THE MODULATION OF RAT HIPPOCAMPAL SYNAPTIC CONDUCTANCES BY BACLOFEN AND GAMMA-AMINOBUTYRIC-ACID

1. We examined the effects of gamma-aminobutyric acid (GABA) and baclofen on preand postsynaptic membrane conductances in dissociated rat hippocampal cells. Both GABA (5-mu-M with 10-mu-M-bicuculline) and baclofen (50-mu-M) caused small but significant increases in membrane conductance that were blocked by 2-hydroxysaclofen (100-mu-M), a GABA(B) receptor antagonist. This increase in membrane conductance seems to be mediated by GABA(B) receptors. 2. At a low concentration of GABA (1-mu-M) which has a very small direct postsynaptic effect on GABA(A) receptors, no postsynaptic GABA(B) effect was detected. However, at this concentration, GABA near maximally attenuated both excitatory and inhibitory synaptic currents. This GABA effect on transmitter release was significantly attenuated by 2-hydroxysaclofen. 3. Baclofen was also more potent in attenuating the inhibitory synaptic conductance than increasing postsynaptic conductance. Concentrations below 1-mu-M diminished synaptic currents by greater than 50%. At these low baclofen concentrations 2-hydroxysaclofen significantly attenuated baclofen's reduction of synaptic currents. 4. The effects of GABA and baclofen on synaptic conductances were blocked by pretreating the cultures with pertussis toxin, suggesting that a GTP-associated protein, G(i) or G(o) is responsible for reducing transmitter release. 5. Despite the ability of GABA to diminish inhibitory synaptic currents through GABA(B) receptor activation, we observed no effect of 2-hydroxysaclofen on paired-pulse depression. Therefore, these presynaptic GABA(B) receptors may not be true 'autoreceptors'. 6. Our findings indicate that in culture, at least, the presynaptic GABA(B) effect responsible for synaptic modulation has a pharmacological profile similar to the postsynaptic GABA(B) effect. At present, it is unnecessary to postulate two different types of GABA(B) receptors.