Elsevier

Behavioural Brain Research

Volume 118, Issue 1, 8 January 2001, Pages 107-110
Behavioural Brain Research

Short communication
Effects of the 5-HT6 receptor antagonist Ro 04-6790 on learning consolidation

https://doi.org/10.1016/S0166-4328(00)00316-8Get rights and content

Abstract

The 5-HT6 receptor antagonist Ro-04-6790 or 8-OH-DPAT injection improved learning consolidation on an autoshaping task, while mCPP, scopolamine and dizocilpine decreased the performance. The effect induced by scopolamine, but not that induced by mCPP, was reversed completely by Ro-04-6790, while dizocilpine effect was antagonized partially. Nevertheless, ritanserin or WAY 100635, but not Ro 04-6790, antagonized the 8-OH-DPAT facilitatory effects on learning consolidation. As WAY 100635 did not modify the Ro 04-6790 facilitatory effect, hence 5-HT1A, and/or 5-HT7, but not 5-HT6, receptors might mediate the 8-OH-DPAT facilitatory effect on learning consolidation. Since, the Ro 04-6790 facilitatory effect was unaffected by 5-HT1A, 5-HT2A/2B/2C, 5-HT3 or 5-HT4 receptor blockade, thereby, the facilitatory effect induced by Ro 04-6790 involved specifically 5-HT6 receptors. Indeed, the present data provide further support to the notion that, 5-HT6 receptors play a significant part in the learning consolidation under normal and dysfunctional memory conditions.

Introduction

Serotonergic neurotransmission involves multiple 5-hydroxytryptamine (5-HT) receptor subtypes (5-HT1 to 5-HT7) [1]. Among these, the 5-HT6 and 5-HT7 receptors show a regional distribution within the central nervous system [1], [4], [8], in areas, which have been associated with learning and memory processes (see [13], [14], for reviews). Diverse physiological and/or behavioral effects following manipulation of 5-HT6 receptors have been reported [1], [4], [9]. For instance, 5-HT6 antisense oligonucleotide decreased 5-HT6 gene expression and the induced behaviors by antisense treatment were antagonized by atropine (a muscarinic antagonist) [3]. Rats 5-HT6 antisense treatment produced an enhanced spatial learning acquisition in the water maze [2]. It should be noticed that, the studies mentioned above were based upon the sole use of nonselective either, agonist or antagonist drugs for 5-HT6 receptor. Nevertheless, a growing interest for the 5-HT6 receptors as target by the drugs development useful for psychiatric disorders treatment [9], such as schizophrenia. Interestingly, an association between the 5-HT6 receptor polymorphism C267T and Alzheimer's disease (AD) has been reported [20]. Indeed, two novel, presenilin 1 (PS1) and presenilin 2 (PS2) have been implicated casually in the pathogenesis of AD and more than 50 misense mutations of PS1 are known [5], including the polymorphism C267T. Accordingly, drugs acting at 5-HT6 receptors could modulate learning and memory. Hence, in the current work, it was decided to study the effect of the 5-HT6 antagonist Ro 04-6790 [4], the 5-HT1A/7 agonist 8-OH-DPAT, the 5-HT1A antagonist WAY100635, the 5-HT1A/1B/1D/2A/2C/7 agonist/antagonist mCPP, the 5-HT2A antagonist ketanserin, the 5-HT2A/2C/6/7 antagonist ritanserin, the 5-HT3 antagonist ondansetron, the 5-HT4 antagonist GR125487 [1], [10], scopolamine (an anticholinergic), dizocilpine (an NMDA antagonist) and phenserine (an AChE inhibitor) [13] on associative learning. An autoshaping test was used here, which had shown to be useful to study learning and memory changes produced by age and/or drugs (see [13], [18]). Importantly, whether drugs are administered before training, results very difficult to determine whether these act on memory or other processes (e.g. attention, motivation, locomotor activity, etc.; [13]; for recent review, see [11]); however, the post-learning treatment strategy allows to exclude most of the problems that the former strategy presents, i.e. producing changes on attention, motivation, locomotor activity, etc.; unrelated with learning and memory per se.

Section snippets

Methods

Adult male Wistar rats were housed collectively in a temperature- and light-controlled room under a 12-:12-h light-dark cycle (light on at 7:00 h). Water and food were provided ad libitum for a week. After that period, body weights were reduced to 85% by gradually reducing the food intake during 7 days.

Results

As depicted in Table 1, the Ro 04-6790 administration increased significantly the CR% [F(4,39)=6.2; P<0.05], and this effect was significant at the 5 mg/kg dose. As reported previously [16], 8-OH-DPAT, significantly [F(4,39)=3.5; P<0.05] increased the CR%. At the tested doses, neither WAY100635, ketanserin, ritanserin, ondansetron, nor GR125487 by itself, affected the CR percentage of mCPP [F(6,55)=1.0; P>0.05], [F(6,55)=1.3; P>0.05]. In contrast, scopolamine [F(3,31)=3.9; P<0.05] or

Discussion

Inasmuch as, in the present study, the animals received the drugs after the first training session and once they had the opportunity to learn where to find food-pellets, and thus excluding nonspecific change [11]. Therefore, these data reflect an effect in the learning consolidation [11], [13], [14]. The major finding of the present study was that, post-training injection of the 5-HT6 receptor antagonist Ro 04-6790 alone enhanced learning consolidation. While, ritanserin or WAY 100635 had no

Acknowledgements

The author thanks the pharmaceutical companies for the generous gifts (see Section 2.2). The author wants to thank Sofia Meneses for the review of the language. The author appreciates greatly the technical assistance of R. Gonzdlez and H. Vazquez for the bibliographic assistance. Supported by CONACYT grant 28398M.

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