Binge drinking, defined as achieving blood ethanol concentrations (BEC) of 80 mg%, has been increasing in adolescents and was reported to predispose later physical dependence. The present experiments utilized an animal model of binge drinking to compare the effect of ethanol “binge” experience during adolescence or adulthood on subsequent ethanol intake in male and female C57BL/6 mice. Adolescent and adult mice were initially exposed to the scheduled high alcohol consumption procedure, which produces BECs that exceed the levels for binge drinking following a 30 min ethanol session every third day. Ethanol intake and BECs were significantly higher in the adolescent (∼3 g/kg, 199 mg%) versus adult (∼2 g/kg, 135 mg%) mice during the first three ethanol sessions, but were more equivalent during the final two ethanol sessions (1.85-2.0 g/kg, 129-143 mg%). Then, separate groups of the ethanol experienced mice were tested with ethanol naïve adolescent and adult mice for 2-hr limited access (10 and 20% solutions) or 24-hr (5, 10 and 20% solutions) ethanol preference drinking. Limited access ethanol intake was significantly higher in female versus male mice, but was not altered by age or ethanol experience. In contrast, 24-hr ethanol intake was significantly higher in the adolescent versus adult mice and in female versus male mice. Furthermore, binge drinking experience in the adolescent mice significantly increased subsequent ethanol intake, primarily due to intake in female mice. Thus, adolescent binge drinking significantly increased unlimited ethanol intake during adulthood, with female mice more susceptible to this effect.
Background-Allopregnanolone (ALLO) is a physiologically-relevant neurosteroid modulator of GABA A receptors, and it exhibits a psychopharmacological profile that closely resembles the postingestive effects of ethanol. The 5α-reductase inhibitor finasteride (FIN), which inhibits biosynthesis of ALLO and structurally-related neurosteroids, was previously demonstrated to reduce the maintenance of limited-access ethanol consumption. The primary aim of the current work was to determine whether FIN would reduce the acquisition of drinking in ethanol-naïve mice.
Recent evidence suggests that GABAA receptor ligands may regulate ethanol intake via effects at both synaptic and extrasynaptic receptors. For example, the endogenous neurosteroid, allopregnanolone (ALLO) has a similar pharmacological profile as ethanol, and it alters ethanol intake in rodent models. Additionally, recent evidence suggests that δ-subunit containing extrasynaptic GABAA receptors may confer high sensitivity to both ethanol and neurosteroids. The purpose of the present study was to determine the effects of ganaxolone (GAN; an ALLO analogue) and gaboxadol (THIP; a GABAA receptor agonist with selectivity for the extrasynaptic δ-subunit) on ethanol intake, drinking patterns, and bout characteristics in operant and limited access self-administration procedures. In separate studies, the effects of GAN (0 – 10 mg/kg) and THIP (2 – 16 mg/kg) were tested in C57BL/6J male mice provided with two-hour access to a two-bottle choice of water or 10% ethanol or trained to respond for 30 minutes of access to 10% ethanol. GAN had no overall significant effect on operant ethanol self-administration, but tended to decrease the latency to consume the first bout. In the limited-access procedure, GAN dose-dependently decreased ethanol intake. THIP dose-dependently decreased ethanol intake in both paradigms, altering both the consummatory and appetitive processes of operant self-administration as well as shifting the drinking patterns in both procedures. These results add to literature suggesting time-dependent effects of neurosteroids to promote the onset, and to subsequently decrease, ethanol drinking behavior, and they support a role for extrasynaptic GABAA receptor activation in ethanol reinforcement.
Rationale Recent work in our laboratory documented that the “sipper” method of operant ethanol self-administration produced high ethanol intake and blood ethanol concentrations as well as the typical extinction “burst” in responding under non-reinforced conditions in male C57BL/6 mice. However, the neurochemical basis for reinstatement of responding following extinction has not been examined in mice with this model. Objectives Based on findings that the GABAergic neurosteroid allopregnanolone (ALLO) significantly increased the consummatory phase of ethanol self-administration, the present study determined the effect of ALLO on reinstatement of extinguished ethanol-seeking behavior and compared this effect to reinstatement of responding for sucrose reward. Methods Separate groups of male C57BL/6 mice were trained to lever press for access to a 10% ethanol (10E) or a 5% sucrose (5S) solution. A single response requirement of 16 presses (RR16) on an active lever resulted in 30 min of continuous access to the 10E or 5S solution. After the animals responded on the RR16 schedule for 14 weeks, mice were exposed to 30 min extinction sessions where responding had no scheduled consequence. Once responding stabilized below the pre-extinction baseline, mice received an IP injection of ALLO (0, 3.2, 5.6, 10 or 17 mg/kg) 15 min prior to the extinction session in a within-subjects design. Results ALLO produced a dose-dependent increase in responding under non-reinforced conditions in both the 10E and 5S groups. Additional work documented the ability of a conditioned cue light or a compound cue (light+lever retraction) to reinstate non-reinforced responding on the previously active lever. Conclusions These findings definitively show that conditioned cues and priming with ALLO are potent stimuli for reinstating both ethanol and sucrose seeking behavior in C57BL/6 mice.
Neuronal nicotinic acetylcholine receptors (nAChRs) are believed to be critically involved in ethanol-related behaviors as well as in neurochemical responses to ethanol. However, discernment of nAChR contribution to ethanol reinforcement and consumption remains incomplete. The current studies examined the influence of the nAChR antagonist mecamylamine (MEC) on operant ethanol self-administration using a procedure that independently assessed appetitive and consumptive processes, and compared these findings to effects of MEC on sucrose self-administration. Male C57BL/6J (B6) mice were trained to respond for 30-min access to a retractable drinking tube containing either 10% v/v ethanol (10E) or 5% w/v sucrose (5S). Once trained, mice were habituated to saline injection and then treated with a series of MEC doses (0 - 8 mg/kg; i.p.) in a within-subject design. In a separate cohort, MEC was evaluated for its influence on locomotor activity. MEC dose-dependently reduced 10E and 5S self-administration. The suppression in ethanol intake was attributable to a reduction in bout frequency, whereas the attenuation in sucrose intake was due to a decrease in bout size. Doses of MEC (6 - 8 mg/kg) that altered drinking patterns were also found to impair locomotor activity. Although MEC non-selectively reduced 10E and 5S intakes in mice, there was some specificity in alterations of the underlying drinking pattern for each reinforcer. Assessment of drinking topography within an operant self-administration procedure may provide useful insights regarding the role of nAChR function in the regulation of ethanol consumption.
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