2-HYDROXY-SACLOFEN CAUSES A PHACLOFEN-REVERSIBLE REDUCTION IN POPULATION SPIKE AMPLITUDE IN THE RAT HIPPOCAMPAL SLICE

2-Hydroxy-saclofen is known to be active at GABA(B) receptors in the m ammalian central nervous system, and we have investigated its effects on synaptic transmission in the rat hippocampal slice preparation. Ort hodromic stimuli were applied to the stratum radiatum, and population spike responses from the CAl pyramidal cell layer were recorded extrac ellularly. A second, identical stimulus was applied at a variable inte rpulse interval (IPI) after the initial conditioning stimulus. GABAerg ic synaptic inhibition was observed as a decrease in the spike amplitu de of the second response compared to the first. Both the GABA(B) rece ptor antagonist phaclofen (1 mM) and 2-hydroxy-saclofen (200 mu M) pre vented a slow phase of inhibition for IPIs of 200-400 ms. However, the se agents differed markedly in their effects on overall synaptic trans mission. Phaclofen had no effect on the amplitude of the initial condi tioning spike amplitude, whereas 2-hydroxy-saclofen reduced it signifi cantly, in a manner similar to baclofen (1 mu M). The direct actions o f 2-hydroxy-saclofen were unexpected for a pure antagonist of GABA(B) receptors, but could be prevented by the co-administration of phaclofe n (1 mM), but not bicuculline (1 mu M). Reduction in conditioning spik e amplitude due to antagonism of GABA(B) autoreceptors on inhibitory i nterneurones and subsequent enhancement of GABA(A) tonic inhibition wo uld have been blocked by bicuculline. The blockade of the 2-hydroxy-sa clofen effect by phaclofen implies a GABA(B) receptor partial agonist action. The possible sites of this action are discussed.