PRESYNAPTIC MODULATION BY GABA-B RECEPTORS OF GLUTAMATERGIC EXCITATION AND GABAERGIC INHIBITION OF NEOSTRIATAL NEURONS

1. The present experiments investigated the effects of gamma-aminobutyric acid(B) (GABA(B)) receptor stimulation on the excitatory and inhibitory responses of neostriatal neurons evoked by stimulation of the subcortical white matter in a rat neostriatal slice preparation. 2. Intracellular recordings showed that single-impulse stimulation of the corpus callosum evoked monosynaptic, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX)-sensitive excitatory postsynaptic potentials (EPSPs) that were attenuated by the GABA(B) receptor agonist, p-chlorophenyl-GABA (baclofen, 0.5-10-mu-M) in a concentration-dependent manner. Baclofen also blocked the GABA(A)-mediated inhibition of neostriatal cell responses, which were revealed by paired-impulse stimulation of the subcortical white matter. Both of these effects persisted in slices in which the anterior cortex was removed, indicating that the site of action for baclofen was intrinsic to the neostriatum. The GABA(B) antagonist 3-amino-2-hydroxy-2-(4-chlorophenyl)-propanesulfonic acid (saclofen, 250-500-mu-M) reversed the depressant actions of baclofen on both the excitatory and inhibitory responses of neostriatal cells. 3. Concentrations of baclofen as high as 100-mu-M, which markedly attenuated EPSP amplitude, did not exert direct effects on resting membrane potential, current-voltage relationship, input resistance, or spike threshold and thus appeared to have no post-synaptic effect on the population of neurons recorded. 4. These results indicate that, in contrast to other regions of the CNS, the depressant effects of baclofen on glutamate-dependent EPSPs are mediated exclusively through GABA(B) receptors located presynaptically on the terminals of glutamatergic afferents. In addition, these data suggest that the attenuation of GABA(A)-mediated inhibition is produced at a site presynaptic to the neurons recorded, either on the terminals of GABAergic afferents and/or on an interposed GABAergic neuron. Thus GABA(B) receptors may provide a local feedback mechanism through which glutamatergic excitation and GABAergic inhibition of neostriatal neurons can be regulated.