The 5-HT6 receptor agonist WAY181187 enhances extra-dimensional set-shifting in the rat

Katherine E Burnham1, Mark G Baxter2, J Bainton1, Eric Southam3, Lee A Dawson3, Trevor Sharp1, David M Bannerman2
1Department of Pharmacology, Mansfield Road, Oxford, United Kingdom, 2Department of Experimental Psychology, South Parks Road, Oxford, United Kingdom, 3Psychiatry CEDD, GlaxoSmithKline, New Frontiers Science Park, Harlow, United Kingdom

Impairments in executive function are strongly linked to the cognitive deficits of psychiatric disorders. One aspect of executive function can be modelled, in both humans and animals, by measuring the ability to shift attention from one dimension of a complex perceptual stimulus to another, the so-called extra-dimensional (ED) shift. Lesion studies in rodents demonstrate that ED shifting and not intradimensional (ID) shifting is dependent on the medial prefrontal cortex (mPFC) (Birrell and Brown, 2000). The 5-HT6 receptor is expressed in the mPFC and this receptor has been linked to cognitive performance through studies with 5-HT6 receptor antagonists. Specifically, subchronic administration of the 5-HT6 receptor antagonist SB399885 was reported to enhance ED shifting in rats (Hatcher et al., 2005). However, there are no reports of the effects of 5-HT6 receptor agonists in such models. Here we investigated the effects of the novel 5-HT6 receptor agonist WAY181187 (Schechter et al., 2007) on ED set-shifting in the rat.

Adult male Lister hooded rats (190-230 g; n=8/group) were injected s.c. with 10 mg/kg WAY181187, 10 mg/kg SB399885, WAY181187 plus SB399885, or appropriate vehicle, 30 min prior to testing in the ED/ID paradigm (Tunbridge et al., 2004). Separate experiments examined the effect of 10 mg/kg WAY181187 or vehicle injected after the ID shift but before the ED shift (ie. after the attentional set had been formed). The number of trials to reach criterion was recorded by an observer blind to treatment. Data were analysed using 2-way ANOVA (repeated measures) followed by post-hoc Duncan’s test.

There was a statistically significant overall effect of treatment during the ED shift (F(3, 24)=3.09; p<0.05) but no effect at any other stage (F<1.95; p>0.15). Post hoc analysis revealed that WAY181187 significantly reduced trials to reach criterion during the ED shift (13.88±2.41) compared to vehicle (21.88±2.61) (p<0.05). In addition, the trials to criterion after WAY181187 were significantly less than WAY181187 plus SB399885 (21.63±2.61) (p<0.05), indicating attenuation of the effect of WAY181187 by SB399885. The effect of WAY181187 alone was not due to impaired formation of the initial attentional set, since the drug had the same effect when injected after the latter had been acquired.

These data show that the 5-HT6 receptor agonist, WAY181187, enhances cognition in a translational rodent model of mPFC-dependent executive function. In contrast to recent studies (Hatcher et al., 2005), the 5-HT6 receptor antagonist SB399885 alone was inactive in this task, although the current study used acute and not subchronic dosing. Therefore, under appropriate experimental conditions, it would appear that both 5-HT6 receptor agonists and antagonists can improve executive functioning



KB is supported by a MRC Industrial Collaborative studentship with GSK.

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