GABA(A) receptors containing (alpha)5 subunits in the CA1 and CA3 hippocampal fields regulate ethanol-motivated behaviors: an extended ethanol reward circuitry

dc.contributor.authorJune, Harry L.
dc.contributor.authorHarvey, Scott C.
dc.contributor.authorFoster, Katrina L.
dc.contributor.authorMcKay, Peter F.
dc.contributor.authorCummings, Rancia
dc.contributor.authorGarcia, Marin
dc.contributor.authorMason, Dynesha
dc.contributor.authorGrey, Collette
dc.contributor.authorMcCane, Shannan
dc.contributor.authorWilliams, La Shone
dc.contributor.authorJohnson, Timothy B.
dc.contributor.authorHe, Xiaohui
dc.contributor.authorRock, Stephanie
dc.contributor.authorCook, James M.
dc.contributor.departmentPsychology, School of Scienceen_US
dc.date.accessioned2020-02-18T21:13:53Z
dc.date.available2020-02-18T21:13:53Z
dc.date.issued2001-03-15
dc.description.abstractGABA 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 alpha5 subunit-selective ( approximately 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 microgram) and unilateral (0.01-40 microgram) RY dose-dependently reduced EtOH-maintained responding, with saccharin-maintained responding being reduced only with the highest doses (e.g., 20 and 40 microgram). The competitive BDZ antagonist ZK 93426 (ZK) (7 microgram) 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 alpha1 and alpha2 subunits, respectively, we determined whether RY exhibited a "negative" or "neutral" pharmacological profile at recombinant alpha1beta3gamma2, alpha2beta3gamma2, and alpha5beta3gamma2 receptors expressed in Xenopus oocytes. RY produced "classic" inverse agonism at all alpha 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 alpha5-containing GABA(A) receptors in the hippocampus play an important role in regulating EtOH-seeking behaviors.en_US
dc.eprint.versionFinal published versionen_US
dc.identifier.citationJune, H. L., Harvey, S. C., Foster, K. L., McKay, P. F., Cummings, R., Garcia, M., Mason, D., Grey, C., McCane, S., Williams, L. S., Johnson, T. B., He, X., Rock, S., & Cook, J. M. (2001). GABA(A) receptors containing (alpha)5 subunits in the CA1 and CA3 hippocampal fields regulate ethanol-motivated behaviors: an extended ethanol reward circuitry. The Journal of neuroscience : the official journal of the Society for Neuroscience, 21(6), 2166–2177. https://doi.org/10.1523/JNEUROSCI.21-06-02166.2001en_US
dc.identifier.urihttps://hdl.handle.net/1805/22099
dc.language.isoen_USen_US
dc.publisherSociety for Neuroscienceen_US
dc.relation.isversionof10.1523/JNEUROSCI.21-06-02166.2001en_US
dc.relation.journalJournal of Neuroscienceen_US
dc.rightsPublisher Policyen_US
dc.sourcePMCen_US
dc.subjectEthanolen_US
dc.subjectGABAen_US
dc.subjectα5 subuniten_US
dc.subjectReinforcementen_US
dc.subjectHippocampusen_US
dc.subjectAlcohol-preferring (P) raten_US
dc.titleGABA(A) receptors containing (alpha)5 subunits in the CA1 and CA3 hippocampal fields regulate ethanol-motivated behaviors: an extended ethanol reward circuitryen_US
dc.typeArticleen_US
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