Stereoselective effects of (R)- and (S)-zacopride on cognitive performance in a spatial navigation task in rats.
In the present studies we investigated the actions of (R)- and (S)-zacopride, potent 5-HT3 receptor antagonists with 5-HT4 receptor agonists properties, on performance in a spatial learning and memory task in rats, the Morris water maze. A significant cognitive/performance deficit, as indicated by the increased escape latency across several trials, was produced by systemic administration of the muscarinic receptor antagonist atropine (30 mg/kg, IP). (R)-zacopride (0.001-1 microgram/kg, but not 10 or 100 micrograms/kg) significantly reduced escape latency in atropine-treated animals. (S)-Zacopride was inactive over the entire dose range examined (0.001-100 micrograms/kg, i.p.). Moreover, pretreatment with (S)-zacopride (1 or 100 micrograms/kg) did not alter the procognitive effects of (R)-zacopride (1 microgram/kg). These data demonstrate that the cognition enhancing properties of zacopride in this model of cholinergic hypofunction are exclusive to its (R)-enantiomer and imply that this action is unrelated to 5-HT, receptor antagonism or 5-HT4 receptor agonism. The possibility that the procognitive effects of (R)-zacopride may be related to actions at the novel "(R)-zacopride site" is discussed.
Fontana
D J
DJ
Neurobiology Unit, Roche Bioscience, Palo Alto, CA 94304, USA.
Daniels
S E
SE
Eglen
R M
RM
Wong
E H
EH
D000818:Animals; D001285:Atropine / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013237:Stereoisomerism
D001549:Benzamides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018727:Muscarinic Antagonists; D012702:Serotonin Antagonists; D001285:Atropine; C055971:zacopride