Noninvasive tFUS stimulation of the parabrachial nucleus suppresses lever pressing during extinction of cocaine self-administration through aversive circuit engagement.

INTRODUCTION: Drug addiction is a significant public health concern, and persistent drug-seeking behavior remains difficult to control in severe cases. While invasive interventions have been explored to suppress these behaviors, their use is limited by procedural complexity, highlighting the need for effective noninvasive neuromodulatory approaches. Transcranial focused ultrasound (tFUS) provides a noninvasive approach for deep-brain neuromodulation, but its ability to produce persistent behavioral effects by targeting the extralateral parabrachial nucleus (elPBN) remains unknown. METHODS: Mice were trained to self-administer cocaine using an operant lever-press paradigm. Following stable cocaine self-administration, active lever presses triggered response-contingent tFUS stimulation instead of cocaine delivery. Stimulation was delivered through the intact skull and targeted to the elPBN for four consecutive days. RESULTS: tFUS delivered to the elPBN elicited aversive-related behavioral responses consistent with those previously reported using optogenetic stimulation of this region. In the operant task, tFUS stimulation significantly reduced active lever responding compared with controls. Together, these results indicate that response-contingent engagement of aversive signaling within the elPBN suppressed operant responding previously reinforced by cocaine. This behavioral suppression persisted after a two-week abstinence period, indicating that the effect extended beyond the stimulation phase. CONCLUSION: Noninvasive tFUS targeting the elPBN produced persistent suppression of operant responding previously reinforced by cocaine. Replacing cocaine delivery with response-contingent stimulation of an aversion-related brainstem region produced a lasting change in reward-associated behavior. These findings support further investigation of deep-brain tFUS as a noninvasive neuromodulation approach for modifying maladaptive drug-related behaviors.