Transcranial direct current stimulation restores addictive behavior via prefrontal-striatal circuit.

Dependence on methamphetamine (METH) is a severe brain disorder characterized by high relapse rates and cognitive decline following detoxification. Recent research suggests that transcranial direct current stimulation (tDCS) may treat addiction, but the underlying neural mechanisms remain unknown. Here, we employed METH-conditioned place preference (CPP) paradigm integrated with fMRI, electrophysiology, chemogenetics, in vivo fiber photometry recordings and a novel rodent tDCS model to examine the neural circuit underlying tDCS modulation on METH-induced addictive behavior. We demonstrated that tDCS targeted at the medial prefrontal cortex (mPFC) prevents relapse. Specifically, tDCS enhanced the activity of neurons in both the infralimbic cortex (IL) and the nucleus accumbens shell (NAcSh) simultaneously. Furthermore, chemogenetic inhibition of the IL-NAcSh circuit eliminated the modulatory effects of tDCS, while activation of the IL-NAcSh circuit was sufficient to suppress the relapse. These findings reveal that the IL-NAcSh pathway functions as a descending regulatory circuit mediating the therapeutic outcomes of tDCS in the treatment of substance use disorder, offering new insights into circuit-based neuro-modulatory treatments for addiction.