5-HT6 receptor agonists and antagonists enhance learning and memory in a conditioned emotion response paradigm by modulation of cholinergic and glutamatergic mechanisms

Abstract

BACKGROUND AND PURPOSE 5-HT6 receptors are abundant in the hippocampus, nucleus accumbens and striatum, supporting their role in learning and memory. Selective 5-HT6 receptor antagonists produce pro-cognitive effects in several learning and memory paradigms while 5-HT 6 receptor agonists have been found to enhance and impair memory. EXPERIMENTAL APPROACH The conditioned emotion response (CER) paradigm was validated in rats. Then we examined the effect of the 5-HT6 receptor antagonist, EMD 386088 (10 mg·kg-1, i.p.), and agonists, E-6801 (2.5 mg·kg-1, i.p.) and EMD 386088 (5 mg·kg -1, i.p.) on CER-induced behaviour either alone or after induction of memory impairment by the muscarinic receptor antagonist, scopolamine (0.3 mg·kg-1, i.p) or the NMDA receptor antagonist, MK-801 (0.1 mg·kg-1, i.p). KEY RESULTS Pairing unavoidable foot shocks with a light and tone cue during CER training induced a robust freezing response, providing a quantitative index of contextual memory when the rat was returned to the shock chamber 24 h later. Pretreatment (-20 min pre-training) with scopolamine or MK-801 reduced contextual freezing 24 h after CER training, showing production of memory impairment. Immediate post-training administration of 5-HT6 receptor antagonist, SB-270146, and agonists, EMD 386088 and E-6801, had little effect on CER freezing when given alone, but all significantly reversed scopolamine- and MK-801-induced reduction in freezing. CONCLUSION AND IMPLICATIONS Both the 5-HT6 receptor agonists and antagonist reversed cholinergic- and glutamatergic-induced deficits in associative learning. These findings support the therapeutic potential of 5-HT6 receptor compounds in the treatment of cognitive dysfunction, such as seen in Alzheimer's disease and schizophrenia. © 2012 The Authors. British Journal of Pharmacology.