Neurocircuitry of methamphetamine action and addiction

Methamphetamine (METH) is a highly addictive psychostimulant that profoundly remodels brain circuits underlying compulsive drug seeking, cognitive impairment, and relapse. Although extensive pharmacological, circuit-based, and neuroimaging studies have identified widespread alterations in cortical and subcortical networks, these findings have not yet been integrated into a comprehensive circuit-level framework. In this review, we synthesize current evidence on how METH-induced remodeling of excitatory/inhibitory (E/I) balance reshapes neural circuitry to drive behavioral adaptations and addiction. We highlight how METH disrupts dopaminergic, glutamatergic, and GABAergic neurotransmission within corticostriatal and mesocorticolimbic pathways, while also altering noradrenergic and cholinergic signaling. Emerging circuit nodes, including the claustrum and cerebellum, are discussed as previously underappreciated contributors to METH-associated neuroadaptations. Furthermore, neuroimaging studies consistently demonstrate aberrant connectivity across large-scale brain networks, particularly the default mode, salience, and frontoparietal networks. Collectively, converging evidence identifies the medial prefrontal cortex (mPFC) as a central integrative hub that coordinates cortical and subcortical communication governing reward processing, executive control, and relapse vulnerability. Based on these findings, we propose a unified framework in which METH-induced remodeling of E/I balance within the mPFC disrupts cortical-subcortical network integration, thereby promoting maladaptive reward processing, cognitive dysfunction, and relapse. This circuit-based perspective provides a mechanistic framework for understanding METH addiction and identifies mPFC-centered network dysfunction as a promising target for future therapeutic interventions.