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NEUROPHARMACOLOGY

Differential Modulation by the GABA_B Receptor Allosteric Potentiator 2,6-Di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl)-phenol (CGP7930) of Synaptic Transmission in the Rat Hippocampal CA1 Area

School of Biomedical and Molecular Sciences, University of Surrey, Guildford, United Kingdom (Y.C.); and Eli Lilly & Co. Ltd., Erl Wood Manor, Windlesham, United Kingdom (N.M.-R., E.S.)

The recently discovered GABA_B receptor-positive allosteric modulators enhanced the potency and efficacy of GABA_B receptor agonists in in vitro experiments. These GABA_B modulators also attenuated reward and anxiety in behavioral experiments without causing the untoward side effects associated with GABA_B receptor activation by agonist administration and hence exhibited potential therapeutic utility. However, the underlying molecular mechanisms enabling the GABA_B allosteric modulators to dissociate from the GABA_B agonistic side effects remain elusive. To address this question, we have examined the effects of a typical GABA_B modulator, 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl)-phenol (CGP7930), on GABA_B receptor-mediated modulations of both the excitatory and the delayed inhibitory components of hippocampal CA1 synaptic transmission. Using baclofen as an agonist and a multielectrode recording system, we recorded GABA_B receptor-mediated modulations of both the field excitatory postsynaptic potentials and the population spikes simultaneously, as well as the paired-pulse inhibition of the population spike. We found that CGP7930 selectively enhanced the baclofen-induced modulation of synaptic inhibition without having any significant effects on the synaptic excitation. Our experiments have therefore revealed a pathway-selective differential modulation of synaptic transmission by CGP7930. This finding provides a synaptic mechanism to support the hypothesis that GABA_B potentiators may be a better therapeutic alternative than GABA_B agonists for central nervous system disorders.

Address correspondence to: Dr. Ying Chen, School of Biomedical and Molecular Sciences, University of Surrey, Guildford, UK GU2 7XH. E-mail: ying.chen{at}surrey.ac.uk