Betaine improves METH-induced depressive-like behavior and cognitive impairment by alleviating neuroinflammation via NLRP3 inflammasome inhibition

Methamphetamine abuse has been associated with central nervous system damage, contributing to the development of neuropsychiatric disorders such as depressive-like behavior and cognitive impairment. With the escalating prevalence of METH abuse, there is a pressing need to explore effective therapeutic interventions. Thus, the objective of this research was to investigate whether betaine can protect against depressive-like behavior and cognitive impairment induced by METH. Following intraperitoneal injections of METH in mice, varying doses of betaine were administered. Subsequently, the behavioral responses of mice and the impact of betaine intervention on METH-induced neural damage, synaptic plasticity, microglial activation, and NLRP3 inflammatory pathway activation were assessed. Administration 30 mg/kg and 100 mg/kg of betaine ameliorated METH-induced depressive-like behaviors in the open field test, tail suspension test, forced swimming test, and sucrose preference test and cognitive impairment in the novel object recognition test and Barnes maze test. Moreover, betaine exerted protective effects against METH-induced neural damage and reversed the reduced synaptic plasticity, including the decline in dendritic spine density, as well as alterations in the expression of hippocampal PSD95 and Synapsin-1. Additionally, betaine treatment suppressed hippocampal microglial activation induced by METH. Likewise, it also inhibited the activation of the hippocampal NLRP3 inflammasome pathway and reduced IL-1β and TNF-α release. These results collectively suggest that betaine's significant role in mitigating depressive-like behavior and cognitive impairment resulting from METH abuse, presenting potential applications in the prevention and treatment of substance addiction.