Effects of N-ethylmaleimide on dopamine release in the rat striatum after repeated treatment with methamphetamine

Abstract

Effects of N-ethylmaleimide or forskolin on electrically evoked dopamine release were investigated in striatal slices of rats pretreated with methamphetamine. N-Ethylmaleimide and forskolin both enhanced the evoked dopamine release in a concentration-dependent manner. The enhancement by N-ethylmaleimide of spontaneous dopamine release was not abolished by tetrodotoxin; the electrically evoked release was abolished, irrespective of its magnitude. Moreover, N-ethylmaleimide prevented the inhibitory effect of the dopamine receptor agonist, 2-amino-6- allyl-5,6,7,8-tetrahydro-4 H-thiazolo(5,4- d)-azepine dihydrochloride(B-HT 920) and the stimulatory effect of the dopamine receptor antagonist, (−)-sulpiride, on the evoked dopamine release. In contrast, forskolin had no effect on the B-HT 920-induced inhibition and (−)-sulpiride-induced enhancement of the evoked dopamine release. These data indicate that release-modulating dopamine autoreceptors are N-ethylmaleimide-sensitive and forskolin-insensitive. As N-ethylmaleimide has been reported to inactivate G i protein and to block the regulation of noradrenaline release by α 2-adrenoceptors, the present results suggest that N-ethylmaleimide inactivates inhibitory GTP binding proteins to block the regulation by dopamine autoreceptors of evoked dopamine release. Methamphetamine pretreatment, which caused behavioral sensitization to a challenge dose of methamphetamine, attenuated the stimulatory effect of N-ethylmaleimide but not forskolin on the evoked dopamine release. The data indicate that the repeated administration of methamphetamine reduces a function of N-ethylmaleimide sensitive signal transduction system, probably including inhibitory GTP binding protein.