Cocaine- and Amphetamine-Regulated Transcript Peptide Plays a Role in the Manifestation of Depression: Social Isolation and Olfactory Bulbectomy Models Reveal Unifying Principles

We investigated the effect of cocaine- and amphetamine-regulated transcript (CART) peptide on depression-like behavior in socially isolated and olfactory bulbectomized (OBX) rats. Administration of CART (54-102) into the lateral ventricle (50-100 ng) or central nucleus of amygdala (CeA) (10-20 ng) caused significant decrease in immobility time in the forced swim test (FST) without influencing locomotion, suggesting antidepressant-like effect. Social isolation as well as OBX models were undertaken to produce depression-like conditions. Although isolation reared (6 weeks) rats showed significant increase in immobility time in FST, OBX animals exhibited hyperactivity (increase in the ambulation, rearing, grooming, and defecation scores) on day 14 in the open-field test. The isolation-or OBX-induced depression-like phenotypes were reversed following acute or subchronic treatment of CART, respectively, given via intracerebroventricular and intra-CeA routes. Drastic reduction in CART-immunoreactivity was observed in most cells in the paraventricular (PVN), arcuate and Edinger-Westphal nuclei of the socially isolated and OBX animals. Although the fibers in the PVN showed variable response, those in ARC and prefrontal cortex did not change. The CART-immunoreactive fibers in the locus coeruleus also showed highly significant reduction. However, dramatic increase in CART-immunoreactive fibers was noticed in the CeA in both the experimental models. The response by the cells and fibers in the periventricular area and perifornical nucleus in the OBX and socially isolated rats was variable. The study underscores the possibility that endogenous CART system might play a major role in mediating symptoms of depression.