1 The release of endogenous gamma-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 outflows of GABA and glutamate from superfused synaptosomes were largely increased during depolarization with 15 mM KCl. The K+-evoked overflows of both amino acids were almost totally dependent on the presence of Ca2+ in the superfusion medium. 3 The GABA(B) receptor agonist (-)-baclofen (1, 3 or 10 mu M) inhibited the overflows of GABA and glutamate in a concentration-dependent manner. The inhibition caused by 10 mu M of the agonist ranged from 45-50%. 4 The effect of three selective GABA(B) receptor antagonists on the inhibition of the K+-evoked GABA and glutamate overflows elicited by 10 mu M (-)-baclofen was investigated. Phaclofen antagonized (by about 50% at 100 mu M; almost totally at 300 mu M) the effect of (-)-baclofen on GABA overflow but did not modify the inhibition of glutamate release. The effect of (-)-baclofen on the K+-evoked GABA overflow was unaffected by 3-amino-propyl (diethoxymethyl)phosphinic acid (CGP 35348; 10 or 100 mu M); however, CGP 35348 (10 or 100 mu M) antagonized (-)-baclofen (complete blockade at 100 mu M) at the heteroreceptors on glutamatergic terminals. Finally. [3-[[(3,3-dichlorophenyl) methyl]amino]propyl] (diethoxymethyl) phosphinic aid (CGP 52432), 1 mu M, blocked the GABA(B) autoreceptor, but was ineffective at the heteroreceptors. The selectivity of CGP 52432 was lost at 30 mu M, as the compound, at this concentration, inhibited completely the (-)-baclofen effect 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 affected differentially through pharmacologically distinct GABA(B) receptors.
