Pharmacologically distinct GABABreceptors that mediate inhibition of GABA and glutamate release in human neocortex

The release of endogenous γ‐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.The basal outflows of GABA and glutamate from superfused synaptosomes were largely increased during depolarization with 15 mmKCl. The K+‐evoked overflows of both amino acids were almost totally dependent on the presence of Ca2+in the superfusion medium.The GABABreceptor agonist (−)‐baclofen (1, 3 or 10 μm) inhibited the overflows of GABA and glutamate in a concentration‐dependent manner. The inhibition caused by 10 μmof the agonist ranged from 45–50%.The effect of three selective GABABreceptor antagonists on the inhibition of the K+‐evoked GABA and glutamate overflows elicited by 10 μm(−)‐baclofen was investigated. Phaclofen antagonized (by about 50% at 100 μm; almost totally at 300 μm) 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 μm); however, CGP 35348 (10 or 100 μm) antagonized (−)‐baclofen (complete blockade at 100 μm) at the heteroreceptors on glutamatergic terminals. Finally, [3‐[[(3,4‐dichlorophenyl) methyl]amino]propyl] (diethoxymethyl) phosphinic aid (CGP 52432), 1 μm, blocked the GABABautoreceptor, but was ineffective at the heteroreceptors. The selectivity of CGP 52432 was lost at 30 μm, as the compound, at this concentration, inhibited completely the (−)‐baclofen effect both on GABA and glutamate release.It is concluded that GABA and glutamate release evoked by depolarization of human neocortex nerve terminals can be affected differentially through pharmacologically distinct GABABreceptors.