A PHYSIOLOGICAL-ROLE FOR GABA(B) RECEPTORS AND THE EFFECTS OF BACLOFEN IN THE MAMMALIAN CENTRAL-NERVOUS-SYSTEM

The inhibitory neurotransmitter GABA acts in the mammalian brain throu gh two different receptor classes: GABA(A) and GABA(B) receptors. GABA (B) receptors differ fundamentally from GABA(A) receptors in that they require a G-protein. GABA(B) receptors are located pre- and/or post-s ynaptically, and are coupled to various K+ and Ca2+ channels presumabl y through both a membrane delimited pathway and a pathway involving se cond messengers. Baclofen, a selective GABA(B) receptor agonist, as we ll as GABA itself have pre- and post-synaptic effects. Pre-synaptic ef fects comprise the reduction of the release of excitatory and inhibito ry transmitters. GABAergic receptors on GABAergic terminals may regula te GABA release, however, in most instances spontaneous inhibitory syn aptic activity is not modulated by endogenous GABA. Post-synaptic GABA (B) receptor-mediated inhibition is likely to occur through a membrane delimited pathway activating K+ channels, while baclofen, in some neu rons, may activate K+ channels through a second messenger pathway invo lving arachidonic acid. Some, but not all GABA(B) receptor-gated K+ ch annels have the typical properties of those G-protein-activated K+ cha nnels which are also gated by other endogenous ligands of the brain. N ew, high affinity GABA(B) antagonists are now available, and some phar macological evidence points to a receptor heterogeneity. The pharmacol ogical distinction of receptor subtypes, however, has to await final s upport from a characterization of the molecular stucture. The function al importance of post-synaptic GABA(B) receptors is highlighted by a s egregation of GABA(A) and GABA(B) synapses in the mammalian brain.