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

Abstract

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.

Differential Effects of Aripiprazole on Electroencephalography-Recorded Gamma-Band Auditory Steady-State Response, Spontaneous Gamma Oscillations and Behavior in a Schizophrenia Rat Model

“…One rat study, for instance, found that aripiprazole administered at lower doses than those used in our study could reverse the social interaction deficit induced by an acute administration of MK-801 [59]. On the other hand, other studies found that aripiprazole used at comparable doses as well as other atypical antipsychotics such as olanzapine, risperidone and clozapine had no effect on the social deficit provoked by MK-801 or PCP [32,[60][61][62], which perfectly aligns with our results. Hence, it is possible that the lack of effect of aripiprazole was either because the dose tested was too strong or because it was not able to produce an effect on the root cause of social dysfunction.…”

Alpha2-Adrenergic Receptors as a Pharmacological Target for Spike-Wave Epilepsy

“…Mice with overexpressed alpha2C ARs showed an impairment in searching behavior during water maze training [ 91 ]. More recently some possibilities of therapeutic interventions through alpha2C ARs were discovered since its selective antagonist showed antidepressant and antipsychotic effects [ 92 , 93 ]. It is known that subtypes A and B undergo pronounced desensitization after 30 min of exposure to NA, while subtype C becomes less sensitive to its endogenous agonist only after 24 h [ 94 ].…”

Clozapine prevented social interaction deficits and reduced c-Fos immunoreactivity expression in several brain areas of rats exposed to acute restraint stress

“…For instance, Becker and Grecksch [ 24 ] showed that a single injection of clozapine induced social interaction deficit in sham-lesioned rats compared to control rats, in the ventral hippocampus lesion model, while subchronic administration of clozapine did not affect social behavior. Other authors showed that clozapine failed to reverse social interaction deficit induced by acute [ 25 ] or 3 days [ 13 ] phencyclidine (PCP) treatment in male Wistar rats. Sams-Dodd et al [ 26 ], demonstrated that clozapine did not ameliorate social interaction deficits in the neonatal hippocampal lesion rat model.…”