STEREOSELECTIVE EFFECTS OF (R)-ZACOPRIDE 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)-zac opride, potent 5-HT3 receptor antagonists with 5-HT4 receptor agonists properties, on performance in a spatial learning and memory task in r ats, the Morris water maze. A significant cognitive/performance defici t, as indicated by the increased escape latency across several trials, was produced by systemic administration of the muscarinic receptor an tagonist atropine (30 mg/kg, IF). (R)-zacopride (0.001-1 mu g/kg, but not 10 or 100 mu g/kg) significantly reduced escape latency in atropin e-treated animals. (S)-Zacopride was inactive over the entire dose ran ge examined (0.001-100 mu g/kg, i.p.). Moreover, pretreatment with (S) -zacopride (1 or 100 mu g/kg) did not alter the pro-cognitive effects of(R)-zacopride (1 mu g/kg). These data demonstrate that the cognition enhancing properties of zacopride in this model of cholinergic hypofu nction are exclusive to its (R)-enantiomer and imply that this action is unrelated to 5-HT3 receptor antagonism or 5-HT4 receptor agonism. T he possibility that the pro-cognitive effects of (R)-zacopride may be related to actions at the novel ''(R)-zacopride site'' is discussed. C opyright (C) 1996 Elsevier Science Ltd.