Increased Expression of 5-HT6 Receptors in the Rat Dorsomedial Striatum Impairs Instrumental Learning

Abstract

A number of studies have shown that systemic 5-HT 6 receptor antagonists can improve learning and memory, but the mechanism for these observations is not known. As striatum normally expresses 5-HT 6 receptors abundantly and is important in consolidating stimulusresponse learning, we used targeted gene delivery to further increase the expression of 5-HT 6 receptors in rat striatum and then examined learning. Increased 5-HT 6 expression had no effect on performance in the Morris water maze, a hippocampal-dependent learning paradigm, and did not alter the latency to approach or consume sucrose tablets. However, rats with increased 5-HT 6 expression failed to acquire a reward-based instrumental learning task, a striatum-dependent learning model, during 3 days of successive sessions as compared to sham surgery or GFP-expressing control rats. This behavioral deficit was observed in rats overexpressing 5-HT 6 receptors in the dorsomedial striatum, but not in rats with increased dorsocentral striatal expression. The 5-HT 6 receptor-associated deficit was reversed by administration of a 5-HT 6 antagonist, SB-258585, before each training session. When animals learned the instrumental learning task before gene transfer, increased 5-HT 6 receptor expression had no effect on long-term recall or performance of the task or on extinction of operant responding. Thus, 5-HT 6 receptor activity in rat striatum disrupts acquisition of new instrumental learning but does not impair memory or performance of reward-motivated behavior once established.

Impact of regional 5-HT depletion on the cognitive enhancing effects of a typical 5-ht6 receptor antagonist, Ro 04-6790, in the Novel Object Discrimination task

“…The striatum does, however, express some of the highest levels of 5-ht 6 receptors (Monsma et al 1993;Ruat et al 1993;Kohen et al 1996;Gérard et al 1996Gérard et al , 1997, and the combined failure of DR 5,7-DHT to deplete striatal 5-HT and to alter the cognitive response to Ro 04-6790 suggests this region may be important. This proposal is supported by the recent finding that increased striatal 5-ht 6 receptor expression impairs cognition (Mitchell et al 2007), presumably by enhancing GABAergic inhibition (Schechter et al 2008). Within the striatum 5-ht 6 receptors are expressed on GABAergic projections to the globus pallidus (Ward and Dorsa 1996), and this region has been implicated in NOD task performance (Ennaceur 1998).…”

Pro-cognitive effects of 5-HT6 receptor antagonists in the social recognition procedure in rats: implication of the frontal cortex

“…The regional specificity of this finding is underpinned by the lack of effect of SB-271046 upon its introduction into the striatum, a structure likewise possessing a high density of 5-HT 6 receptors (Gérard et al 1997;Boess et al 1998;Yoshioka et al 1998) but implicated in other dimensions of mnemonic function, including procedural and instrumental learning and speed of processing (Chudasama and Robbins 2006;Dalley et al 2004). Further, a recent study showed that increased expression of 5-HT 6 receptors in the rat dorsomedial striatum impaired performance in an instrumental learning task but not in the Morris water maze (Mitchell et al 2007). Finally, despite the importance of cholinergic mechanisms in social recognition (Perio et al 1989;Winslow and Camacho 1995;Di Cara et al 2007;Millan et al 2007), the lack of effect of SB-271046 upon administration into the NBM suggest that the pro-cognitive actions of 5-HT 6 receptor antagonists are not due to the activation of perikarya giving rise to the cholinergic NBM-cortical pathway.…”

Anxiety-like behaviors produced by acute fluoxetine administration in male Fischer 344 rats are prevented by prior exercise

“…Whether caused indirectly by 5-HT 1A autoreceptor internalization in the DRN or by direct 5-HT transporter blockade, excessive 5-HT in the amygdala could potentially increase freezing (Graeff et al 1996), whereas excessive 5-HT in the periaqueductal gray could interfere with fight or flight responding required for a successful FR-2 escape response (Graeff et al 1993(Graeff et al , 1997. 5-HT in the striatum has also recently been associated with deficits in instrumental learning, although this effect may be mediated by the 5-HT 6 receptor (Mitchell et al 2007). Severe stress has recently been shown to increase 5-HT 2C gene expression in the amygdala (Harada et al 2008), and 5-HT 2C receptors are expressed in the amygdala, periaqueductal gray, and striatum (Huang et al 2007;Pompeiano et al 1994), further implicating the involvement of these regions in the observed anxiety-like effects of acute fluoxetine.…”