GABA_A Receptor Modulation During Adolescence Alters Adult Ethanol Intake and Preference in Rats

Abstract

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.

Comparison of dehydroepiandrosterone (DHEA) and pregnanolone with existing pharmacotherapies for alcohol abuse on ethanol- and food-maintained responding in male rats

“…As mentioned earlier, the failure of DHEA and pregnanolone to selectively lower ethanol-maintained responding under the multiple FR-10 VI-80 schedule was somewhat surprising given their effects in several previous studies (Amato et al, 2012; Gurkovskaya et al, 2009; Hulin et al, 2012), and the demonstration of these effects for both home-cage (voluntary) and operant (conditioned) intake procedures. Even without the knowledge gained from these studies, obtaining more potent drug-induced decreases under the ratio schedule for ethanol than the interval schedule for food would not have been surprising.…”

“…Males were used exclusively to limit the differential influence of ovarian hormones on self-administration behavior (Anker & Carroll, 2010, 2011). Eight of the subjects serving in Experiment 1 were involved in a previous experiment during which they received subchronic administration of lorazepam ( n = 3), DHEA ( n = 1), or vehicle ( n = 3) during adolescence (postnatal days 35–64) (Hulin et al, 2012). These adolescent treatments were found to alter their preference for ethanol or saccharin, but following behavioral training under the operant procedure detailed below, the effects of adolescent exposure were no longer evident.…”

“…Voluntary ethanol intake using either a modified saccharin-fading procedure (Amato et al, 2012), or a home-cage procedure (Hulin et al, 2012) was used prior to shaping the subjects to respond on the lever in each experimental chamber. During initial training sessions, the green stimulus light above the lever was illuminated and every response on the lever dispensed 0.1 mL of 32% v/v ethanol to the liquid reservoir.…”

“…Two promising compounds are the neurosteroids dehydroepiandrosterone (DHEA) and pregnanolone, which have been shown to decrease voluntary home-cage ethanol intake and operant responding for ethanol reinforcement in male rats, likely via negative and positive modulation of the GABA A receptor, respectively (Amato, Hulin, & Winsauer, 2012; Gurkovskaya, Leonard, Lewis, & Winsauer, 2009; Hulin, Amato, & Winsauer, 2012). For these substances to be viable clinical options for the treatment of alcohol abuse, however, they should be at least as effective as current treatment options, and ideally, demonstrate selectivity for ethanol-maintained behavior relative to other behaviors (Haney & Spealman, 2008; Wojnicki, Rothman, Rice, & Glowa, 1999).…”

GABAergic contributions to alcohol responsivity during adolescence: Insights from preclinical and clinical studies

“…DHEA-treated animals, however, showed no preference for any of the available solutions. These data demonstrate that GABA A receptor modulation during adolescence can alter intake and preference for ethanol in adulthood, highlighting the importance of drug history as an important variable in the liability for alcohol abuse (Hulin, Amato, & Winsauer, 2012). In contrast, it was reported that exposure to alcohol during adolescence does not necessarily enhance ethanol’s reinforcing properties later in life, findings that could have been related to ethanol initiation/oral self-administration procedures (Tolliver & Samson, 1991).…”