Selective adrenergic alpha2C receptor antagonist ameliorates acute phencyclidine-induced schizophrenia-like social interaction deficits in rats

RATIONALE: Social withdrawal is a core feature of the negative symptoms of schizophrenia. Currently available pharmacotherapies have only limited efficacy towards the negative symptoms, i.e., there is a significant unmet medical need in the treatment of these symptoms. OBJECTIVE: We wanted to confirm whether selective adrenergic α(2C) receptor (AR) antagonist therapy could ameliorate acute phencyclidine (PCP)-induced schizophrenia-like social interaction deficits in rats, and to compare the effects of an α(2C) AR antagonist to another putative therapeutic alternative, an α(7) nicotinic acetylcholine receptor (nAChR) partial agonist, as well against three commonly used atypical antipsychotics. METHODS: Here, we used acute PCP administration and modified a protocol for testing social interaction deficits in male Wistar rats and then used this model to compare the effects of an α(2C) AR antagonist (ORM-13070 0.3 and 1.0 mg/kg s.c.) with an α(7) nAChR partial agonist (EVP-6124 0.3 mg/kg s.c.) and three atypical antipsychotics (clozapine 2.5 mg/kg i.p., risperidone 0.04 and 0.08 mg/kg s.c., olanzapine 0.125 and 0.5 mg/kg s.c.) on social interaction behavior. RESULTS: Acute PCP (1.5 mg/kg s.c.) produced robust and reproducible deficits in social interaction behavior without affecting locomotor activity. The selective α(2C) AR antagonist significantly ameliorated PCP-induced social interaction deficits. In contrast, neither the partial α(7) nAChR agonist nor any of the three atypical antipsychotics were able to reverse the behavioral deficits at the selected doses. CONCLUSION: Our findings confirm that α(2C) AR antagonism is a potential mechanism for the treatment of the negative symptoms of schizophrenia.