2-Hydroxy-saclofen causes a phaclofen-reversible reduction in population spike amplitude in the rat hippocampal slice

Abstract

2-Hydroxy-saclofen is known to be active at GABA B receptors in the mammalian central nervous system, and we have investigated its effects on synaptic transmission in the rat hippocampal slice preparation. Orthodromic stimuli were applied to the stratum radiatum, and population spike responses from the CA1 pyramidal cell layer were recorded extracellularly. A second, identical stimulus was applied at a variable interpulse interval (IPI) after the initial conditioning stimulus. GABAergic synaptic inhibition was observed as a decrease in the spike amplitude of the second response compared to the first. Both the GABA B receptor antagonist phaclofen (1 mM) and 2-hydroxy-saclofen (200 μM) prevented a slow phase of inhibition for IPIs of 200–400 ms. However, these agents differed markedly in their effects on overall synaptic transmission. Phaclofen had no effect on the amplitude of the initial conditioning spike amplitude, whereas 2-hydroxy-saclofen reduced it significantly, in a manner similar to baclofen (1 μM). The direct actions of 2-hydroxy-saclofen were unexpected for a pure antagonist of GABA B receptors, but could be prevented by the co-administration of phaclofen (1 mM), but not bicuculline (1 μM). Reduction in conditioning spike amplitude due to antagonism of GABA B autoreceptors on inhibitory interneurones and subsequent enhancement of GABA A tonic inhibition would have been blocked by bicuculline. The blockade of the 2-hydroxy-saclofen effect by phaclofen implies a GABA B receptor partial agonist action. The possible sites of this action are discussed.