Article date: September 2012
By: S Woods, NN Clarke, R Layfield, KCF Fone in Volume 167, Issue 2, pages 436-449
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‐HT6 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.
DOI: 10.1111/j.1476-5381.2012.02022.x
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