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

摘要

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 multielec-trode 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.