Dehydroepiandrosterone (DHEA), 7-keto DHEA, and several comparison drugs (ethanol, chlordiazepoxide, rauwolscine, and RO15-4513) were administered to male rats responding under a multiple schedule of food and ethanol presentation to determine their selectively for decreasing ethanol-maintained responding. DHEA and 7-keto DHEA significantly decreased both ethanol- and food-maintained responding, compared to control, while also decreasing blood ethanol concentration (BEC). Acute ethanol administration also decreased responding for both food and ethanol; however, ethanol-maintained responding was more potently decreased than food-maintained responding. BEC remained relatively stable after increasing ethanol doses. Among the other drugs tested, RO15-4513 was the most selective for decreasing ethanol-maintained responding compared to food-maintained responding, and it decreased BECs as ethanol-maintained responding decreased. The largest dose of rauwolscine significantly decreased responding for food, while not affecting ethanol-maintained responding compared to control. Low to intermediate doses of rauwolscine produced small, non-significant increases in ethanol-maintained responding and BECs. Chlordiazepoxide produced significant decreases in food-maintained responding and the dose of ethanol presented, but only at the highest dose tested. Although DHEA and 7-keto DHEA did not decrease ethanol-maintained responding as selectively as ethanol or RO15-4513 under the multiple schedule, these neurosteroids may be valuable pharmacological tools in the development of new treatments for alcohol abuse and dependence.

Background To address the hypothesis that GABAA receptor modulation during adolescence may alter the abuse liability of ethanol during adulthood, the effects of adolescent administration of both a positive and negative GABAA receptor modulator on adult alcohol intake and preference were assessed. Methods Three groups of adolescent male rats received 12 injections of lorazepam (3.2 mg/kg), dehydroepiandrosterone (DHEA, 56 mg/kg), or vehicle on alternate days starting on postnatal day (PD) 35. After this time, the doses were increased to 5.6 and 100 mg/kg, respectively, for three more injections on alternate days. Subjects had access to 25–30 g of food daily during the period of the first six injections, and 18–20 g thereafter. Food intake of each group was measured 60-min after food presentation, which occurred immediately after drug administration on injection days or at the same time of day on non-injection days. When subjects reached adulthood (PD 88), ethanol preference was determined on two separate occasions, an initial 3-day period and a 12-day period in which increasing concentrations of ethanol were presented. During each preference test, intake of water, saccharin, and an ethanol/saccharin solution was measured after each 23-hour access period. Results During adolescence, lorazepam increased 60-minute food intake, and this effect was enhanced under the more restrictive feeding schedule. DHEA had the opposite effect on injection days, decreasing food intake compared to non-injection days. In adulthood, the lorazepam-treated group preferred the two lowest concentrations of ethanol/saccharin more than saccharin alone compared to vehicle-treated subjects, which showed no preference for any concentration of ethanol/saccharin over saccharin. DHEA-treated subjects showed no preference among the three solutions. Conclusions These data demonstrate that GABAA receptor modulation during adolescence can alter intake and preference for ethanol in adulthood, and highlights the importance of drug history as an important variable in the liability for alcohol abuse.

Despite the prevalence of alcohol abuse and dependence in the US and Europe, there are only five approved pharmacotherapies for alcohol dependence. Moreover, these pharmacotherapeutic options have limited clinical utility. The purpose of this paper is to present pertinent literature suggesting that both alcohol and the neurosteroids interact at the GABAA receptor complex and that the neurosteroid sites on this receptor complex could serve as new targets for the development of novel therapeutics for alcohol abuse. This paper will also present data collected by our laboratory showing that one neurosteroid in particular, dehydroepiandrosterone (DHEA), decreases ethanol intake in rats under a variety of conditions. In the process, we will also mention relevant studies from the literature suggesting that both particular subtypes and subunits of the GABAA receptor play an important role in mediating the interaction of neurosteroids and ethanol.

The present study compared two putative pharmacotherapies for alcohol abuse and dependence, dehydroepiandrosterone (DHEA) and pregnanolone, with two Food and Drug Administration (FDA)-approved pharmacotherapies, naltrexone and acamprosate. Experiment 1 assessed the effects of different doses of DHEA, pregnanolone, naltrexone, and acamprosate on both ethanol- and food-maintained responding under a multiple fixed-ratio (FR)-10 FR-20 schedule, respectively. Experiment 2 assessed the effects of different mean intervals of food presentation on responding for ethanol under an FR-10 variable-interval (VI) schedule, whereas Experiment 3 assessed the effects of a single dose of each drug under a FR-10 VI-80 schedule. In Experiment 1, all four drugs dose-dependently decreased response rate for both food and ethanol, although differences in the rate-decreasing effects were apparent among the drugs. DHEA and pregnanolone decreased ethanol-maintained responding more potently than food-maintained responding, whereas the reverse was true for naltrexone. Acamprosate decreased responding for both reinforcers with equal potency. In Experiment 2, different mean intervals of food presentation significantly affected the number of food reinforcers obtained per session; however, changes in the number of food reinforcements did not significantly affect responding for ethanol. Under the FR-10 VI-80 schedule in Experiment 3, only naltrexone significantly decreased both the dose of alcohol presented and blood ethanol concentration (BEC). Acamprosate and pregnanolone had no significant effects on any of the dependent measures, whereas DHEA significantly decreased BEC, but did not significantly decrease response rate or the dose presented. In summary, DHEA and pregnanolone decreased ethanol-maintained responding more potently than food-maintained responding under a multiple FR-10 FR-20 schedule, and were more selective for decreasing ethanol self-administration than either naltrexone or acamprosate under that schedule. Experiment 2 showed that ethanol intake was relatively independent of the density of reinforcement in the food-maintained component, and Experiment 3 showed that naltrexone was the most effective drug at the doses tested when the density for food reinforcement was low and maintained under a variable-interval schedule.

Low‐efficacy positive modulators of the GABAA receptor, such as bretazenil, could potentially treat anxiety disorders with less liability for abuse and dependence than traditional benzodiazepines. For this reason, bretazenil was compared with pentobarbital and lorazepam (high‐efficacy positive modulators) in rats trained to discriminate 10 mg/kg of pentobarbital from saline under a fixed‐ratio 20 schedule of food reinforcement. To establish a dose‐response curve in a single session, a cumulative‐dosing procedure was used in which subjects received increasing doses prior to each of four test components. Full substitution was defined as greater than 80% of total lever presses occurring on the pentobarbital‐associated lever. When increasing doses of pentobarbital were administered, pentobarbital‐lever responding increased up to doses that decreased response rate. Unlike pentobarbital, lorazepam only substituted for pentobarbital at doses that decreased response rate. Bretazenil fully substituted in each subject tested. Furthermore, ineffective doses of bretazenil were able to shift the lorazepam dose‐response curve upward and to the left. Together, these data indicate that bretazenil produces pentobarbital‐like discriminative stimulus effects and enhances the effects of lorazepam, indicating that this combination could be clinically useful for long‐term treatment of anxiety disorders.This work supported by an NIH grant from the National Institute on Alcohol Abuse and Alcoholism AA019848‐01