Significance of the nicotinic alpha7 receptor in cognition and antipsychotic-like behavior in the rat.
Schizophrenic (SCH) patients show cognitive impairment in attentional performance. Positive allosteric modulators (PAMs) of α7 nicotinic acetylcholine receptors (nAChRs) such as the Alzheimers drug galantamine (GAL) and PAM-2 are documented to have pro-cognitive properties. However, it is not well established if these properties would be lost, or may hamper antipsychotic efficacy, when given as an adjunct to an antipsychotic which is needed for managing psychotic symptoms. Using adult male Wistar rats, we here investigated the effects of a) GAL, alone or co-administered with the antipsychotic risperidone (RISP), on acute phencyclidine (PCP)-induced deficits in the attentional set-shifting (ASST) test b) PAM-2, alone and co-administered with RISP, in the conditioned avoidance response (CAR) test for antipsychotic activity. Acute PCP produced selective and significant SCH-like impairment in extra dimensional shift (EDS) performance, which was completely reversed by GAL. The ability of GAL to reverse PCP-induced EDS impairment was not prevented when co-administered with RISP, suggesting that the combination of GAL and low doses of RISP may be used to improve the cognitive impairment in SCH. Pretreatment with methyllycaconitine (MLA), a selective α7 nAChR antagonist, completely prevented the reversal elicited by GAL, supporting the concept that α7 nAChRs are involved in this process. On the other hand, PAM-2 alone had no effects on CAR, but enhanced, although not significantly, the antipsychotic-like effect of RISP when administered together. In conclusion, α7 PAMs, in addition to alleviate the cognitive impairments observed in SCH patients, may enhance the antipsychotic efficacy of atypical antipsychotics.