Clonidine enhances the release of endogenous gamma-aminobutyric acid through alpha-2 and alpha-1 presynaptic adrenoceptors differentially located in rat cerebral cortex subregions

Abstract

Clonidine (0.001-1 microM) increased the basal release of endogenous gamma-aminobutyric acid (GABA) in superfused synaptosomes from whole rat cerebral cortex. The effects of 0.1 to 1 microM clonidine were only in part sensitive to the alpha-2 adrenoceptor antagonist yohimbine; a complete antagonism by yohimbine could be seen only with 0.001 microM clonidine. The release of GABA induced by 0.1 to 1 microM clonidine was increasingly sensitive to the alpha-1 adrenoceptor antagonist prazosin. At all the concentrations tested clonidine was antagonized fully by a mixture yohimbine-prazosin (1 microM). The release of GABA was increased by phenylephrine in a concentration-dependent (0.01-1 microM) manner. At 1 microM phenylephrine was antagonized fully by 1 microM prazosin. When synaptosomes prepared from frontal, parietal, temporal and occipital cortex were exposed to clonidine (0.005 microM) or to phenylephrine (0.1 microM), the release of GABA was found to be region specific. Clonidine-induced GABA release could not be seen in temporal and occipital cortex but it was pronounced in parietal and frontal cortex. The effect of phenylephrine did not parallel that of clonidine: for instance, GABA release was most sensitive to phenylephrine in the occipital cortex where clonidine was ineffective. The opposite occurred in parietal cortex synaptosomes, where phenylephrine was much less effective than clonidine.

In conclusion: 1) clonidine stimulates the release of GABA in rat cerebral cortex synaptosomes; 2) the effect is likely to occur by activation of alpha-1 and alpha-2 adrenoceptors possibly situated on GABAergic nerve endings; and 3) a differential distribution of alpha-1 and alpha-2 adrenoceptors regulating GABA release exists within the cortical subregions.