Optogenetically Evoked Accumbal Dopamine Transients Are Sufficient to Drive Locomotor Sensitization and Cross-Sensitization to Cocaine

Abstract Repeated exposure to psychostimulants produces locomotor sensitization, a durable behavioral adaptation thought to reflect enhanced incentive salience driven by mesolimbic dopamine. However, the causal contribution of dopamine transients themselves, independent of drug pharmacology, remains elusive. Here we show that repeated optogenetic activation of ventral tegmental area (VTA) dopamine neurons is sufficient to induce persistent locomotor sensitization. Across successive stimulation sessions, mice exhibited a progressive escalation of locomotor activity that persisted for at least ten days after the last stimulation. Sensitization generalized beyond laser-on epochs, elevating baseline locomotion throughout the session. Importantly, mice previously exposed to optogenetic dopamine neuron stimulation displayed an enhanced locomotor response to a subsequent cocaine challenge, demonstrating cross-sensitization between optogenetic and pharmacological reinforcers. These findings establish phasic dopamine neuron activation as a sufficient driver of locomotor sensitization and reveal shared neural substrates underlying dopamine-dependent behavioral plasticity induced by optogenetic and drug reinforcers.