Sj. Caddick et al., 2-HYDROXY-SACLOFEN CAUSES A PHACLOFEN-REVERSIBLE REDUCTION IN POPULATION SPIKE AMPLITUDE IN THE RAT HIPPOCAMPAL SLICE, European journal of pharmacology, 274(1-3), 1995, pp. 41-46
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.