Selective adrenergic alpha2C receptor antagonist ameliorates acute phencyclidine-induced schizophrenia-like social interaction deficits in rats
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CitationSavolainen, Katja. Ihalainen, Jouni. Jalkanen, Aaaro J. Forsberg, Markus M. (2018). Selective adrenergic alpha2C receptor antagonist ameliorates acute phencyclidine-induced schizophrenia-like social interaction deficits in rats. PSYCHOPHARMACOLOGY, [Epub ahead of print 10 Dec 2018], 10.1007/s00213-018-5130-2.
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.
We wanted to confirm whether selective adrenergic α2C receptor (AR) antagonist therapy could ameliorate acute phencyclidine (PCP)-induced schizophrenia-like social interaction deficits in rats, and to compare the effects of an α2C AR antagonist to another putative therapeutic alternative, an α7 nicotinic acetylcholine receptor (nAChR) partial agonist, as well against three commonly used atypical antipsychotics.
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 α2C 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.
Acute PCP (1.5 mg/kg s.c.) produced robust and reproducible deficits in social interaction behavior without affecting locomotor activity. The selective α2C 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.
Our findings confirm that α2C AR antagonism is a potential mechanism for the treatment of the negative symptoms of schizophrenia.
Subjectsα2C adrenergic receptor antagonist α7 nicotinic acetylcholine receptor partial agonist atypical antipsychotics rat schizophrenia social interaction deficit
Link to the original itemhttp://dx.doi.org/10.1007/s00213-018-5130-2
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