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 α₇ 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 α₇ 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 α₇ 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.