title: GABAA receptors in the posterior, but not anterior, ventral tegmental area mediate Ro15-4513-induced attenuation of binge-like ethanol consumption in C57BL/6J female mice.
abstract: GABA(A) receptors have been shown to modulate dopaminergic output from the ventral tegmental area (VTA) in studies of both natural and drug rewards, including alcohol. Ro15-4513, the imidazobenzodiazepine derivative and allosteric modulator at the GABA(A) receptor, reliably antagonizes the behavioral effects of alcohol. Various models of alcohol consumption show a decrease in consummatory behaviors, specific to ethanol, following acute administration of the drug. In the present study, Ro15-4513 was systemically administered, or microinjected into the anterior or posterior VTA, to explore the role of GABA(A) receptors at this region in modulating the high pattern of alcohol consumption by C57BL/6J inbred mice in the Drinking in the Dark (DID) model. Animals had 2h access to ethanol for 6 days prior to drug manipulations. Immediately before the seventh day of access, mice were systemically (I.P.) or site-specifically administered Ro15-4513. Systemic Ro15-4513 (at 10mg/kg) decreased binge-like ethanol intake in the DID paradigm. Additionally, there was a stepwise decrease in consumption following Ro15-4513 microinjection into the posterior VTA, with the highest dose significantly decreasing ethanol intake. There was no effect found following microinjection into the anterior VTA, nor was there an effect of systemic or intra-posterior VTA Ro15-4513 on consumption of a 5% sucrose solution or water. The present findings support a role for Ro15-4513 sensitive VTA-GABA(A) receptors in modulating binge-like ethanol consumption. Moreover, the work here adds to the growing body of literature suggesting regional heterogeneity in the VTA.
authors.affiliation: Psychobiology of Addictions, Department of Psychology, Indiana University/Purdue University-Indianapolis, Indianapolis, IN 46202, USA. lcmelon@iupui.edu
authors.forename: Laverne C
authors.initials: LC
authors.lastname: Melón
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Boehm
mesh_terms: D000428:Alcohol Drinking / Q000097:blood / Q000188:drug therapy*; D000704:Analysis of Variance; D000818:Animals; D001386:Azides / Q000627:therapeutic use*; D001569:Benzodiazepines / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004326:Drinking / Q000187:drug effects; D004333:Drug Administration Routes; D000431:Ethanol / Q000008:administration & dosage* / Q000097:blood; D005260:Female; D018757:GABA Modulators / Q000627:therapeutic use*; D058785:GABA-A Receptor Agonists / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008845:Microinjections / Q000379:methods; D013395:Sucrose / Q000008:administration & dosage; D017557:Ventral Tegmental Area / Q000033:anatomy & histology* / Q000187:drug effects / Q000378:metabolism*
chemical_list: D001386:Azides; D018757:GABA Modulators; D058785:GABA-A Receptor Agonists; D001569:Benzodiazepines; D000431:Ethanol; D013395:Sucrose; C042957:Ro 15-4513