Sertindole improves sub-chronic PCP-induced reversal learning and episodic memory deficits in rodents: involvement of 5-HT6 and 5-HT2A receptor mechanisms

This study examined the efficacy of sertindole in comparison with a selective 5-HT6 and a 5-HT2A receptor antagonist to reverse sub-chronic phencyclidine (PCP)-induced cognitive deficits in female rats. In the first test, adult female hooded Lister rats were trained to perform an operant reversal learning task to 90% criterion. After training, rats were treated with PCP at 2 mg/kg (i.p.) or vehicle twice daily for 7 days, followed by 7 days washout. For the second test, novel object recognition (NOR), a separate batch of rats, had the same sub-chronic PCP dosing regime and washout period. In reversal learning, rats were treated acutely with sertindole, the selective 5-HT2A receptor antagonist M100.907 or the selective 5-HT6 receptor antagonist SB-742457. The PCP-induced selective reversal learning deficit was significantly improved by sertindole, M100.907 and SB-742457. Sertindole also significantly improved the sub-chronic PCP-induced deficit in NOR, a test of episodic memory following a 1 min and 1 h inter-trial interval. In vivo binding studies showed that the dose-response relationship for sertindole in this study most closely correlates with affinity for 5-HT6 receptor in vivo binding in striatum, although contribution from binding to 5-HT2A receptors in vivo in cortex may also provide an important mechanism. The efficacies of selective 5-HT2A and 5-HT6 receptor antagonists suggest potential mechanisms mediating the effects of sertindole, which has high affinity for these 5-HT receptor subtypes. The sertindole-induced improvement in cognitive function in this animal model suggests relevance for the management of cognitive deficit symptoms in schizophrenia.