Ethanol consumption in the Sprague–Dawley rat increases sensitivity of the dorsal raphe nucleus to 5,7-dihydroxytryptamine

•Intermittent access 2-bottle choice induces 20% EtOH intake in Sprague–Dawley rats.•Individual EtOH consumption patterns separate rats into Drinkers and Non-drinkers.•EtOH intake is not affected by 5-HT depletion with 5,7-DHT.•The ventromedial DRN sub-region is preserved with icv administered 5,7-DHT.•Drinkers are more sensitive to 5-HT depletion than Non-drinkers.

Alcoholism afflicts 1 in 13 US adults, and comorbidity with depression is common. Levels of serotonin (5-HT) metabolites in alcoholic or depressed humans and rat strains are lower compared to healthy counterparts. Rats bred for ethanol (EtOH) preference are common in EtOH studies, however out-bred strains better model the range of EtOH consumption in humans. We examined voluntary EtOH consumption in out-bred Sprague–Dawley (SD) rats placed in the 20% EtOH intermittent access drinking paradigm (IA). Acquisition of 20% EtOH consumption (g EtOH/kg/24 h) was assessed during the first 6–8 weeks of IA. Rats naturally separated into two groups (Drinkers or Non-drinkers) based on EtOH intake above or below 0.5 g/kg/24 h prior to treatment intervention. We examined the effect of central 5-HT depletion on EtOH consumption by infusing 5,7-dihyroxytryptamine (5,7-DHT; i.c.v., 200–300 μg) or vehicle and measured EtOH consumption for 4 weeks post-operatively in IA. Compared to baseline, there was no effect of vehicle or 5,7-DHT on EtOH consumption during the post-operative period. Quantification of 5-HT depletion in the dorsal raphe nucleus (DRN) using tryptophan hydroxylase-2 (TPH2) immunohistochemistry resulted in a 76% decrease in staining with 5,7-DHT treatment. Interestingly, preservation of the ventromedial (VM) sub-regions was evident in all animals treated with 5,7-DHT, regardless of drinking behavior. In addition, Drinkers treated with 5,7-DHT had significantly more TPH2 depletion in the DRN compared to Non-drinkers. Our findings indicate that out-bred SD rats exhibit a natural EtOH consumption behavior (Drinker or Non-drinker) that is stable across time and independent of 5-HT depletion in the CNS. In addition, rats that regularly consumed >0.5 g EtOH/kg had greater sensitivity to 5,7-DHT in the DRN, indicating an interaction between EtOH and sensitivity of DRN 5-HT cells to neurotoxic substances. This may contribute to the dysfunctionality of the 5-HT system in alcoholic humans and lead to a better understanding of current pharmacological treatments for this addiction.