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Blockade of nicotinic responses by physostigmine, tacrine and other cholinesterase inhibitors in rat striatum
Author(s) -
Clarke P.B.S.,
Reuben M.,
ElBizri H.
Publication year - 1994
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1994.tb14793.x
Subject(s) - physostigmine , tacrine , neostigmine , nicotine , chemistry , nicotinic agonist , pharmacology , acetylcholine , cholinesterase , cytisine , atropine , acetylcholinesterase , endocrinology , medicine , biochemistry , enzyme , receptor
1 The acetylcholinesterase inhibitors physostigmine, neostigmine, tetrahydroaminoacridine (tacrine; THA) and diisopropylfluorophosphate (DFP) were tested for possible direct nicotinic actions in rat striatal synaptosomes preloaded with [ 3 H]‐dopamine. In this preparation, nicotinic cholinoceptor activation evoked [ 3 H]‐dopamine release. 2 Antagonist activity was examined by giving a brief nicotine (1 μ m ) challenge after 30 min superfusion with an acetylcholinesterase (AChE) inhibitor (0.3–300 μ m ). Physostigmine, neostigmine and tacrine produced a concentration‐dependent blockade. Physostigmine and tacrine were particularly potent (IC 50 S approx. 10 μ m and 1 μ m , respectively). DFP reduced nicotinic responses only at the highest concentration tested (300 μ m ). 3 Nicotinic blockade produced by superfusion with physostigmine (30 μ m ) was insurmountable when tested against nicotine (0.1–100 μ m ). 4 Physostigmine (30 μ m ) also reduced responses to the nicotinic agonists 1,1‐dimethyl‐4‐phenylpiperazinium iodide (DMPP) and cytisine, but did not alter responses to high K + or (+)‐amphetamine. A higher concentration of physostigmine (300 μ m ) completely blocked responses to nicotine, somewhat reduced responses to amphetamine, and did not alter responses to high K + . Tacrine (3 μ m ) reduced responses to nicotine and to high K + but did not affect responses to amphetamine. 5 Physostigmine (0.3–300 μ m ), given as a brief pulse, did not produce a nicotinic agonist‐like effect. 6 Physostigmine, neostigmine, tacrine and DFP (all at 30 μ m ) each produced near‐total (>96%) inhibition of AChE activity. However, DFP at a concentration (60 μ m ) that produced a degree of AChE inhibition equal to that of physostigmine 30 μ m , did not significantly reduce nicotine‐induced dopamine release. 7 It thus appears that physostigmine blocks CNS nicotinic receptors in an insurmountable and pharmacologically selective manner, independent of its ability to inhibit acetylcholinesterase. Tacrine reduced nicotinic responses, quite possibly by an indirect mechanism. The possibility of direct or indirect blockade of nicotinic receptor‐mediated actions may complicate the interpretation of preclinical studies that have employed physostigmine and tacrine.