Divergent effects of the 'biased' 5-HT1A receptor agonists F15599 and F13714 in a novel object pattern separation task

Background and PurposePattern separation, that is, the formation of distinct representations from similar inputs, is an important hippocampal process implicated in cognitive domains like episodic memory. A deficit in pattern separation could lead to memory impairments in several psychiatric and neurological disorders. Hence, mechanisms by which pattern separation can be increased are of potential therapeutic interest. Experimental approach5-HT1A receptors are involved in spatial memory. Herein we tested the biased' 5-HT1A receptor agonists F15599, which preferentially activates post-synaptic heteroreceptors, and F13714, which preferentially activates raphe-located autoreceptors, in rats in a novel spatial task assessing pattern separation, the object pattern separation (OPS) task. Key ResultsThe acetylcholinesterase inhibitor donepezil, which served as a positive control, significantly improved spatial pattern separation at a dose of 1mgkg(-1), p.o. F15599 increased pattern separation at 0.04mgkg(-1), i.p., while F13714 decreased pattern separation at 0.0025mgkg(-1), i.p. The selective 5-HT1A receptor antagonist WAY-100635 (0.63mgkg(-1), s.c.) counteracted the effects of both agonists. These data suggest that acute preferential activation of post-synaptic 5-HT1A heteroreceptors improves spatial pattern separation, whereas acute preferential activation of raphe-located 5-HT1A autoreceptors impairs performance. Conclusions and ImplicationsWe successfully established and validated a novel, simple and robust OPS task and observed a diverging profile of response with biased' 5-HT1A receptor agonists based on their targeting of receptors in distinct brain regions. Our data suggest that the post-synaptic 5-HT1A receptor consists of a potential novel molecular target to improve pattern separation performance.