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

• Published in: Psychopharmacology 2019-04, Vol.236 (4), p.1245-1253
• Main Authors: Savolainen, Katja, Ihalainen, Jouni, Jalkanen, Aaro J., Forsberg, Markus M.
• Format: Article
• Language: English
• Subjects: Acetylcholine; Acetylcholine receptors (nicotinic); Adrenergic alpha-Antagonists - pharmacology; Adrenergic alpha-Antagonists - therapeutic use; Animals; Antipsychotic agents; Antipsychotic Agents - therapeutic use; Antipsychotics; Biomedical and Life Sciences; Biomedicine; Clozapine; Dose-Response Relationship, Drug; Emotional behavior; Excitatory Amino Acid Antagonists - toxicity; Health aspects; Interpersonal Relations; Locomotor activity; Male; Mental disorders; Neurosciences; Olanzapine; Original Investigation; Pharmacology/Toxicology; Phencyclidine; Phencyclidine - toxicity; Psychiatry; Psychotropic drugs; Rats; Rats, Wistar; Receptors, Adrenergic, alpha-2 - physiology; Risperidone; Rodents; Schizophrenia; Schizophrenia - chemically induced; Schizophrenia - drug therapy; Social Behavior; Social interaction
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-018-5130-2

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.