Ethanol Self‐Administration in Deprived Rats: Effects of Ro15‐4513 Alone, and in Combination with Flumazenil (Ro15‐1788)

Abstract

Previous work in our laboratory demonstrated that Ro15-4513, a partial inverse benzodiazepine agonist, decreases self-administration of ethanol (ETOH) in rats maintained on a two-bottle regmine of a saccharin ethanol solution (ES) and water over a 35-day consumption period. The present study extended the consumption period to 60 days and examined the effects of Ro15-4513 (2.5 mg/kg), flumazenil (Ro15-1788) (8.0 mg/kg), and Ro15-4513 in combination with Ro15-1788 on the time course of ETOH self-administration. High initial intake of ES observed during the first 4 weeks declined significantly over subsequent weeks. Ro15-4513 pretreatment, however, resulted in significant reduction of ES, while significantly preventing the "normal" reduction of consumption as was observed under control conditions. The antagonistic actions of Ro15-4513 were blocked/attenuated by the benzodiazepine receptor antagonist, Ro15-1788, independent of whether consumption of the ES was low or high. Both Ro15-4513 and Ro15-1788 affected water intake differentially compared with vehicle-injected controls. The results suggest that GABA-benzodiazepine mechanisms may be important in altering chronic ETOH drinking patterns depending upon experience with ETOH, tolerance, or learning.

GABAA receptor regulation of voluntary ethanol drinking requires PKCϵ

“…The findings of the present work are consistent with diazepam (20 mg/kg)-induced decreases in ethanol intake using a continuous access two-bottle voluntary drinking procedure in rats (Hedlund and Wahlstrom, 1998). Flumazenil, the BZ receptor antagonist, has been shown to reverse reductions in drinking induced by GABA A /BZ partial inverse agonists (June et al, 1992;McBride et al, 1988); however, to our knowledge the effects of a BZ receptor antagonist on diazepam-induced reductions in ethanol intake have not been evaluated. Pretreatment with the GABA A a5 partial inverse agonist L-655,708 increased ethanol intake in the wild-type mice, but was without effect on ethanol consumption in the PKCe null-mutant mice.…”

The discriminative stimulus properties of self-administered ethanol are mediated by GABA A and NMDA receptors in rats

“…One implication of this finding is that the neurobiological mechanisms that mediate the discriminative stimulus effects of alcohol are also recruited during alcohol self-administration. NMDA and GABA A receptor systems are known to mediate the discriminative stimulus effects of ethanol (Barry 1991;Barry and Krimmer 1978;Grant et al 1991;Hiltunen and Järbe 1986;Hodge and Cox 1998;Kline and Young 1986;Kubena and Barry 1969;Overton 1977;York 1978) and to modify alcohol self-administration behavior (Hodge et al 1995;June et al 1992June et al , 1994McBride et al 1988;Rassnick et al 1992Rassnick et al , 1993Samson et al 1989), suggesting that discrimination and self-administration behavior are jointly mediated by NMDA and GABA A systems. The results of the present study extend these findings and suggest that self-administered ethanol produces its discriminative stimulus effects via modulation of NMDA or GABA A receptor systems.…”

“…Positive modu-lators of GABA A receptor function decrease alcohol selfadministration behavior (Hodge et al 1995;June et al 1992June et al , 1994McBride et al 1988;Rassnick et al 1993;Samson et al 1989). Allosteric GABA A -positive modulators such as barbiturates (Barry 1991;Barry and Krimmer 1978;Kline and Young 1986;Overton 1977;York 1978) and benzodiazepines (Hiltunen and Järbe 1986;Kubena and Barry 1969) produce ethanol-like discriminative stimulus effects.…”

Biological Components of Substance Abuse and Addiction

“…These results indicate that the GABA A -BDZ-chloride channel receptor complex may be involved in mediating the reinforcing actions of ethanol that promote alcohol drinking behavior in these rats. The observation that RO 15-4513 blocks oral self-administration of alcohol supports this idea (56,108). Furthermore, treatment with a drug that activates the GABA A receptor was shown to markedly increase the acquisition of voluntary ethanol consumption in laboratory rats (123).…”