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

Abstract

The efficacies of selective 5-HT(2A) and 5-HT(6) 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.

Animal models of cognitive dysfunction and negative symptoms of schizophrenia: Focus on NMDA receptor antagonism

“…In contrast, Rodefer and colleagues subsequently found that clozapine and risperidone to be ineffective in reversing the PCP-induced deficit, however sertindole and the selective 5-HT 6 (SB-271046) and 5-HT 2A (M100907) receptor antagonists did attenuate the PCP-induced impairment (Rodefer et al, 2008), which is similar to our findings using reversal learning paradigm (Idris et al 2010). This same dosing regime was shown again in male hooded-Lister rats to produce deficits in the EDS phase; an effect which was ameliorated by sertindole and the anti-narcoleptic drug modafinil but not by risperidone or haloperidol (Goetghebeur and Dias, 2009).…”

“…These deficits can be subsequently improved by the acute administration of SGAs clozapine and risperidone but not by the FGA haloperidol (Grayson et al, 2007). We have also demonstrated efficacy of sertindole (Idris et al, 2010), and several novel agents including the 5-HT 6 receptor antagonist, Lu AE58054 (Arnt et al 2010);ampakines, CX546 and CX516 (Daamgard et al 2010) and the full agonist at α7 nicotinic receptors, PNU282987 (McLean et al 2010a). In addition, BL1020, glycine uptake inhibitors and the novel antipsychotic, asenapine also show efficacy to reverse the PCPinduced deficit in this task using a 1 min and 1 hour (for sertindole) ITI.…”

“…We have consistently shown that sub-chronic PCP treatment (2 mg/kg twice daily, i.p., for 7 days followed by 7 days washout period) induces a robust enduring deficit in reversal learning performance, again selective for the reversal phase leaving initial phase performance intact in female hooded-Lister rats (Abdul-Monim et al, 2006;2007;Idris et al 2010;McLean et al, 2009a;2009b). …”

“…These sub-chronic PCP-induced deficits in reversal learning were ameliorated by SGAs such as clozapine, but not by FGAs, haloperidol and chlorpromazine (Abdul-Monim et al, 2006) showing some predictive validity for the clinic. Several newer antipsychotics such as asenapine (M c Lean et al 2010b) and sertindole (Idris et al, 2010) reverse the sub-chronic PCP-induced deficit in this paradigm. The dopamine D 1 receptor agonist SKF 38393 and antagonists at several 5-HT receptor subtypes including 5-HT 6 , 5-HT 7 , 5-HT 2C and 5-HT 2A (Idris et al 2010;McLean et al, 2009a;2009b) also show efficacy in this test making it of particular relevance for exploration of mechanisms of antipsychotics important for improvement of cognitive function.…”

“…Several newer antipsychotics such as asenapine (M c Lean et al 2010b) and sertindole (Idris et al, 2010) reverse the sub-chronic PCP-induced deficit in this paradigm. The dopamine D 1 receptor agonist SKF 38393 and antagonists at several 5-HT receptor subtypes including 5-HT 6 , 5-HT 7 , 5-HT 2C and 5-HT 2A (Idris et al 2010;McLean et al, 2009a;2009b) also show efficacy in this test making it of particular relevance for exploration of mechanisms of antipsychotics important for improvement of cognitive function. In a reversal-learning task similar to that employed in our laboratory, however, using an innovative touch screen-based system, sub-chronic PCP (5 mg/kg twice daily for 7 days, followed by a 7-day washout period) in male C57BL/6J mice did not affect reversal learning ability (Brigman et al, 2009).…”