Activation of 5-HT6 receptors facilitates attentional set shifting

Prefrontal cortex (PFC)-dependent executive function is disrupted in a range of psychiatric disorders and can be modelled in non-human primates and rodents using attentional set-shifting paradigms. There are few current pharmacological strategies for enhancing attentional set shifting, although the PFC is rich in relevant neurotransmitter targets, including 5-hydroxytryptamine (5-HT). Although 5-HT depletion studies do not support a role for 5-HT in attentional set shifting, the effect of 5-HT activation using specific receptor agonists has not been tested. This study investigated the effect of a novel, selective 5-HT6 receptor agonist, WAY181187, in a rat model of PFC-dependent extra-dimensional (ED) attentional set shifting. The effect of this agent on immediate early gene expression in the medial PFC and other regions was also examined. Compared to vehicle-injected controls, WAY181187 facilitated ED set shifting but did not change other non-ED phases of the task (including intra-dimensional set shifting and reversal). This effect was blocked by the selective 5-HT6 antagonist SB399885, which alone had no effect. WAY181187 enhanced ED set shifting even when administered after the attentional set had been acquired, thereby ruling out impairments in attentional set formation. In separate experiments, at a dose that increased ED set shifting, WAY181187 increased Fos-like immunoreactivity in the medial PFC in a SB399885-sensitive manner, suggesting a 5-HT6 receptor-mediated activation of this region. Through use of a novel 5-HT agonist, these experiments reveal a previously unrecognised role for 5-HT activation in PFC-dependent executive function, mediated by 5-HT6 receptor activation.