Abstract : Anxiety is one of the prevailing symptoms observed during the initial period of abstinence in cocaine abusers and is considered as an important factor of relapse. The aim of this study was to provide further insight into the cerebral dysregulations that might contribute to this pathological state in rats. Rats were treated chronically with cocaine and anxiety-behaviors were assessed in different paradigms during withdrawal (elevated plus maze, open arm and shock probe burying tests). Our results demonstrated that cocaine withdrawal induced persistent heightened levels of anxiety that last for at least 28 days. We then used Fos immunohistochemistry to map neuronal activation patterns in withdrawn rats confined to one open arm (OA) of an elevated plus maze. Our data showed that the exacerbated anxiety observed in cocaine treated rats exposed to an OA was accompanied by an altered reactivity of the dorsal part of the medial prefrontal cortex (dmPFC) glutamatergic neurons and some sub-cortical regions (anterior and lateral hypothalamic areas and the paraventricular nucleus of the thalamus). Finally, we showed that pharmacological inactivation of the dmPFC with muscimol considerably attenuated anxiety-related behaviors in cocaine withdrawn rats suggesting an exaggerated response of this cortical area during the processing of anxiogenic stimuli. The present study provides new data on the neural substrate underlying pathological anxiety observed during cocaine withdrawal and highlights the importance of the dmPFC in the regulation of this pathological anxiety state.