GAMMA-AMINOBUTYRIC-ACID (GABA) AUTORECEPTORS IN RAT CEREBRAL-CORTEX AND SPINAL-CORD REPRESENT PHARMACOLOGICALLY DISTINCT SUBTYPES OF THE GABA(B) RECEPTOR

Gamma-Aminobutyric acid (GABA) autoreceptors regulating release of [H-3]GABA have been characterized pharmacologically by using rat cerebral cortex and spinal cord synaptosomes exposed in superfusion to mild depolarization (9 mM KCl). In both regions GABA inhibited the K+-evoked overflow of [H-3]GABA. The EC50 values amounted to 1.23 muM (cortex) and to 1.01 muM (spinal cord). Also the GABA(B) receptor agonist 3-aminopropylphosphonous acid (3-APPA) decreased the [H-3]GABA overflow: EC50 values = 0.095 muM (cortex) and 0.078 muM (spinal cord). The classical GABA(B) receptor agonist (-)-baclofen was equipotent to GABA at the cortical autoreceptor (EC50 = 1.37 muM), whereas it was almost ineffective in the spinal cord (EC50 = 425 muM). (+)-Baclofen was extremely weak in both brain areas, Two GABA(B) receptor antagonists, phaclofen and (CGP 35348) [3-aminopro-pyl(diethoxymethyl)phosphinic acid] provided opposite results at the two autoreceptors examined. The IC50 values for phaclofen amounted to 47.9 muM (cortex) and to > 1000 muM (spinal cord), respectively. In contrast, CGP 35348 was almost ineffective at the cortex autoreceptors (IC50 > 300 muM), but was rather potent in the spinal cord (IC50 = 1.07 muM). To conclude, GABA autoreceptors in the cerebral cortex are classically sensitive to (-)-baclofen and to 3-APPA; they are also sensitive to phaclofen, but resistant to CGP 35348. Surprisingly, GABA autoreceptors in the spinal cord are poorly sensitive to (-)-baclofen, although they are as sensitive as the cortical autoreceptors to 3-APPA; moreover they are resistant to phaclofen, but highly sensitive to CGP 35348. The data show that pharmacologically distinct release-regulating GABA(B) autoreceptors exist in the central nervous system of a same animal species.