Propranolol disrupts fear-induced persistent cocaine place preference and unmasks an aversion component

Post-traumatic stress disorder (PTSD) and cocaine use disorder frequently co-occur, but how traumatic memories influence drug-associated behavior during drug withdrawal is unclear. We combined traumatic-like conditioned fear memory recall (FR) with cocaine-induced conditioned place preference (CPP) in male mice, and tested preference repeatedly during withdrawal, with or without prior FR sessions. The effects of the β-adrenergic antagonist propranolol and the CRF-R1 antagonist antalarmin administered before each FR and before fear extinction were also tested. Progressive extinction of CPP occurred along repeated testing sessions in the control condition. In contrast, repeated FRs maintained a stable, persistent preference for the cocaine-associated compartment, accompanied by an increased compulsive-like behavior in the marble burying test, hyperthermia and elevated corticosterone plasma levels. Antalarmin did not prevent the FR-induced persistence of CPP. Cluster analysis revealed instead that propranolol split animals into two subgroups: one subgroup that progressively lost preference and developed even an apparent conditioned place aversion to the cocaine-associated compartment, and another subgroup that maintained and incubated CPP. The divergence toward place aversion was somehow associated with increased conditioned freezing during FRs. Subsequent fear extinction reduced preferences in both propranolol subgroups, indicating a shared dependence on ongoing fear memory engagement. Our findings identify fear memory reactivations as an active regulator of drug-associated motivational states during withdrawal, with a noradrenergic mechanism as a proximal mediator, suggesting that β-adrenergic blockade combined with exposure-based extinction may benefit comorbid PTSD and cocaine use disorder.