GHSR1A blockade by JMV2959 following memory retrieval disrupts reconsolidation and suppresses heroin-seeking behavior.

Opioid addiction persists as a critical public health crisis, where drug-seeking behaviors frequently re-emerge despite extended periods of abstinence. Current therapeutic approaches often fail to effectively address the substantial risk of relapse triggered by drug-related cues. Existing pharmacotherapies primarily focus on alleviating withdrawal symptoms or cravings, but they do not directly intervene in the memory processes that underlie relapse. Here, we assessed the promise of JMV2959, a specific GHSR1A antagonist, in disrupting the reconsolidation of heroin-associated memories by a rat assay. After retrieval of heroin-associated conditioned stimuli, JMV2959 administration led to a significant reduction in cue-induced and drug-primed reinstatement of heroin-seeking behaviors. This effect was observed only during the reconsolidation window-administration outside this critical period, or without prior retrieval, did not produce any noticeable effect. Importantly, the reduction in cue-induced heroin-seeking behavior persisted following a 4-week withdrawal phase, suggesting a lasting disruption of the memory trace. These findings suggest that JMV2959, by targeting GHSR1A, offers a promising pharmacological strategy to weaken drug-seeking behavior and prevent relapse in opioid addiction.