Neuromodulatory roles of the sigma-1 receptor in behavior and drug sensitization during development

The sigma-1 receptor (S1R), which functions as both a receptor and molecular chaperone, plays pivotal roles in various biological processes. Its widespread involvement in central neurotransmitter regulation positions S1R as a potential target for neuropsychiatric disorders, including drug addiction, schizophrenia and neurodegenerative diseases. However, the mechanisms underlying the heightened susceptibility of individuals with S1R deficiency to neurological diseases remain elusive. This study investigated the neuromodulatory role of S1R in pyramidal neurons in the barrel field of the primary somatosensory cortex (S1BF) and the medial prefrontal cortex (mPFC) in young mice across three developmental time points (postnatal days 14, 21, and 28). By employing whole-cell recordings, we revealed distinct effects of S1R on sEPSCs, sIPSCs, and the excitatory/inhibitory (E/I) balance during the critical period. Specifically, S1R^-/- mice at P21 had substantially reduced sIPSC frequency, resulting in a noteworthy increase in the excitatory/inhibitory (E/I) ratio. In contrast, at P14 and P28, the sEPSCs and sIPSCs of the S1R^-/- mice were not affected. Adult knockout mice exhibited drug-induced behavioral sensitization to methamphetamine (METH). Mechanistic studies revealed that the administration of METH caused an E/I imbalance of pyramidal neurons in the mPFC and a decrease in the density of dendritic spines, which was accompanied by a decrease in the protein levels of brain-derived neurotrophic factor (BDNF). SOMCL-668, an allosteric modulator of S1R, attenuated METH-induced behavioral sensitization in a dose-dependent manner through attenuating excitatory synaptic transmission and modulating the p-CREB/CREB ratio. Collectively, our results underscore the developmental dynamics of S1R-mediated regulation of synaptic plasticity, offering significant implications for treatment strategies targeting S1R deficiency and disruptions in E/I balance. Finally, our findings demonstrated that S1R is involved in METH-induced behavioral sensitization and that SOMCL-668 could be a potential therapeutic agent for drug addiction.