we investigated the effects of inhaling alcohol vapor for 20 consecutive days on the levels of DA and 5-HT and their metabolites, dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindoleacetic acid (5HIAA)
Summary
It is generally thought that alcohol is consumed for its positive reinforcing effects, and that chronic exposure to alcohol results in adaptations with abnormal drinking patterns (Clapp et al, 2008; Koob & Volkow, 2010). While 5-HT2C receptor activation has been shown to decrease cocaine (Fletcher et al, 2004) and alcohol (Tomkins et al, 2002) selfadministration, the 5-HT2A ⁄ 2C receptor antagonists ritanserin and ketanserin failed to alter cocaine or amphetamine self-administration (Schenk, 2000). 5-HT2C receptors play an inhibitory role in the regulation of reward-related behavior (De Deurwaerdere et al, 2004; Hayes & Greenshaw, 2011). It is not clear which 5HT receptors are involved in synaptic functions of the mesoaccumbens reward pathway that is associated with enhanced voluntary alcohol-drinking behavior
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