KCNQ2/3 Regulates the Synaptic Remodeling Associated with Drug Seeking in Addiction

Drug-seeking behavior during withdrawal represents a critical obstacle to addiction treatment. In the nucleus accumbens, hyperactive dopamine D1 receptor-expressing medium spiny neurons (D1R-MSNs) promote cocaine-seeking through aberrant synaptic remodeling, including synapse formation and calcium-permeable AMPA receptor (CP-AMPAR) insertion. However, the intermediate molecular control mechanism remains unclear. We identified KCNQ2/3 potassium channels as key regulators of synaptic pathology during withdrawal. Cocaine-conditioned mice showed increased spine density, enhanced surface CP-AMPAR, and elevated neuronal activity 14 days after withdrawal. These phenotypes were reversed by repeated administration of KCNQ2/3 openers or D1R-MSN-specific expression of constitutively active KCNQ2. Functional restoration of KCNQ2/3 suppressed cocaine-seeking behavior and normalized D1R-MSN excitability. These findings suggest that sustained KCNQ2/3 deactivation drives synaptic remodeling during withdrawal, while channel activation offers a potential therapeutic strategy. Furthermore, the results position KCNQ2/3 as a master regulator of drug-seeking behavior and channel activation in D1R-MSNs as a logical target for relapse prevention in addiction.