Differential modulation by the GABAB 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

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.