GABAB(1) Receptor Subunit Isoforms Exert a Differential Influence on Baseline but Not GABAB Receptor Agonist-Induced Changes in Mice

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Abstract
GABAB receptor agonists produce hypothermia and motor incoordination. Two GABAB(1) receptor subunit isoforms exist, but because of lack of specific molecular or pharmacological tools, the relevance of these isoforms in controlling basal body temperature, locomotor activity, or in vivo responses to GABAB receptor agonists has been unknown. Here, we used mice deficient in the GABAB(1a) and GABAB(1b) subunit isoforms to examine the influence of these isoforms on both baseline motor behavior and body temperature and on the motor-incoordinating and hypothermic responses to the GABAB receptor agonists l-baclofen and γ-hydroxybutyrate (GHB). GABAB(1b)–/– mice were hyperactive in a novel environment and showed slower habituation than either GABAB(1a)–/– or wild-type mice. GABAB(1b)–/– mice were hyperactive throughout the circadian dark phase. Hypothermia in response to l-baclofen (6 and 12 mg/kg) or GHB (1 g/kg), 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 GABAB(1a)–/– and GABAB(1b)–/– mice. We conclude that l-baclofen and GHB are nonselective for either GABAB(1) receptor isoform in terms of in vivo responses. However, GABAB(1) receptor isoforms have distinct and different roles in mediating locomotor behavioral responses to a novel environment. Therefore, GABAB(1a) and GABAB(1b) isoforms are functionally relevant molecular variants of the GABAB(1) receptor subunit, which are differentially involved in specific neurophysiological processes and behaviors.