Post-stroke depression (PSD) and post-stroke anxiety (PSA) are usually undertreated and many cases may remain undiagnosed, indicating a need for a better understanding of the underlying mechanisms. Current animal models of PSD and PSA using the middle cerebral artery occlusion model may be associated with motor deficits that can interfere with behavioral tests of depression- and anxiety-like behavior. Unilateral lesions of the medial prefrontal cortex (mPFC) have been reported to induce a depression- and anxiety-like phenotype in mice. The aim of this study was to examine the effects of unilateral microinjections of the vasoconstrictor endothelin-1 (ET-1) in the mPFC alone or in combination with the nucleus accumbens (NAc) on the behavior of rats after 2 and 6 weeks. Specifically, we measured anxiety- and depressive-like behavior, locomotion, and cognition. ET-1 injections in the mPFC and NAc resulted in replicable and localized lesions. Lesions to the mPFC and NAc resulted in more time spent in the open arms of the Elevated Plus Maze compared to sham-operated animals at 2 weeks post stroke, indicating decreased anxiety. This effect did not persist until 6 weeks post injection. No differences in locomotion, cognition and depressive-like behavior were found at either time point. In summary, unilateral lesions of mPFC and NAc did not produce a reliable and persistent anxiety and depression phenotype in rats.