Role of 5-HT6 receptors in memory formation

Mice lacking the 5-HT6 receptor presented neither gross anatomical or behavioral abnormalities nor obvious changes in microscopic brain morphology, and their performance in rotarod, open field and novel object testing paradigms revealed no differences compared with wild-type animals. Nevertheless, an association between the 5-HT6 receptor polymorphism C267T and Alzheimer's disease has been reported. Interestingly, the 5-HT6 antisense oligonucleotide decreased 5-HT6 gene expression and enhanced spatial learning acquisition in the water maze. Similarly, injection of the 5-HT6 receptor antagonist Ro-04-6790 improved learning consolidation in an autoshaping task, while mCPP, scopolamine and dizocilpine decreased performance. The effect induced by scopolamine or dizocilpine, but not that induced by mCPP, was completely or partially reversed by Ro-04-6790. Ro-04-6790 did not modify the 8-OH-DPAT facilitatory effects on learning consolidation. Since Ro-04-6790 facilitatory effect was unaffected by 5-HT1A, 5-HT2A/2B/2C, 5-HT3, 5-HT4 or 5-HT7 receptor blockade, the facilitatory effect induced by Ro-04-6790 involved specifically 5-HT6 receptors. Similarly, the 5-HT6 receptor antagonist SB-271046 improved retention in the water maze and produced a significant performance improvement in aged rats in an operant-delayed alternation task. A series of Ro-04-6790 analogues that penetrate the brain and specifically bind to 5-HT6 receptors reversed scopolamine-induced retention deficit in a passive avoidance learning test. Collectively, these data provide further support to the notion that 5-HT systems, via 5-HT6 receptors, also play a significant role in memory formation under normal and dysfunctional memory conditions. (C) 2001 Prous Science. All rights reserved.