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NEUROPHARMACOLOGY

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

Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland (L.H.J., K.K., J.F.C.); and Institute of Physiology, Department of Clinical-Biological Sciences, Pharmazentrum, University of Basel, Basel, Switzerland (B.B.)

GABA_B receptor agonists produce hypothermia and motor incoordination. Two GABA_B(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 GABA_B receptor agonists has been unknown. Here, we used mice deficient in the GABA_B(1a) and GABA_B(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 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) 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 GABA_B(1a)^–/– and GABA_B(1b)^–/– mice. We conclude that L-baclofen and GHB are nonselective for either GABA_B(1) receptor isoform in terms of in vivo responses. However, GABA_B(1) receptor isoforms have distinct and different roles in mediating locomotor behavioral 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.

Address correspondence to: John F. Cryan, Senior Lecturer in Pharmacology, School of Pharmacy, Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland. E-mail: j.cryan{at}ucc.ie

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