Modulation of relapse-like drinking in male Sprague-Dawley rats by ligands targeting the α5GABAA receptor.

Preclinical evidence suggests a key role for GABAA receptors containing the α5 subunit (i.e., α5GABAA receptors) in the abuse-related effects of alcohol, including the reinforcing and discriminative stimulus effects, as well as cue-induced alcohol-seeking behavior. However, the contribution of this GABAA receptor subtype to relapse-like drinking behavior remains unknown. The present study evaluated the capacity of ligands targeting α5GABAA receptors to modulate the alcohol deprivation effect (ADE), a model of relapse-like drinking. Groups of Sprague-Dawley rats underwent repeated cycles of long-term access to alcohol solutions (5%, 10%, 20% v/v) and water in the home cage followed by water only deprivation periods. Upon evidence that the ADE could be reliably expressed across cycles, drug treatment was initiated. One group received the α5GABAA receptor-preferring agonist QH-ii-066 and the other group received the α5GABAA receptor-selective inverse agonist L-655,708. At the end of ADE testing, rats underwent testing in the elevated zero maze under vehicle or L-655,708 treatment for assessment of anxiety-like behavior. The ADE was reliably expressed across repeated cycles of alcohol access/deprivation in a subset of rats. Low doses of QH-ii-066 enhanced expression of the ADE; whereas, L-655,708 dose-dependently inhibited expression of the ADE. L-655,708 did not engender anxiogenic effects in the elevated zero maze under the conditions evaluated. These findings suggest a key role for α5GABAA receptor mechanisms in relapse-like drinking. Moreover, they suggest that α5GABAA receptors may represent a novel pharmacological target for the development of medications to prevent or reduce alcohol relapse.

α5GABAA subunit-containing receptors and sweetened alcohol cue-induced reinstatement and active sweetened alcohol self-administration in male rats.

RATIONALE: GABAA receptors containing the α5 subunit (i.e., α5GABAA receptors) appear to be critically involved in the reinforcing and subjective effects of alcohol. Their role in alcohol relapse remains unknown. OBJECTIVES: Pharmacological approaches were used to probe the role of α5GABAA receptors in alcohol seeking induced by re-exposure to a sweetened alcohol-paired cue, as well as in alcohol + sucrose vs. sucrose self-administration. METHODS: For reinstatement studies, rats were trained to self-administer alcohol under a fixed-ratio schedule in which responding was maintained by alcohol + sucrose deliveries and an alcohol-paired stimulus. Sweetened alcohol seeking was extinguished by eliminating solution deliveries and the sweetened alcohol-paired stimulus. During reinstatement tests, animals received pretreatments of an α5GABAA inverse agonist (L-655,708) or an agonist (QH-ii-066) prior to sessions in which presentation of the sweetened alcohol-paired stimulus was restored, but no solution was delivered. For self-administration studies, rats were trained to self-administer alcohol + sucrose or sucrose under a fixed-ratio schedule. Once stable, animals received pretreatments of QH-ii-066, L-655,708, the inverse agonist RY-023, or naltrexone. RESULTS: L-655,708 attenuated reinstatement of sweetened alcohol seeking by alcohol + sucrose-paired cues; whereas sweetened alcohol-seeking behavior was augmented by QH-ii-066, albeit at different doses in different rats. Both L-655,708 and RY-023 selectively reduced alcohol + sucrose vs. sucrose self-administration. In contrast, naltrexone reduced both alcohol + sucrose and sucrose self-administration; whereas QH-ii-066 enhanced sucrose self-administration only. CONCLUSIONS: α5GABAA receptors play a key role in the modulation of sweetened alcohol cue-induced reinstatement, as well as in alcohol + sucrose but not sucrose self-administration. Inverse agonist activity at α5GABAA receptors may offer a novel strategy for both the reduction of problematic drinking and the prevention of relapse.

An antidepressant-related pharmacological signature for positive allosteric modulators of α2/3-containing GABAA receptors.

Data from transgenic animals and novel pharmacological agents has realigned scientific scrutiny on the therapeutic potential of positive allosteric modulators (PAMs) of α2/3-containing GABAA receptors. Evidence for analgesic, anticonvulsant, and anxiolytic activity of α2/3-selective PAMs has been presented along with the clinical potential for a milder motor-impacting profile compared to non-selective GABAA receptor PAMs. A new series of α2/3-selective PAMs was recently introduced which has anxiolytic and anticonvulsant activity in rodent models. These molecules also produce efficacy against pain in multiple animal models. Additionally, co-morbid states of depression are prevalent among patients with pain and patients with anxiety. Compounds were shown to be selective for α2 and α3 constructs over α1 (except KRM-II-82), α4, α5, and α6 proteins in electrophysiological assays in transfected HEK-293T cells. Utilizing the forced-swim assay in mice that detects conventional and novel antidepressant drugs, we demonstrate for the first time that α2/3-selective PAMs are active in the forced-swim assay at anxiolytic-producing doses. In contrast, activity in a related model, the tail-suspension test, was not observed. Diazepam was not active in the forced-swim assay when given alone but produced an antidepressant-like effect in mice when given in conjunction with the α1-preferring antagonist, ß-CCT, that attenuated the motor-impairing effects of diazepam. We conclude that these α2/3-selective PAMs deserve further scrutiny for their potential treatment of major depressive disorder. If effective, such a mechanism could add a beneficial antidepressant component to the anxiolytic, analgesic, and anticonvulsant spectrum of effects of these compounds.