THE SELECTIVE 5-HT3 RECEPTOR ANTAGONIST, WAY100289, ENHANCES SPATIAL MEMORY IN RATS WITH IBOTENATE LESIONS OF THE FOREBRAIN CHOLINERGIC PROJECTION SYSTEM

The effects of three doses (0.003, 0.03 and 1.0 mg/kg sc) of the 5-HT3 receptor antagonist, WAY 100289, on spatial learning and memory in th e water maze were examined in rats before and after ibotenate lesions to the nucleus basalis and medial septal brain regions at the source o f cholinergic projections to cortex and hippocampus. The representativ e cholinergic nicotinic and muscarinic receptor agonists nicotine (0.1 mg/kg) and arecoline(1.0 mg/kg) were also tested for comparison. Both arecoline and nicotine improved initial acquisition in rats before le sioning, in terms of latency to find a hidden platform and accuracy of search strategy. WAY 100289 did not affect the performance of normal rats significantly, apart from some non-significant trends towards imp rovement with the highest dose. However, in animals showing transient navigational deficits in retention and relearning after lesioning, WAY 100289 improved performance at all three doses, tho ugh ameliorative effects of nicotine and arecoline were more marked also in lesioned ra ts. These results show that WAY 100289 improved spatial learning in an imals impaired after lesions to cholinergic projection nuclei, which m ay reflect an interaction with cholinergic transmission to enhance cog nitive function. However, in the present study, WAY 100289 appeared to be less effective than direct cholinergic agonists.