The Flinders sensitive line (FSL) rat is a proposed genetic hypercholinergic animal model of human depression. Considering the strong comorbidity between depression and cocaine dependence we investigated the well-documented behavioral and molecular effects of cocaine in the FSL and their control Flinders resistant line (FRL) rats. First, we found no difference between the two lines to establish cocaine self-administration; both lines reached stable responding within 10 days of training at a fixed ratio-1 schedule of reinforcement (1.5 mg/kg/injection). However, the FSL rats exhibited reduced cocaine intake at a dose of 0.09 mg/kg/injection in a within-session dose-response curve (0.02, 0.09, 0.38, 1.5 mg/kg/injection). Second, we examined the effects of repeated cocaine administration on locomotor activity, dopamine overflow and striatal prodynorphin mRNA expression. We found the FSL rats to be low responders to novelty and to exhibit less locomotor activation after repeated cocaine administration (30 mg/kg, i.p., daily injections for 10 days) than their controls. Microdialysis sampling from the nucleus accumbens shell revealed no significant difference in the dopamine overflow between the rat lines, neither during baseline nor after cocaine stimulation. Postmortem analyses of striatal prodynorphin mRNA expression (using in situ hybridization histochemistry) revealed a differentiated response to the cocaine exposure. In contrast to control FRL rats, the FSL rats showed no typical cocaine-evoked elevation of prodynorphin mRNA levels in rostral subregions of the striatum whereas both strains expressed increased prodynorphin mRNA levels in the caudal striatum after cocaine administration. In conclusion, the FSL animal model of depression demonstrates marked blunting of the locomotor and dynorphin neuroadaptative responses to cocaine in accordance with its enhanced cholinergic sensitivity.