Blockade of nicotinic receptor‐mediated release of dopamine from striatal synaptosomes by chlorisondamine and other nicotinic antagonists administered in vitro

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Abstract
1 Central nicotinic receptor function examined in vitro, by measuring nicotine-induced [3H]-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 [3H]-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 [3H]-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 × 10−5 m); in the absence of external Ca2+, blockade was only partial. 4 Chlorisondamine, mecamylamine and dihydro-β-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 × 10−6, respectively. Chlorisondamine and mecamylamine blocked responses to nicotine (10−7–10−4 m) insurmountably, whereas dihydro-β-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-β-erythroidine.