The mechanistic role of secretin and its receptor in regulating hippocampal dentate gyrus glutamatergic neuronal activity in methamphetamine addiction.

Methamphetamine (METH) is highly addictive and causes severe public health burdens and social harm. Secretin (SCT), secreted by S cells of the duodenum and jejunum, exerts multiple biological functions in the central nervous system. Nevertheless, the role and neural mechanism of the secretin/secretin receptor (SCT/SCTR) axis in METH addiction remain largely unclear. Here, we investigated the effects of the SCT/SCTR pathway on METH-induced conditioned place preference (CPP), neuronal activity, and associated molecular alterations. Our results demonstrated that SCT expression in plasma and colon was significantly decreased in METH-addicted mice. Both intraperitoneal SCT injection and colon-specific SCT overexpression effectively alleviated METH-evoked CPP. SCTR was abundantly expressed in glutamatergic neurons of the hippocampal dentate gyrus (DG) and markedly downregulated upon METH exposure. DG-specific SCTR knockdown exacerbated addiction-like behaviors, while SCTR overexpression mitigated these deficits. METH activated DG glutamatergic neurons, and SCT/SCTR modulation substantially reversed such neuronal hyperactivity. SCTR overexpression suppressed DG neuronal excitability and glutamate levels, and SCTR knockdown abolished the protective effect of SCT. Moreover, activation of DG glutamatergic neurons abrogated the inhibitory action of SCTR overexpression on METH-induced CPP. RNA-seq further identified differentially expressed molecules associated with immune response and cytokine production following SCTR overexpression. Collectively, the SCT/SCTR pathway represents a promising novel therapeutic target for METH addiction.