GABA AND GLUTAMATE RELEASE AFFECTED BY GABA(B) RECEPTOR ANTAGONISTS WITH SIMILAR POTENCY - NO EVIDENCE FOR PHARMACOLOGICALLY DIFFERENT PRESYNAPTIC RECEPTORS

1 The effects of a series of nine GABA(B) receptor antagonists of wide ly varying potencies on electrically stimulated release from cortical slices of [H-3]-GABA in the absence or presence of 10 mu M of the GABA (B) agonist, (-)-baclofen and of endogenous glutamate in the presence of (-)-baclofen were compared. 2 The concentrations of the compounds h alf maximally increasing [H-3]-GABA release (EC(50)'s) at a stimulatio n frequency of 2 Hz correlated well with the IC50 values obtained from the inhibition of the binding of the agonist, [H-3]-CGP 27492, to GAB A(B) receptors in rat brain membranes (rank order of potency: CGP 5699 9 A greater than or equal to CGP 55845 A > CGP 52432 greater than or e qual to CGP 56433 A) CGP 57034 A > CGP 57070 A greater than or equal t o CGP 57976 > CGP 51176 > CGP 35348). 3 Likewise, the concentrations c ausing half-maximal increases of [H-3]-GABA in the absence or presence of (-)-baclofen, and of endogenous glutamate in the presence of (-)-b aclofen, correlated well with each other. Reports in the literature su ggesting the CGP 35348 exhibits a 70 fold preference for inhibition of (-)-baclofen's effects on glutamate over [H-3]-GABA release, and that CGP 52432 shows a 100 fold preference in the opposite sense, could no t be confirmed in our model. 4 Therefore, our results suggest that, if there are pharmacological differences between GABA(B) autoreceptors a nd GABA(B) heteroreceptors on glutamatergic nerve endings in the rat c ortex, they are not revealed by this series of compounds of widely dif ferent potencies. 5 In particular, our results with CGP 35348 and CGP 52432 do not support the hypothesis that GABA(B) autoreceptors and GAB A(B) heteroreceptors on glutamatergic nerve endings represent subtypes with different pharmacology.