The Effect Of Sigma-1 Receptor Allosteric Modulator SOMCL-668 On Schizophrenia

Aims:3-methyl-phenyl-2,3,4,5-tetrahydro-1 H-benzo[d]azepin-7-ol(SOMCL-668)is a novel selective allosteric modulator of sigma-1 receptor which can promote the binding of sigma-1 receptor agonist such as[3H]-(+)-pentazocine.Activation of sigma-1 receptors can ameliorate symptoms of schizophrenia and whether sigma-1 receptor modulator has the same effect remains a question.The objective of this study is to examine if SOMCL-668 has an anti-schizophrenic activity and to explore the potential mechanisms.Methods:Acute and subchronic schizophrenia models were established by intraperitoneal injection of PCP,an antagonist of N-methyl-D-aspartate(NMDA)glutamate receptor,with different regime.Locomotor activity and prepulse inhibition(PPI)of the acute model were tested after treatment with SOMCL-668 and PRE-084,and compared with the control group.Social interrection(SI)and Novel object recognition(NOR)were tested in the subchronic model after SOMCL-668 and PRE-084 treatment.The mRNA and protein levels of sigma-1 receptor were detected with Real-time qPCR and Western blot respectively,in the frontal lobe and hippocampus of mice in the acute and subchronic model group.Results:In the acute PCP model,decrease of PPI was reversed by SOMCL-668while the PCP-induced increase of locomotor activity was not changed.There are no significant difference in the mRNA and protein levels of sigma-1 receptor between the SOMCL-668 treated group and the model.In the subchronic PCP model,decrease of SI and NOR were both improved by SOMCL-668 treatment,while there is no improvement on PCP-induced decrease of sigma-1 receptor expression.Conclusions:Sigma-1 receptor allosteric modulator SOMCL-668 can improve the behavior of mice in both acute and subchronic PCP model of schizophrenia without alteration in the mRNA or protein level of sigma-1 receptor.