5‐HT6 receptor agonists and antagonists enhance learning and memory in a conditioned emotion response paradigm by modulation of cholinergic and glutamatergic mechanisms
- 22 August 2012
- journal article
- Published by Wiley in British Journal of Pharmacology
- Vol. 167 (2), 436-449
- https://doi.org/10.1111/j.1476-5381.2012.02022.x
Abstract
5-HT(6) receptors are abundant in the hippocampus, nucleus accumbens and striatum, supporting their role in learning and memory. Selective 5-HT(6) 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. The conditioned emotion response (CER) paradigm was validated in rats. Then we examined the effect of the 5-HT(6) 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). 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-HT(6) 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-HT(6) receptor agonists and antagonist reversed cholinergic- and glutamatergic-induced deficits in associative learning. These findings support the therapeutic potential of 5-HT(6) receptor compounds in the treatment of cognitive dysfunction, such as seen in Alzheimer's disease and schizophrenia.Keywords
This publication has 88 references indexed in Scilit:
- Guide to Receptors and Channels (GRAC), 5th editionBritish Journal of Pharmacology, 2011
- Central nervous system effects of the interaction between risperidone (single dose) and the 5‐HT6 antagonist SB742457 (repeated doses) in healthy menBritish Journal of Clinical Pharmacology, 2011
- Physical Interaction of Jab1 with Human Serotonin 6 G-protein-coupled Receptor and Their Possible Roles in Cell SurvivalPublished by Elsevier BV ,2010
- Impairment in Long-Term Retention of Preference Conditioning in SchizophreniaBiological Psychiatry, 2009
- Using the MATRICS to guide development of a preclinical cognitive test battery for research in schizophreniaPharmacology & Therapeutics, 2009
- Effects of 5‐HT6 receptor antagonism and cholinesterase inhibition in models of cognitive impairment in the ratBritish Journal of Pharmacology, 2008
- Fear conditioning in frontotemporal lobar degeneration and Alzheimer's diseaseBrain, 2008
- Regulatory Mechanisms of Fear Extinction and Depression-Like BehaviorNeuropsychopharmacology, 2007
- Efficacy of selective 5-HT6 receptor ligands determined by monitoring 5-HT6 receptor-mediated cAMP signaling pathwaysBritish Journal of Pharmacology, 2006
- Chronic 5‐HT6receptor modulation by E‐6837 induces hypophagia and sustained weight loss in diet‐induced obese ratsBritish Journal of Pharmacology, 2006