A comparison of dehydroepiandrosterone and 7-keto dehydroepiandrosterone with other drugs that modulate ethanol intake in rats responding under a multiple schedule

Abstract

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 selectivity for decreasing ethanol-maintained responding. DHEA and 7-keto DHEA significantly decreased both ethanol-maintained and food-maintained responding, compared with the control, while also decreasing the 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 with food-maintained responding, and it decreased BECs as ethanol-maintained responding decreased. The largest dose of rauwolscine significantly decreased responding for food, whereas it did not affect ethanol-maintained responding compared with the control. Low to intermediate doses of rauwolscine produced small, nonsignificant 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.

Fig. 1

Effects of peripheral ethanol administration in 8 rats responding under a multiple schedule of food (FR 20) and ethanol (FR 10) presentation. Unfilled circles represent response rate during the ethanol component, whereas filled circles represent response rate during the food component. The reinforcer in the ethanol component was 0.1 ml of 32% (v/v) ethanol, whereas the reinforcer in the food component was 45-mg food pellets. The dependent measures were response rate (response/min), blood ethanol concentration (mg/dl), and the ethanol dose presented (g/kg). The points and vertical lines above “V” indicate the mean and standard error of the mean (SEM) for sessions in which vehicle was administered (control). The mean rate of responding for food was 59.39 ± 8.48 responses/min, whereas the mean rate of responding for ethanol was 16.94 ± 6.56 responses/min. The points with vertical lines in the dose-effect data indicate the mean and SEM for sessions in which ethanol was administered. The points without vertical lines indicate instances in which the SEM is encompassed by the point. Asterisks indicate significant differences from control.

Fig. 2

Effects of acute administration of DHEA (n=7) and 7-keto DHEA (n=9) in rats responding under a multiple schedule of food and ethanol presentation. Unfilled symbols represent response rate during the ethanol component, whereas filled symbols represent response rate during the food component. The dependent measures were response rate (response/min), blood ethanol concentration (mg/dl), and the ethanol dose presented (g/kg). The mean rate of responding for food was 46.42 ± 5.43 responses/min during testing with DHEA and 49.14 ± 8.48 responses/min during testing with 7-keto DHEA, whereas the mean rate of responding for ethanol was 13.95 ± 3.56 responses/min and 12.97 ± 3.97 responses/min, respectively. The numbers in parentheses indicate the number of subjects for that data point when it was less than 7 (DHEA) or 8 (7-keto DHEA) due to the elimination of responding in some subjects at the higher doses. Asterisks indicate significant differences from vehicle administration (control). The bracket in the top panel indicates that the main effect of DHEA dose was analyzed with the data for each reinforcer combined as the interaction was not significant. In the middle panel, all of the data points within the bracket were significantly different from vehicle (control).

Fig. 3

Effects of acute administration of chlordiazepoxide in 9 rats responding under a multiple schedule of food and ethanol presentation. Unfilled circles represent response rate during the ethanol component, whereas filled circles represent response rate during the food component. The dependent measures were response rate (response/min) and dose of ethanol presented (g/kg). The mean rate of responding for food was 62.84 ± 10.68 responses/min, whereas the mean rate of responding for ethanol was 18.79 ± 6.05 responses/min. Letters indicate significant differences among doses (e.g., ‘a’ is significantly different from ‘b’, but not significantly different from ‘a,b’). Asterisks indicate significant differences from vehicle (control).

Fig. 4

Effects of acute administration of rauwolscine in 7 rats responding under a multiple schedule of food and ethanol presentation. Unfilled circles represent response rate during the ethanol component, whereas filled circles represent response rate during the food component. The dependent measures were response rate (response/min), blood ethanol concentration (mg/dl), and dose of ethanol presented (g/kg). The mean rate of responding for food was 49.90 ± 13.75 responses/min, whereas the mean rate of responding for ethanol was 9.30 ± 1.57 responses/min. Letters indicate significant differences among doses. For further detail, see legend for Fig. 3.

Fig. 5

Effects of acute administration of RO15-4513 in 9 rats responding under a multiple schedule of food and ethanol presentation. Unfilled circles represent response rate during the ethanol component, whereas filled circles represent response rate during the food component. The dependent measures were response rate (response/min), blood ethanol concentration (mg/dl), and dose of ethanol presented (g/kg). The mean rate of responding for food was 58.05 ± 10.32 responses/min, whereas the mean rate of responding for ethanol was 13.39 ± 3.02 responses/min. Asterisks indicate significant differences from control.