Activation of extrasynaptic delta-GABA(A) receptors globally or within the posterior-VTA has estrous-dependent effects on consumption of alcohol and estrous-independent effects on locomotion

作者：Melon Laverne C; Nolan Zachary T; Colar Delphine; Moore Eileen M; Boehm Stephen L II^*

来源：Hormones and Behavior, 2017, 95: 65-75.

DOI：10.1016/j.yhbeh.2017.07.015

• GABA(A)
• Extrasynaptic
• Binge drinking
• THIP
• Females
• Mouse
• Alcohol
• Delta
• Tonic inhibition

Recent reports support higher than expected rates of binge alcohol consumption among women and girls. Unfortunately, few studies have assessed the mechanisms underlying this pattern of intake in females. Studies in males suggest that alcohol concentrations relevant to the beginning stages of binge intoxication may selectively target tonic GABAergic inhibition mediated by GABA(A) receptor subtypes expressing the delta-subunit protein (delta-GABA(A)Rs). Indeed, administration of agonists that interact with these delta-GABA(A)Rs prior to alcohol access can abolish binge drinking behavior in male mice. These delta-GABA(A)Rs have also been shown to exhibit estrous-dependent plasticity in regions relevant to drug taking behavior, like the hippocampus and periaqueductal gray. The present experiments were designed to determine whether the estrous cycle would alter binge drinking, or our ability to modulate this pattern of alcohol use with TRIP, an agonist with high selectivity and efficacy at delta-GABA(A)Rs. Using the Drinking-in-the-Dark (DID) binge-drinking model, regularly cycling female mice were given 2 h of daily access to alcohol (20%v/v). Vaginal cytology or vaginal impedance was assessed after drinking sessions to track estrous status. There was no fluctuation in binge drinking associated with the estrous cycle. Both Intra-posterior-VTA administration of TRIP and systemic administration of the drug was also associated with an estrous cycle dependent reduction in drinking behavior. Pre-treatment with finasteride to inhibit synthesis of 5 alpha-reduced neurosteroids did not disrupt THIP's effects. Analysis of delta-subunit mRNA from posterior-VTA enriched tissue samples revealed that expression of this GABAA receptor subunit is elevated during diestrus in this region. Taken together, these studies demonstrate that delta-GABA(A)Rs in the VTA are an important target for binge drinking in females and confirm that the estrous cycle is an important moderator of the pharmacology of this GABA(A) receptor subtype.

• 出版日期2017-9