QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (38) Citing Articles via Google Scholar Google Scholar Articles by June, H. L. Articles by Cook, J. M. Search for Related Content PubMed PubMed Citation Articles by June, H. L. Articles by Cook, J. M.

 Previous Article  |  Next Article 

The Journal of Neuroscience, March 15, 2001, 21(6):2166-2177

GABA_A Receptors Containing 5 Subunits in the CA1 and CA3 Hippocampal Fields Regulate Ethanol-Motivated Behaviors: An Extended Ethanol Reward Circuitry

Harry L. June¹, Scott C. Harvey², Katrina L. Foster¹, Peter F. McKay¹, Rancia Cummings¹, Marin Garcia¹, Dynesha Mason¹, Collette Grey¹, Shannan McCane¹, La Shone Williams¹, Timothy B. Johnson¹, Xiaohui He³, Stephanie Rock¹, and James M. Cook³

¹ Psychobiology Program, Department of Psychology, Indiana University-Purdue University, Indianapolis, Indiana 46202, ² Laboratory of Neuroscience, Eli Lilly & Company, Indianapolis, Indiana 46285, and ³ Department of Chemistry, University of Wisconsin, Milwaukee, Wisconsin 53201

GABA receptors within the mesolimbic circuitry have been proposed to play a role in regulating alcohol-seeking behaviors in the alcohol-preferring (P) rat. However, the precise GABA_A receptor subunit(s) mediating the reinforcing properties of EtOH remains unknown. We examined the capacity of intrahippocampal infusions of an 5 subunit-selective (~75-fold) benzodiazepine (BDZ) inverse agonist [i.e., RY 023 (RY) (tert-butyl 8-(trimethylsilyl) acetylene-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5a] [1,4] benzodiazepine-3-carboxylate)] to alter lever pressing maintained by concurrent presentation of EtOH (10% v/v) and a saccharin solution (0.05% w/v). Bilateral (1.5-20 µg) and unilateral (0.01-40 µg) RY dose-dependently reduced EtOH-maintained responding, with saccharin-maintained responding being reduced only with the highest doses (e.g., 20 and 40 µg). The competitive BDZ antagonist ZK 93426 (ZK) (7 µg) reversed the RY-induced suppression on EtOH-maintained responding, confirming that the effect was mediated via the BDZ site on the GABA_A receptor complex. Intrahippocampal modulation of the EtOH-maintained responding was site-specific; no antagonism by RY after intra-accumbens [nucleus accumbens (NACC)] and intraventral tegmental [ventral tegmental area (VTA)] infusions was observed. Because the VTA and NACC contain very high densities of 1 and 2 subunits, respectively, we determined whether RY exhibited a "negative" or "neutral" pharmacological profile at recombinant 132, 232, and 532 receptors expressed in Xenopus oocytes. RY produced "classic" inverse agonism at all  receptor subtypes; thus, a neutral efficacy was not sufficient to explain the failure of RY to alter EtOH responding in the NACC or VTA. The results provide the first demonstration that the 5-containing GABA_A receptors in the hippocampus play an important role in regulating EtOH-seeking behaviors.

Key words: ethanol; GABA; 5 subunit; reinforcement; hippocampus; alcohol-preferring (P) rat

---

Copyright © 2001 Society for Neuroscience  0270-6474/01/2162166-12$05.00/0

This article has been cited by other articles:

				J. R. Atack, A. Pike, A. Clarke, S. M. Cook, B. Sohal, R. M. McKernan, and G. R. Dawson RAT PHARMACOKINETICS AND PHARMACODYNAMICS OF A SUSTAINED RELEASE FORMULATION OF THE GABAA {alpha}5-SELECTIVE COMPOUND L-655,708 Drug Metab. Dispos., May 1, 2006; 34(5): 887 - 893. [Abstract] [Full Text] [PDF]

				D. M. Platt, A. Duggan, R. D. Spealman, J. M. Cook, X. Li, W. Yin, and J. K. Rowlett Contribution of {alpha}1GABAA and {alpha}5GABAA Receptor Subtypes to the Discriminative Stimulus Effects of Ethanol in Squirrel Monkeys J. Pharmacol. Exp. Ther., May 1, 2005; 313(2): 658 - 667. [Abstract] [Full Text] [PDF]

				R. T. Robinson, B. C. Drafts, and J. L. Fisher Fluoxetine Increases GABAA Receptor Activity through a Novel Modulatory Site J. Pharmacol. Exp. Ther., March 1, 2003; 304(3): 978 - 984. [Abstract] [Full Text] [PDF]

				S. C. Harvey, K. L. Foster, P. F. McKay, M. R. Carroll, R. Seyoum, J. E. Woods II, C. Grey, C. M. Jones, S. McCane, R. Cummings, et al. The GABAA Receptor alpha 1 Subtype in the Ventral Pallidum Regulates Alcohol-Seeking Behaviors J. Neurosci., May 1, 2002; 22(9): 3765 - 3775. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help