Dose-related impairment of spatial learning by intrahippocampal scopolamine: antagonism by ondansetron, a 5-HT3 receptor antagonist.

To study the role of hippocampal muscarinic receptors in spatial learning, various doses of scopolamine were injected bilaterally into the CA1 region of the dorsal hippocampus of rats trained in a two-platform spatial discrimination task. Scopolamine administered 10 min before each training session at doses ranging from 3.75 to 15 micrograms/microliter impaired choice accuracy, had no effect on choice latency and increased the errors of omission only with 7.5 micrograms on day 1 and with 15 micrograms on days 1 and 2 of training. No dose affected choice accuracy or latency of a non-spatial visual discrimination task. A subcutaneous dose of 1 microgram/kg ondansetron, a 5-HT3 receptor antagonist, 30 min before each training session prevented the impairment of choice accuracy by intrahippocampal 3.75 micrograms scopolamine but 0.1 microgram/kg ondansetron had no such effect. No dose of ondansetron by itself modified the acquisition of spatial learning. The results suggest that relatively low doses of scopolamine in the dorsal hippocampus selectively impair the acquisition of a spatial discrimination task, and that blockade of 5-HT3 receptors prevents the deficit caused by the muscarinic antagonist. The utility of the deficit of spatial learning induced by intrahippocampal scopolamine for modelling some aspects of memory disturbances in Alzheimer's disease is discussed.

(S)-WAY 100135, a 5-HT1A receptor antagonist, prevents the impairment of spatial learning caused by intrahippocampal scopolamine.

Scopolamine, 3.75 micrograms/microliters infused bilaterally into the CA1 region of the dorsal hippocampus 10 min before each training session, impaired choice accuracy but had no effect on choice latency or errors of omission in rats trained in a two-platform spatial discrimination task. Administered subcutaneously at 3 and 10 mg/kg 30 min before each training session, N-tert-butyl-3-4-(2-methoxyphenyl)piperazin-1-yl-2-phenylpropanami de dihydrochloride ((S)-WAY 100135), a 5-HT1A receptor antagonist, prevented the impairment of choice accuracy induced by intrahippocampal scopolamine. No subcutaneous dose of (S)-WAY 100135 by itself modified the acquisition of spatial learning. Administered into the dorsal hippocampus 15 min before each training session, (S)-WAY 100135 at doses of 0.2, 1 and 5 micrograms/microliters did not affect the acquisition of spatial learning but dose dependently prevented the impairment of choice accuracy caused by scopolamine, 3.75 micrograms/microliters infused into the same area. These findings suggest that blockade of 5-HT1A receptors can compensate the loss of cholinergic excitatory input on pyramidal cells, probably by favouring the action of other excitatory transmitters.

8-OH-DPAT impairs spatial but not visual learning in a water maze by stimulating 5-HT1A receptors in the hippocampus.

The effect of 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), a 5-HT1A receptor agonist, on spatial and non-spatial learning in a water maze was studied using two tasks of equal difficulty, with the same motor, motivational and reinforcement demands. Rats were examined for choice accuracy in a two-platform spatial discrimination task. Rats treated subcutaneously with 100 micrograms/kg 8-OH-DPAT were impaired in choice accuracy with no effect on latency. Treated rats made more errors of omission than controls only on days 1 and 2 of training. Infusion of 1 microgram/microliter spiroxatrine (SPX) or 5 micrograms/microliters of (+)WAY100135, two potent 5-HT1A receptor antagonists, in the CA1 region of the dorsal hippocampus antagonized the impairment in choice accuracy caused by 8-OH-DPAT. The effect on errors of omission on days 1 and 2 of training were not significantly modified by spiroxatrine or (+)WAY100135. Rats treated with 8-OH-DPAT were not impaired in their ability to learn a visual discrimination in a water maze. The results suggest that stimulation of 5-HT1A receptors in the CA1 region of the dorsal hippocampus impairs spatial but not visual discrimination in rats.