Effects of the potential 5-HT7 receptor agonist AS 19 in an autoshaping learning task

doi:10.1016/j.bbr.2005.04.014

Behavioural Brain Research

Volume 163, Issue 1, 30 August 2005, Pages 136-140

https://doi.org/10.1016/j.bbr.2005.04.014 Get rights and content

Abstract

This work aimed to evaluate further the role of 5-HT₇ receptors during memory formation in an autoshaping Pavlovian/instrumental learning task. Post-training administration of the potential 5-HT₇ receptor agonist AS 19 or antagonist SB-269970 enhanced memory formation or had no effect, respectively. The AS 19 facilitatory effect was reversed by SB-269970, but not by the selective 5-HT_1A antagonist WAY100635. Amnesia induced by scopolamine (cholinergic antagonist) or dizocilpine (NMDA antagonist) was also reversed by AS 19. Certainly, reservations regarding the selectivity of AS 19 for 5-HT₇ and other 5-HT receptors in vivo are noteworthy and, therefore, its validity for use in animal models as a pharmacological tool. Having mentioned that, it should be noticed that together these data are providing further support to the notion of the 5-HT₇ receptors role in memory formation. Importantly, this 5-HT₇ receptor agonist AS 19 appears to represent a step forward respect to the notion that potent and selective 5-HT₇ receptor agonists can be useful in the treatment of dysfunctional memory in aged-related decline and Alzheimer's disease.

Introduction

A growing body of evidence from snails to humans shows that serotonin (5-hydroxytryptamine, 5-HT) input participates in memory formation [6], [7]. It remains unclear if this 5-HT influence is tonic or phasic, involving different 5-HT receptors (for review, see [7]) and/or multiple cell signaling pathways [12]. Actually, compromised serotonergic function may have an important contribution to cognitive decline related to aging, Alzheimer's disease (AD) [1], [2] and schizophrenia. Serotonergic dysfunction represents a potential target for treatment of memory dysfunctions [6], [7], and opens opportunities for the exploration of 5-HT agonists, antagonists, inverse agonists and mix activity ligands (agonists/antagonists). Recent evidence indicates that the 5-HT_1A/7 receptor agonist 8-OH-DPAT facilitated memory formation, and such an effect was blocked by the selective 5-HT_1A receptor antagonist WAY 100635 and 5-HT₇ antagonist SB-269970 [8]. Until recently there were not selective 5-HT₇ receptor agonists. Hence, in this work, we aim to re-evaluate further the role of 5-HT₇ receptors during memory formation in an autoshaping Pavlovian/instrumental learning task. Herein, post-training administration of the potentially selective 5-HT₇ receptor agonist (2S)-(+)-8-(1,3,5-trimethylpyrazolin-4-yl)-2-(dimethylamino) tetralin (AS 19) (binding IC₅₀ = 0.83 nM; Tocris; see Sanin et al. [13] or the selective 5-HT_1A (WAY 100635) or 5-HT₇ receptor antagonist (SB-269970) [8] were tested. In addition, AS 19 was also evaluated in the pharmacological models of amnesia induced by scopolamine (cholinergic antagonist) and dizocilpine (NMDA antagonist).

Section snippets

Materials and methods

Male Wistar rats (12-week-old) were collectively housed in a temperature- and light-controlled room under a 12:12 h light/dark cycle (light on at 7:00 a.m.) with water and food provided ad libitum for a week. After that period, body weights were reduced to 85% by gradually reducing food intake. The autoshaping test has been previously described (see [7]). Briefly, male Wistar rats (12-week-old) were collectively housed (12/cage) in a temperature controlled animal room (22 ± 11 °C) and on an

Discussion

The major finding of the present work is that the 5-HT₇ receptor agonist AS 19 facilitated memory formation and significantly inhibited the amnesic-induced effects of scopolamine or dizocilpine, which is consistent with previous evidence (see below). These data support the notion that serotonergic, glutamatergic, and cholinergic systems interact in cognitively impaired animals [6], [7]. Since a growing interest in 5-HT₇ receptors investigation concerning a number of functions and pathologies,

Acknowledgements

Authors thank GlaxoSmithKline for its generous gifts (see drugs section). This work was partially supported by the CONACYT Scholarship 185583 (G.S.P.G.) and Grant 39534-M (A.M.). We thank Sofia Meneses-Goytia for revised language, and Roberto Gonzalez for his expertise and assistance. Finally, authors want to deeply thank the reviewer's comments, which were very useful and their incorporation significantly improved the original version of our manuscript.

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Short communicationEffects of the potential 5-HT7 receptor agonist AS 19 in an autoshaping learning task

Abstract

Introduction

Section snippets

Materials and methods

Discussion

Acknowledgements

Trends Pharmacol Sci

Behav Brain Res

Neurosci Biobehav Rev

Behav Brain Res

Behav Brain Res

Pharmacol Ther

Neurosci Lett

Neurochemical systems involved in learning and memory

Short communication
Effects of the potential 5-HT₇ receptor agonist AS 19 in an autoshaping learning task