CONTRASTING EFFECTS OF THE IMIDAZOL(IN)E ALPHA-2-ADRENOCEPTOR AGONISTS, MEDETOMIDINE, CLONIDINE AND UK-14,304 ON EXTRANEURONAL LEVELS OF NORADRENALINE IN THE RAT FRONTAL-CORTEX - EVALUATION USING IN-VIVO MICRODIALYSIS AND SYNAPTOSOMAL UPTAKE STUDIES

1 In vivo microdialysis in halothane-anaesthetized rats and synaptosomal [H-3]-noradrenaline uptake studies in vitro were used to evaluate the effects of imidazole (medetomidine) and imidazoline (clonidine and UK 14,304) alpha(2)-adrenoceptor agonists on extraneuronal levels of noradrenaline in the frontal cortex. 2 Levels of noradrenaline in the dialysate were increased by a depolarizing concentration of K+ (60 mM for 20 min) and substantially attenuated by reducing Ca2+ supply in the perfusate. These results suggest that spontaneous efflux of noradrenaline in the cortex is regulated predominantly by cation-dependent exocytotic mechanisms. 3 At a low perfusion concentration (0.5 mu M), medetomidine, clonidine and UK 14,304 all reduced the level of noradrenaline in cortical dialysates. Continuous perfusion of the selective alpha(2)-adrenoceptor antagonist, atipamezole (0.5 mu M) caused a sustained increase in noradrenaline efflux and reversed the inhibitory effects of medetomidine. All these changes are consistent with drug actions at presynaptic alpha(2)-adrenoceptors. 4 Higher concentrations of medetomidine (5-50 mu M), but not clonidine or UK 14,304, evoked a non-desensitizing increase in nonadrenaline efflux. This effect was not antagonized by 0.5 mu M atipamezole. 5 The tricyclic noradrenaline reuptake inhibitor, desmethylimipramine (0.5-50 mu M), increased noradrenaline efflux in a concentration-dependent manner. 6 The specific uptake of [H-3]-noradrenaline into cortical synaptosomes was inhibited by medetomidine and desmethylimipramine with IC50 values of approximately 7 mu M and 8 mu M respectively. Neither clonidine nor UK 14,304 inhibited [H-3]-noradrenaline uptake. 7 These results indicate that micromolar concentrations of the selective alpha(2)-adrenoceptor agonist, medetomidine, can augment extraneuronal levels of noradrenaline in the rat frontal cortex; this effect seems to involve an inhibition of noradrenaline reuptake rather than an action at alpha(2)-adrenoceptors.