Reversal of Subchronic PCP-Induced Deficits in Attentional Set Shifting in Rats by Sertindole and a 5-HT6 Receptor Antagonist: Comparison Among Antipsychotics

Abstract

Currently accepted treatments for schizophrenia can effectively control positive symptoms but have limited impact on cognitive deficits in schizophrenia. The purpose of these experiments was to address this unmet need by characterizing the effects of classical and secondgeneration antipsychotics on cognitive impairments associated with schizophrenia. An additional aim was to characterize the part(s) of the pharmacological profile of drugs that were important to reverse deficits. Cognitive deficits were assessed using a frontally mediated attentional set-shifting task in rats that is analogous to tasks used in humans and nonhuman primates that assess executive function. Mirroring findings in patients with schizophrenia, the classical antipsychotic haloperidol was ineffective in treating set-shifting deficits induced by subchronic treatment with phencyclidine (PCP). Similarly, second-generation antipsychotics, risperidone, clozapine, and olanzapine were ineffective. In contrast, selected doses of sertindole and the 5-HT 6 receptor antagonist SB 271046 attenuated PCPinduced set-shifting deficits. Finally, the 5-HT 2A receptor antagonist M100907 was without effect. Further examination revealed that repeated treatment (21 days) with sertindole, but not olanzapine, also was effective in reversing the executive function deficit. These data suggest that the combination of 5-HT 6 antagonistic activity and the absence of antimuscarinic activity may represent key characteristics of the pharmacological profile for improved antipsychotic drugs for 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).…”

Ventral Striatal Dopamine Modulation of Different Forms of Behavioral Flexibility

“…The D 1 antagonist used in these studies (SCH23390) has affinity for both D 1 and 5HT 2A receptors. However, the observation that systemic blockade of 5HT 2A receptors with M100907 produces no apparent impairment in set-shifting (Rodefer et al, 2008) suggests that the effects of SCH23390 reported here are likely attributable to actions on NAc D 1 receptors.…”

Brexpiprazole II: Antipsychotic-Like and Procognitive Effects of a Novel Serotonin-Dopamine Activity Modulator

“…It has been reported that haloperidol is ineffective whereas risperidone, olanzapine, and clozapine show nonsignificant trends toward improved ED-shift performance, and other antipsychotics, sertindole, and quetiapine show full reversal (Rodefer et al, 2008;Goetghebeur and Dias, 2009;Nikiforuk and Popik, 2012). In addition, studies of selective 5-HT receptor subtype antagonists indicate that the 5-HT 2A antagonist M100907 has borderline effects similar to risperidone whereas a 5-HT 6 antagonist [SB-271046, 5-chloro-N-[4-methoxy-3-(1-piperazinyl) phenyl]-3-methylbenzo[b]thiophene-2-sulfonamide hydrochloride] and 5-HT 7 antagonist [SB-269970, (R)-3-{2-[2-(4-methylpiperidin-1-yl)ethyl]pyrrolidin-1-ylsulfonyl}phenol] replicate the profile of sertindole (Rodefer et al, 2008;Nikiforuk et al, 2013). Therefore, the effect of brexpiprazole in this model would be associated with its potent 5-HT 2A and modest 5-HT 6 receptor antagonist activity (Maeda et al, 2014).…”

“…Subchronic PCP treatment is known to impair cognitive performance in various tests (Rodefer et al, 2008;Neill et al, 2010). Two tests were selected for characterization of brexpiprazole and aripiprazole in the present studies: NOR and ID-ED.…”

“…These latter strains have been shown to acquire cognitive tests faster and more reliably (Andrews et al, 1995). For this reason, the NOR test was validated using LH rats Redrobe et al, 2010), and the ID-ED test was validated with either LH (Goetghebeur and Dias, 2009) or LE rats (Rodefer et al, 2008). However, only the LE rat strain was available in the People's Republic of China, so it was selected for use in the ID-ED test.…”