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 through 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-synaptically, and are coupled to various K+ and Ca2+ channels presumably through both a membrane delimited pathway and a pathway involving second messengers. Baclofen, a selective GABA(B) receptor agonist, as well as GABA itself have pre- and post-synaptic effects. Pre-synaptic effects comprise the reduction of the release of excitatory and inhibitory transmitters. GABAergic receptors on GABAergic terminals may regulate GABA release, however, in most instances spontaneous inhibitory synaptic 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 neurons, may activate K+ channels through a second messenger pathway involving arachidonic acid. Some, but not all GABA(B) receptor-gated K+ channels have the typical properties of those G-protein-activated K+ channels which are also gated by other endogenous ligands of the brain. New, high affinity GABA(B) antagonists are now available, and some pharmacological evidence points to a receptor heterogeneity. The pharmacological distinction of receptor subtypes, however, has to await final support from a characterization of the molecular stucture. The functional importance of post-synaptic GABA(B) receptors is highlighted by a segregation of GABA(A) and GABA(B) synapses in the mammalian brain.