BLOCKADE OF NICOTINIC RECEPTOR-MEDIATED RELEASE OF DOPAMINE FROM STRIATAL SYNAPTOSOMES BY CHLORISONDAMINE AND OTHER NICOTINIC ANTAGONISTS ADMINISTERED IN-VITRO

1 Central nicotinic receptor function examined in vitro, by measuring nicotine-induced [H-3]-dopamine release from rat striatal synaptosomes. 2 The agonists (-)-nicotine, acetylcholine, 1,1 -dimethyl-4-phenylpiperazinium (DMPP) and cytisine (10(-7)-10(-4) M) all increased [H-3]-dopamine release in a concentration-dependent manner. Cytisine did not produce a full agonist response, compared to the other agonists. 3 The actions of nicotine, acetylcholine and cytisine were largely dependent on external Ca2+. In contrast, DMPP (10(-5) and 10(-4) M) evoked a marked release of [3(H)]-dopamine even in the absence of Ca2+. Nevertheless, in the presence of external Ca2+, responses to DMPP were completely blocked by the nicotinic antagonists chlorisondamine and mecamylamine (5 x 10(5) M); in the absence of external Ca2+, blockade was only partial. 4 Chlorisondamine, mecamylamine and dihydro-beta-erythroidine (10(-8)-10(-4) M) produced a concentration-dependent block of responses to nicotine (10(-6) M). Approximate IC50 values were 1.6, 0.3 and 0.2 x 10(-6), respectively. Chlorisondamine and mecamylamine blocked responses to nicotine (10(-7)-10(-4) M) insurmountably, whereas dihydro-beta-erythroidine behaved in a surmountable fashion. 5 The occurrence of use-dependent block was tested by briefly pre-exposing the synaptosomes to nicotine during superfusion with antagonist, and determining the response to a subsequent nicotine application. Consistent with a possible channel blocking action, brief pre-exposure to agonist increased the antagonist potency of chlorisondamine (approximately 25 fold). No significant use-dependent block was detected with dihydro-beta-erythroidine.