Effects of negative modulators of GABAergic efficacy on ethanol intake: Correlation of biochemical changes with pharmacological effect using a behavioral paradigm.

Abstract

Negative allosteric modulators of varying intrinsic efficacies that reduce GABAergic function were evaluated for the ability to decrease the reinforcing properties of ethanol (EtOH) in the selectively bred alcohol-preferring (P) rats. Pretreatment with negative modulators maximally reduced EtOH intake during the initial 15-min interval to 9% to 49% of control levels; however, rank-order potencies of negative modulators to attenuate EtOH intake were not correlated with rank-order potencies of negative modulators to inhibit -/-ammo-butyric acid (GABA) 36 C1~ conductance and enhance 35 S-t-butylbicyclophosphorothionate (TBPS) binding. Thus, the underlying mechanism mediating inhibition of EtOH intake and inhibition of 36 C1~ conductance or enhanced TBPS ratios may not be identical. The ability of inverse agonists to modify the reinforcing actions of EtOH may be related to their affinity at different GABA A -benzodiazepine receptor subtypes.Considerable research has demonstrated that benzodiazepine (BDZ) inverse agonists [negative allosteric modulators of gamma-amino-butyric acid (GABAergic) efficacy] antagonize the actions of ethanol (EtOH) at both the behavioral (for review,

GABAAReceptors Containing α5 Subunits in the CA1 and CA3 Hippocampal Fields Regulate Ethanol-Motivated Behaviors: An Extended Ethanol Reward Circuitry

“…Previously, we reported that rank order potencies of BDZs to attenuate EtOH intake were not correlated with rank order potencies of BDZs to inhibit GABA 36 Cl Ϫ conductance and enhance 35 S-t-butylbicyclophosphorothionate (TBPS) binding (June et al, 1995). Whereas the 36 Cl Ϫ flux and TBPS binding assays use heterogenous subunit populations, with the resulting value obtained representing an "average efficacy," the Xenopus oocyte system permits efficacy to be determined at any different subunit-cDNA combinations (Pritchett et al, 1989;Wafford et al, 1993).…”

A high affinity ligand for GABA A -receptor containing a 5 subunit antagonizes ethanol?s neurobehavioral effects in Long-Evans rats

“…To habituate the rats to the activity monitor prior to any drug treatment, rats were given five daily 10-min sessions (June et al 1995a(June et al , 1995b(June et al , 1998b. These sessions thoroughly habituated the animals to the open field arena.…”

Modulation of α5 Subunit‐Containing GABAA Receptors Alters Alcohol Drinking by Rhesus Monkeys

“…Alcohol's ability to potentiate the activity of γ‐aminobutyric acid (GABA) at GABA A receptors has been implicated as a key mechanism underlying the abuse‐related effects of alcohol in both human and nonhuman subjects (e.g., Hyytiä and Koob, ; June et al., , ; Korpi, ; Söderpalm and Hansen, ). Molecular biological studies have shown that the mammalian GABA A receptor is a pentamer consisting of subunits from at least 5 different families, including the α, β, and γ subunits (McKernan and Whiting, ; Pritchett et al., ; Rudolph et al., ).…”