Effect of a 5-HT7 Receptor Antagonist on Reversal Learning in the Rat Attentional Set-Shifting Test

5-HT7 receptor antagonism has been shown to ameliorate ketamine-induced schizophrenia-like deficits in extradimensional set-shifting using the attentional set-shifting task (ASST). However, this rodent paradigm distinguishes between several types of cognitive rigidity associated with neuropsychiatric conditions. The goal of this study was to test 5-HT7 receptor involvement in the reversal learning component of the ASST because this ability depends primarily on the orbito-frontal cortex, which shows strong 5-HT7 receptor expression. We found that impaired performance on the ASST induced by NMDA receptor blockade (MK-801, 0.2 mg/kg) in 14 rats was reversed by coadministration of the 5-HT7 receptor antagonist SB-269970. The strongest effect was found on the reversal phases of ASST, whereas injection of SB-269970 alone had no effect. These results indicate that 5-HT7 receptor mechanisms may have a specific contribution to the complex cognitive deficits, increasing perseverative responding, in psychiatric diseases, including schizophrenia, depression, and anorexia nervosa, which express different forms of cognitive inflexibility.