Pharmacological characterization of a nicotinic autoreceptor in rat hippocampal synaptosomes.
The modulation of [3H]ACh release by nicotinic compounds was studied in superfused rat hippocampal synaptosomes loaded with [3H]choline, (-)-Nicotine (0.1-10 microM) evoked a dose-dependent increase in [3H]ACh release; higher concentrations were less effective. Nicotine-evoked release was Ca(2+)-dependent, and blocked by the nicotinic antagonists dihydro-beta-erythroidine, mecamylamine, and pempidine. The alpha 7-selective antagonist methyllycaconitine did not inhibit nicotine-evoked release when tested at 1 microM, although at 10 microM some attenuation of the response was observed. Six agonists tested were equally efficacious in stimulating [3H]ACh release, as judged by the maximum responses, and gave the following EC50 values: (+/-)-epibatidine 0.12 microM; (+)-anatoxin-a 0.14 microM; (-)-nicotine 0.99 microM; (-)-cytisine 1.06 microM; ABT-418 2.6 microM; isoarecolone 43 microM. Each agonist generated a "bell-shaped" dose response curve, suggesting desensitisation at higher concentrations. This is supported by analysis of repetitive stimulation with (-)-nicotine and (-)-cytisine: S2/S1 ratios declined sharply with increasing concentration, whereas subsequent KC1-evoked release remained constant. These results are discussed in terms of possible nicotinic receptor subtypes that might be present on hippocampal nerve terminals.
Wilkie
G I
GI
School of Biology and Biochemistry, University of Bath, United Kingdom.
Hutson
P
P
Sullivan
J P
JP
Wonnacott
S
S
D000109:Acetylcholine / Q000378:metabolism*; D000157:Aconitine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002794:Choline / Q000378:metabolism; D004079:Dihydro-beta-Erythroidine / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008464:Mecamylamine / Q000494:pharmacology; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010393:Pempidine / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000502:physiology*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*
D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; C054634:methyllycaconitine; D004079:Dihydro-beta-Erythroidine; D011189:Potassium Chloride; D008464:Mecamylamine; D009538:Nicotine; D010393:Pempidine; D002794:Choline; D000109:Acetylcholine; D002118:Calcium; D000157:Aconitine