Normal electrophysiological and behavioral responses to ethanol in mice lacking the long splice variant of the γ2 subunit of the γ-aminobutyrate type A receptor

NEUROPHARMACOLOGY

卷:38

Article

Homanics, GE ; Harrison, NL ; Quinlan, JJ ; Krasowski, MD ; Rick, CEM ; de Blas, AL ; Mehta, AK ; Kist, F ; Mihalek, RM ; Aul, JJ ; Firestone, LL

关键词: ethanol;    GABA(A) receptor;    gene knockout;    GABA;   

DOI  :  10.1016/S0028-3908(98)00177-4

来源: Elsevier

【 摘 要 】

The gamma subunit of the gamma-aminobutyric acid type A receptor (GABA(A)-R) is essential for bestowing both normal single channel conductance and sensitivity to benzodiazepines on native GABA(A)-Rs. The long splice variant of the gamma 2 subunit (gamma 2L) has been postulated to be essential in mediating the modulatory actions of ethanol at the GABA(A)-R. In order to evaluate this hypothesis, gene targeting was used to delete the 24bp exon which distinguishes gamma 2L from the short splice variant (gamma 2S). Mice homozygous for this exon deletion (gamma 2L(-/-)) are viable and indistinguishable from wild-type (gamma 2L(+/+)) mice. No gamma 2L mRNA was detected in these mice, nor could gamma 2L-containing GABA(A)-R protein be detected by specific antibodies. Radioligand binding studies showed the total amount of gamma 2 subunit protein to be not significantly changed, suggesting that gamma 2S replaces gamma 2L in the brains of the knockout animals. Electrophysiological recordings from dorsal root ganglion neurons revealed a normal complement of functional receptors. There was no difference in the potentiation of GABA currents by ethanol (20-200 mM) observed in neurons from gamma 2L(+/+) or gamma 2L(-/-) mice. Several behavioral effects of ethanol, such as sleep time, anxiolysis, acute functional tolerance, chronic withdrawal hyperexcitability and hyperlocomotor activity were also unaffected by genotype. It is concluded that gamma 2L is not required for ethanol's modulatory action at the GABA(A)-R or whole animal behavioral effects. (C) 1999 Elsevier Science Ltd. All rights reserved.

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