Pharmacologically distinct GABA_B receptors that mediate inhibition of GABA and glutamate release in human neocortex (original) (raw)

The release of endogenous g-aminobutyric acid (GABA) and glutamic acid in the human brain has been investigated in synaptosomal preparations from fresh neocortical samples obtained from patients undergoing neurosurgery to reach deeply located tumours. 2 The basal out¯ows of GABA and glutamate from superfused synaptosomes were largely increased during depolarization with 15 mM KCl. The K +-evoked over¯ows of both amino acids were almost totally dependent on the presence of Ca 2+ in the superfusion medium. 3 The GABA B receptor agonist (7)-baclofen (1, 3 or 10 mM) inhibited the over¯ows of GABA and glutamate in a concentration-dependent manner. The inhibition caused by 10 mM of the agonist ranged from 45 ± 50%. 4 The eect of three selective GABA B receptor antagonists on the inhibition of the K +-evoked GABA and glutamate over¯ows elicited by 10 mM (7)-baclofen was investigated. Phaclofen antagonized (by about 50% at 100 mM; almost totally at 300 mM) the eect of (7)-baclofen on GABA over¯ow but did not modify the inhibition of glutamate release. The eect of (7)-baclofen on the K +-evoked GABA over¯ow was unaected by 3-amino-propyl (diethoxymethyl)phosphinic acid (CGP 35348; 10 or 100 mM); however, CGP 35348 (10 or 100 mM) antagonized (7)-baclofen (complete blockade at 100 mM) at the heteroreceptors on glutamatergic terminals. Finally, [3-[[(3,4-dichlorophenyl) methyl]amino]propyl] (diethoxymethyl) phosphinic aid (CGP 52432), 1 mM, blocked the GABA B autoreceptor, but was ineective at the heteroreceptors. The selectivity of CGP 52432 was lost at 30 mM, as the compound, at this concentration, inhibited completely the (7)-baclofen eect both on GABA and glutamate release. 5 It is concluded that GABA and glutamate release evoked by depolarization of human neocortex nerve terminals can be aected dierentially through pharmacologically distinct GABA B receptors.