Reward deficit, expressed as anhedonia, is one of the major symptoms associated with neuropsychiatric disorders, but the underlying maladaptations have not been understood. Herein, we test the hypothesis that the neuropeptide cocaine- and amphetamine-regulated transcript (CART) may participate in the process. The study is justified since the peptide is a major player in inducing satiety and also processing of reward. The rats were socially isolated to induce reward deficit and conditioned to self-stimulate via an electrode in lateral hypothalamus (LH)-medial forebrain bundle (MFB) region. Compared to group-housed control rats, the socially isolated animals showed decreased lever press activity and elevated ICSS threshold indicating anhedonia-like condition. However, the effects of social isolation were alleviated by CART administered via intracerebroventricular route. The changes in the expression of CART protein and mRNA were screened using immunofluorescence and qRT-PCR methods, respectively. Socially isolated rats showed reduction in the expression of CART in the LH, nucleus accumbens shell (AcbSh) and posterior ventral tegmental area (pVTA) and CART mRNA in the Acb and LH. Double immunostaining with antibodies against CART and synaptophysin revealed significant loss of colabeled elements in LH, AcbSh and pVTA. We suggest that down-regulation of endogenous CARTergic system in the LH-pVTA-AcbSh reward circuitry may be causal to motivational anhedonia like phenotype seen in neuropsychiatric conditions.