期刊
JOURNAL OF NEUROSCIENCE
卷 21, 期 6, 页码 2166-2177出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.21-06-02166.2001
关键词
ethanol; GABA; alpha 5 subunit; reinforcement; hippocampus; alcohol-preferring (P) rat
资金
- NIAAA NIH HHS [AA11555, AA10406] Funding Source: Medline
- NIMH NIH HHS [R01 MH046851, MH 46851] Funding Source: Medline
- PHS HHS [T35M] Funding Source: Medline
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 alpha5 subunit-selective (similar to 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 mug) and unilateral (0.01-40 mug) RY dose-dependently reduced EtOH-maintained responding, with saccharin-maintained responding being reduced only with the highest doses (e.g., 20 and 40 mug). The competitive BDZ antagonist ZK 93426 (ZK) (7 mug) 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 alpha1 beta3 gamma2, alpha2 beta3 gamma2, and alpha5 beta3 gamma2 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.
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