title: Effect of tacrine on in vivo release of dopamine and its metabolites in the striatum of freely moving rats.
abstract: The effects of tacrine (THA) on extracellular concentrations of dopamine (DA), 3,4-dihydroxyphenylacetic acid, homovanillic acid and 5-hydroxyindoleacetic acid were investigated in the striatum of freely moving rats, using a microdialysis technique in which tacrine was administered locally via the microdialysis membrane. THA in concentrations of 10(-8) to 10(-5) M, significantly elevated the levels of the DA metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid, whereas a significantly increased content of extracellular DA was observed at higher concentrations of THA (10(-3) to 10(-2) M). Local administration of the muscarinic antagonist atropine (10(-6) M) or the nicotinic antagonist mecamylamine (10(-5) M) both prevented the effects of THA on DA and its metabolites. In vitro receptor binding studies showed that THA displaced the binding of muscarinic antagonists [3H]pirenzepine (IC50, 2.1 +/- 0.4 microM) and [3H]AFDX 384 (IC50, 3.4 +/- 0.2 microM) equally in striatal tissue, suggesting that THA binds with equal affinity to M1 and M2 muscarinic receptor subtypes. THA showed a 20-fold lower affinity to high-affinity nicotinic receptors compared with muscarinic receptors when determined by [3H]cytisine competition curves. The study indicates that THA enhances monoamine neurotransmission in the rat striatum, probably via an interaction with both muscarinic and nicotinic heteroreceptors.
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Sweden.
authors.forename: U
authors.initials: U
authors.lastname: Warpman
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: A
authors.initials: A
authors.lastname: Nordberg
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D006719:Homovanillic Acid / Q000378:metabolism; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D017551:Microdialysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000187:drug effects; D011978:Receptors, Nicotinic / Q000187:drug effects; D013619:Tacrine / Q000494:pharmacology*
chemical_list: D002800:Cholinesterase Inhibitors; D011976:Receptors, Muscarinic; D011978:Receptors, Nicotinic; D015102:3,4-Dihydroxyphenylacetic Acid; D013619:Tacrine; D008464:Mecamylamine; D001285:Atropine; D004298:Dopamine; D006719:Homovanillic Acid