Activation of alpha 7 nicotinic receptors improves phencyclidine-induced deficits in cognitive tasks in rats: Implications for therapy of cognitive dysfunction in schizophrenia

作者：McLean Samantha L; Grayson Ben; Idris Nagi F; Lesage Anne S; Pemberton Darrel J; Mackie Claire; Neill Jo C^*

来源：European Neuropsychopharmacology, 2011, 21(4): 333-343.

DOI：10.1016/j.euroneuro.2010.06.003

• Reversal learning
• Novel object recognition
• alpha 7 nACh receptor
• Phencyclidine
• Female rat
• Cognition
• Schizophrenia

Rationale: Nicotinic alpha 7 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 alpha 7 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 7 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 once daily dosing of PNU-282987 (10 mg/kg s.c.) does not cause tolerance in the rat. This study suggests that activation of alpha 7 nAChRs, may represent a suitable strategy for improving cognitive deficits of relevance to schizophrenia.

• 出版日期2011-4