Background-Adolescent alcohol use may contribute to long-term changes in the receptors and neuroactive steroids that may mediate its effects and to subsequent alcohol abuse and dependence as an adult. Therefore, in the present study, ethanol preference and intake as an adult were examined after adolescent ethanol or saline administration. In addition, ethanol intake in the same groups was examined after administration of two neuroactive steroids with modulatory effects at GABA A receptors.
Administration of dehydroepiandrosterone (DHEA), a neurosteroid that can negatively modulate the GABAA receptor, has been shown to decrease voluntary intake of ethanol in rats. In vivo, DHEA can be metabolized to a variety of metabolites, including 7-keto DHEA, a metabolite without the prohormonal effects of DHEA. This study compared the effectiveness of 7-keto DHEA to DHEA for reducing ethanol intake in the same group of rats. The subjects, previously trained to drink ethanol using a saccharin-fading procedure, had access to ethanol for thirty minutes daily, and the amount consumed was recorded. Subjects were administered 10 and 56 mg/kg of DHEA or 7-keto DHEA intraperitoneally 15 minutes prior to drinking sessions. Subjects received each particular dose daily until one of two criteria was met; that is, either ethanol intake did not differ by more than 20% of the mean for three consecutive days, or for a maximum of eight days. Both 10 and 56 mg/kg of 7-keto DHEA significantly reduced the dose of ethanol consumed. While 10 mg/kg of 7-keto DHEA produced decreases similar to those found with DHEA, the 56-mg/kg dose of 7-keto DHEA was significantly more effective at decreasing the dose of ethanol consumed than the same dose of DHEA. These results show that 7-keto DHEA is comparable to, or possibly more effective than, DHEA at decreasing ethanol consumption in rats, and that 7-keto DHEA is a compound deserving further investigation as a possible clinical treatment for alcohol abuse without the prohormonal effects of DHEA.
Adolescent alcohol use may produce long-term changes in the receptors and neurosteroids that putatively mediate alcohol's effects and consequently contribute to alcohol abuse and dependence as an adult. To test this possibility, ethanol (0.18-1.8 g/kg) and two neurosteroids, pregnanolone (1-10 mg/kg) and dehydroepiandrosterone (DHEA, 1-100 mg/kg), were administered alone and in combination to adult, male Long-Evans rats discriminating 1 g/kg ethanol (15% v/v) under a fixed ratio (FR) 20 schedule of food presentation after adolescent treatment with 15 injections of ethanol (n=9, 2 g/kg, 20% v/v) or saline (n=7). When compared as adults, ethanol-treated adolescents (as opposed to saline-treated adolescents) had higher percentages of ethanol-lever responding at doses smaller than the training dose, and higher response rates after both control and ethanol injections. Neither pregnanolone nor DHEA substituted for ethanol in either adolescent-treated group up to doses that substantially decreased response rates. When administered with ethanol, 1 and 3.2 mg/kg of pregnanolone enhanced the discriminative stimulus effects of small ethanol doses more in saline-treated adolescents than ethanol-treated adolescents. Unlike pregnanolone, 32 and 100 mg/kg of DHEA attenuated the discriminative stimulus effects of ethanol modestly in both adolescent-treated groups. These results in adult rats suggest that adolescent ethanol administration can enhance the discriminative stimulus effects of small ethanol doses and affect the capacity of pregnanolone, but not DHEA, to interact with ethanol's discriminative stimulus effects.
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