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 [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 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.
el-Bizri
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Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada.
Clarke
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D000818:Animals; D002118:Calcium / Q000502:physiology; D002714:Chlorisondamine / Q000494:pharmacology*; D004079:Dihydro-beta-Erythroidine / Q000494:pharmacology; D004246:Dimethylphenylpiperazinium Iodide / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D005731:Ganglionic Stimulants / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism*; D009538:Nicotine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D018733:Nicotinic Antagonists; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*
D005731:Ganglionic Stimulants; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D004079:Dihydro-beta-Erythroidine; D004246:Dimethylphenylpiperazinium Iodide; D008464:Mecamylamine; D009538:Nicotine; D002714:Chlorisondamine; D011188:Potassium; D002118:Calcium; D004298:Dopamine