The synaptojanin-1 (*SYNJ1*) gene is crucial for dopamine-related disorders. *Synj1* deficient mice (*Synj1^+/-*) show impaired dopaminergic synaptic vesicular recycling. This study investigated how *Synj1* deficits affect the mesolimbic system, reward processing, and motivated behavior in male and female *Synj1^+/-* and *Synj1^+/+* mice using behavioral tests. *Synj1^+/-* mice showed normal reward processing and sucrose motivation. However, male *Synj1^+/-* mice exhibited attenuated cocaine conditioned place preference, not attributable to spatial memory deficits. *Synj1^+/-* mice showed delayed peak dopamine release after cocaine, with female mice also exhibiting slower dopamine decay linked to cocaine-induced DAT responses. These findings reveal abnormal mesolimbic DA signaling due to *SYNJ1* deficiencies, highlighting the need for therapeutics to restore DAT function.

Jennifer I. Mejaes, Jacqueline Saenz, Chris O'Brien, Carina M. Pizzano, Ping-Yue Pan, David J. Barker