A physiological role for GABA_B receptors in the central nervous system

Abstract

The role of GABA in synaptic transmission in the mammalian central nervous system is more firmly established than for any other neurotransmitter. With virtually every neuron studied, the synaptic action of GABA is mediated by bicuculline-sensitive GABA_A receptors which selectively increase chloride conductance. However, it has been shown that GABA has a presynaptic inhibitory action on trasmitter release that is insenstive to bicuculline and is selectively mimicked by baclofen¹. The receptors involved in this action are referred to as GABA_B receptors, to distinguish them from the classic bicuculline-sensitive GABA_A receptors. In hip-pocampal pyramidal cells an additional postsynaptic action of GABA and baclofen has been reported that is also insensitive to GABA_A antagonists^2,3, and may be mediated by GABA_B receptors on the postsynaptic neuron. This action of GABA and baclofen involves an increase in potassium conductance^2–7. Synaptic activation of pathways converging on hippocampal pyramidal cells results in a slow inhibitory postsynaptic potential which involves an increase in potassium conductance^4,8,9, and it has been suggested that GABA_B receptors might be responsible for this synaptic potential⁴. However, to establish convincingly that GABA_B receptors are physiologically important in the central nervous system, a selective GABA_B antagonist is required. Here we provide this missing evidence. Using the hippocampal slice preparation, we now report that the phosphonic acid derivative of baclofen, phaclofen¹⁰, is a remarkably selective antagonist of both the postsynaptic action of baclofen and the bicuculline-resistant action of GABA, and that it selectively abolishes the slow inhibitory postsynaptic potential in pyramidal cells.