Specific inhibition of interpeduncular nucleus GABAergic neurons alleviates anxiety-like behaviors in male mice of prolonged abstinence from methamphetamine

Anxiety is one of the most common withdrawal symptoms of methamphetamine (METH) abuse, which further drives relapse to drugs. Interpeduncular nucleus (IPN) has been implicated in anxiety-like behaviors and addiction, yet its role in METH abstinence-induced anxiety remains unknown. Here, we found that prolonged abstinence from METH enhanced anxiety-like behaviors in male mice, accompanied by more excited IPN GABAergic neurons, as indicated by the increased c-Fos expression and the enhanced neuronal excitability by electrophysiological recording in the GABAergic neurons. Using the DREADDs method, specific inhibition of IPN GABAergic neurons rescued the aberrant neuronal excitation of IPN GABAergic neurons, and efficiently reduced anxiety-like behaviors, whereas did not induce depression-like behaviors in male mice of prolonged abstinence from METH. These findings reveal that IPN GABAergic neurons should be a promising brain target to alleviate late withdrawal symptoms of METH with few side effects.SIGNIFICANCE STATEMENT:Prolonged abstinence from METH triggers IPN GABAergic neurons, and ultimately increases anxiety in male mice. Suppressing IPN GABAergic neurons rescues METH abstinence-induced aberrant neuronal excitation of IPN GABAergic neurons, and efficiently reduces anxiety in mice.