Activation of α7 nicotinic receptors improves phencyclidine-induced deficits in cognitive tasks in rats: Implications for therapy of cognitive dysfunction in schizophrenia

Abstract

Rationale: Nicotinic α7 acetylcholine receptors (nAChRs) have been highlighted as a target for cognitive enhancement in schizophrenia. Aim: To investigate whether the deficits induced by sub-chronic phencyclidine (PCP) in reversal learning and novel object recognition could be attenuated by the selective α7 nAChR full agonist, PNU-282987. Methods: Adult female hooded-Lister rats received sub-chronic PCP (2 mg/kg) or vehicle i.p. twice daily for seven days, followed by 7-days washout. In cohort 1, PCP-treated rats then received PNU-282987 (5, 10, 20 mg/kg; s.c.) or vehicle and were tested in the reversal learning task. In cohort 2, PCP-treated rats received PNU-282987 (10 mg/kg; s.c.) or saline for 15 days and were tested in the novel object recognition test on day 1 and on day 15, to test for tolerance. Results: Sub-chronic PCP produced significant deficits in both cognitive tasks (P<0.01-0.001).PNU-282987 attenuated the PCP-induced deficits in reversal learning at 10 mg/kg (P<0.01) and 20 mg/kg (P<0.001), and in novel object recognition at 10 mg/kg on day 1 (P<0.01) and on day 15 (P<0.001). Conclusions: These data show that PNU-282987 has efficacy to reverse PCP-induced deficits in two paradigms of relevance to schizophrenia. Results further suggest that 15 day daily dosing of PNU-282987 (10 mg/kg s.c.) does not cause tolerance in rat. This study suggests that activation of α7 nAChRs, may represent a suitable strategy for improving cognitive deficits of relevance to schizophrenia.

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

“…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.…”

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

“…PNU-282987 showed both selectivity and potency as an a7 nAChR agonist (K i = 29 nM), retaining full agonist efficacy relative to nicotine in functional assays . PNU-282987 has been thoroughly characterized both in vitro and in vivo, demonstrating the restoration of P50 gating deficits in rodents, and has served as a tool molecule to advance basic research efforts Vicens et al, 2010;McLean et al, 2011). However, a major drawback of this compound was the interaction with the human ether à go-go-related gene (hERG) channel, which could represent a major cardiovascular risk (Walker et al, 2006).…”

Nicotinic α7 and α4β2 agonists enhance the formation and retrieval of recognition memory: Potential mechanisms for cognitive performance enhancement in neurological and psychiatric disorders

“…For experiment 2, 30 rats were used and studies testing the effects of PNU-282987 and RJR-2403 separately were combined, therefore the vehicle group was n=17 (3 rats failed to explore the objects and were excluded from the final analysis). The doses of PNU-282987 were selected based on efficacy to reverse a sub-chronic PCP-induced deficit in reversal learning in our laboratory (McLean et al, 2011b). The doses of RJR-2403 were selected based on efficacy to improve working memory in the odour span task (Rushforth et al, 2010).…”

“…Indeed, NOR has been listed by the TURNS initiative as relevant for studying visual learning and memory deficits in schizophrenia (TURNS.ucla.edu) and may be used to study cognitive deficits occurring in a range of disorders (Grayson et al, 2014). In our laboratory, we have extensively shown that sub-chronic phencyclidine (PCP) treatment impairs object recognition memory following a 1 min inter-trial interval-ITI (Damgaard et al, 2010(Damgaard et al, , 2011Grayson et al, 2007;Idris et al, 2010;McLean et al, 2009McLean et al, , 2011bSnigdha et al, 2010Snigdha et al, , 2011. We have also demonstrated the efficacy of a wide range of selective receptor targets to reverse these sub-chronic PCP-induced deficits (see for review) as have other labs using the same paradigm (see Meltzer et al, 2013 for review).…”