Activation of α7 nicotinic receptors improves phencyclidine-induced deficits in cognitive tasks in rats implications for therapy of cognitive dysfunction in schizophrenia.
Nicotinic α7 acetylcholine receptors (nAChRs) have been highlighted as a target for cognitive enhancement in schizophrenia. 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. Adult female hooded-Lister rats received sub-chronic PCP (2mgkg) or vehicle i.p. twice daily for 7days, followed by 7 days washout. In cohort 1, PCP-treated rats then received PNU-282987 (5, 10, 20mgkg s.c.) or vehicle and were tested in the reversal-learning task. In cohort 2, PCP-treated rats received PNU-282987 (10mgkg s.c.) or saline for 15days and were tested in the novel object recognition test on day 1 and on day 15, to test for tolerance. 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 10mgkg (P<0.01) and 20mgkg (P<0.001), and in novel object recognition at 10mgkg on day 1 (P<0.01) and on day 15 (P<0.001). 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 once daily dosing of PNU-282987 (10mgkg s.c.) does not cause tolerance in the rat. This study suggests that activation of α7 nAChRs, may represent a suitable strategy for improving cognitive deficits of relevance to schizophrenia.