Received for publication August 7, 2006.
Revised September 20, 2006.
Accepted for publication September 20, 2006.

GABA_B(1) receptor subunit isoforms exert a differential influence on baseline but not GABA_B receptor agonist - induced changes in mice

Abstract

GABA_B receptors agonists produce hypothermia and motor in-coordination. Two GABA_B(1) receptor subunit isoforms exist, but due to lack of specific molecular or pharmacological tools, the relevance of these isoforms in controlling basal body temperature, locomotor activity or in vivo responses to GABA_B receptor agonists has been unknown. Here we use mice deficient in the GABA_B(1a) and GABA_B(1b) subunit isoforms to examine the influence of these isoforms on both baseline motor behaviour and body temperature and on the motor-incoodinating and hypothermic responses to the GABA_B receptor agonists L-baclofen and -hydroxybutyrate (GHB). GABA_B(1b)^-/- mice were hyperactive in a novel environment, and showed slower habituation than either GABA_B(1a)^-/- or wild-type mice. GABA_B(1b)^-/- mice were hyperactive throughout the circadian dark phase. Hypothermia in response to L-baclofen (6 and 12 mg kg ^-1) or GHB (1 g kg ^-1), baclofen-induced ataxia as determined on the fixed-speed rotarod, and GHB-induced hypolocomotion were significantly but, for the most part similarly, attenuated in both GABA_B(1a)^-/- and GABA_B(1b)^-/- mice. We conclude that L-Baclofen and GHB are non-selective for either GABA_B(1) receptor isoforms in terms of in vivo responses. However, GABA_B1 receptor isoforms have distinct and different roles in mediating locomotor behavioural responses to a novel environment. Therefore GABA_B(1a) and GABA_B(1b) isoforms are functionally relevant molecular variants of the GABA_B(1) receptor subunit, which are differentially involved in specific neurophysiological processes and behaviors.

Key words: GABAB1, baclofen, isoforms, locomotion, mutation, temperature

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