Antipsychotic effect of the high-affinity sigma-1/2 receptor compound B1F

Current antipsychotics provide limited benefit for the negative and cognitive symptoms of schizophrenia, highlighting the need for novel treatments. We evaluated B1F, a newly identified high-affinity Sigma-1/2 receptor (Sigma-1/2 R) compound. We found that B1F attenuated MK-801-induced hyperlocomotion and reversed deficits in prepulse inhibition. B1F also improved chronic MK-801-induced impairments in social interaction and cognitive function. Pharmacological blockade and genetic deletion of Sigma-1R attenuated, but did not abolish, the effects of B1F on schizophrenia-like behaviors, suggesting that, in addition to Sigma-1R, other components, probably Sigma-2R, may also contribute to the drug's actions. Importantly, unlike the classical antipsychotic drugs, B1F did not induce extrapyramidal symptoms (EPS) at therapeutic doses. Finally, we found that B1F treatment inhibited glycogen synthase kinase 3β and activated cAMP response element-binding protein, thereby promoting brain-derived neurotrophic factor production while reducing endoplasmic reticulum stress. These findings provide proof-of-concept evidence that B1F's antipsychotic-like effects are largely Sigma-1R-dependent, with a Sigma-1R-independent component whose nature remains to be defined. B1F was effective against schizophrenia-like impairments without inducing EPS and may be a promising candidate against schizophrenia.