Abstract
Baclofen, a β-chlorophenyl derivative of γ-aminobutyric acid (GABA), depresses neuronal excitability in various parts of the central nervous system. The site of action for this drug had once been considered to be distinct from GABA recognition sites. In addition to the classical GABA recognition site (GABAA site), a new class of GABA receptor (GABAB site) has been characterized. GABAB sites are mainly present on nerve terminals and, when activated, result in diminished transmitter release, probably through a reduction in Ca2+ influx. Baclofen was shown to be a selective agonist for this novel GABAB recognition. Baclofen also directly hyperpolarizes the membrane of mammalian brain neurons, in addition to its pretynaptic action. This postsynaptic action of baclofen was shown to result from an increase in K+ conductance when studied in hippocampal pyramidal neurons through postsynaptic GABAB receptors. Thus, the inhibitory neurotransmitter GABA activates two receptor subtypes that can be distinguished by their physiological and pharmacological properties. GABAA receptors mediate rapid alterations in the distribution of Cl- across the membrane. GABAA receptors are linked directly to an ion channel, thus contributing to the prompt inhibition of cellular excitability. On the contrary, the GABAB receptor does not contain an integral ion channel and is thus responsible for slower responses through receptor-G-protein-effector complexes. G-protein may be directly coupled to K+ or Ca2+ channels. In addition, G-protein may modulate a variety of regulatory proteins or second messengers, thus contributing to the slower alteration of cellular excitability or to the modulation of neurotransmitter release.
