Nicotine-evoked [3H]5-hydroxytryptamine release from rat striatal synaptosomes.
The aim of this study was to characterize the pharmacology of presynaptic nicotinic cholinoceptors (nAChRs) that modulate release of 5-hydroxytryptamine (5-HT) from superfused rat brain synaptosomes preloaded with [3H]5-HT. Nicotine increased 5-HT release from striatal synaptosomes (maximally by 15-30%) but not from cerebral cortex or hippocampal synaptosomes. Release of striatal 5-HT was increased in a concentration-dependent manner by nicotine, epibatidine, cytisine, and ACh (with added esterase inhibitor and muscarinic antagonist). Respective EC50 values were: 0.5, 0.003, 0.1 and 0.7 microM. The maximal effect of each agonist was virtually completely blocked by a high concentration of the insurmountable nicotinic antagonist mecamylamine; at a higher concentration of epibatidine (3 microM), a mecamylamine-insensitive effect was revealed. Nicotine, ACh and epibatidine appeared equally efficacious, whereas cytisine was of lower efficacy (60-70% of ACh). Release evoked by a half-maximal concentration of nicotine was inhibited by the nicotinic antagonists dihydro-beta-erythroidine (IC50 0.04 microM) and methyllycaconitine (IC50 0.06 microM). Nicotine-evoked 5-HT release was not reduced by tetrodotoxin given in a concentration that blocked veratridine-evoked release. These findings provide functional evidence for a direct action of nicotine on 5-HT neurons in the brain. The presynaptic nAChRs that modulate striatal 5-HT release appear to possess a novel pharmacological profile.
Reuben
M
M
Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada.
Clarke
P B
PB
D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004079:Dihydro-beta-Erythroidine / Q000494:pharmacology; D005730:Ganglionic Blockers / Q000494:pharmacology; D005731:Ganglionic Stimulants / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011950:Receptors, Cholinergic / Q000096:biosynthesis / Q000145:classification; D011994:Recombinant Proteins / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D013574:Synaptosomes / Q000187:drug effects* / Q000378:metabolism; D014701:Veratridine / Q000494:pharmacology; D014793:Visual Cortex / Q000187:drug effects / Q000378:metabolism
D005730:Ganglionic Blockers; D005731:Ganglionic Stimulants; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011950:Receptors, Cholinergic; D011994:Recombinant Proteins; D004079:Dihydro-beta-Erythroidine; D012701:Serotonin; D008464:Mecamylamine; D009538:Nicotine; D014701:Veratridine; D015761:4-Aminopyridine