Neuropeptide CART modulates dopamine turnover in the nucleus accumbens: Insights into the anatomy of rewarding circuits.

Neuropeptide cocaine- and amphetamine-regulated transcript (CART) is known to influence the activity of the canonical mesolimbic dopaminergic pathway and modulate reward seeking behaviour. CART neurons of the lateral hypothalamus (LH) send afferents to the ventral tegmental area (VTA) and paraventricular thalamic nucleus (PVT) and these nuclei, in turn, send secondary projections to nucleus accumbens. We try to dissect the precise sites of CART's action in these circuits in promoting reward. Rats were implanted with bipolar electrode targeted at the lateral hypothalamus-medial forebrain bundle (LH-MFB) and trained to press the lever through intracranial self-stimulation (ICSS) protocol. CART (55-102) administered directly into posterior VTA (pVTA) or PVT of the conditioned rats significantly increased the number of lever presses, indicating reward-promoting activity of the peptide. Concomitant increase in dopamine (DA) and 3, 4-dihydroxyphenylacetic acid (DOPAC) efflux was noted in the microdialysate collected from the nucleus accumbens shell (AcbSh). On the other hand, immunoneutralization of endogenous CART with CART antibodies injected directly in the pVTA or PVT reduced the lever press activity as well as DA and DOPAC efflux in the AcbSh. Injection of CART (1-39) in pVTA or PVT was ineffective. We suggest that CART cells in the LH-MFB area send afferents to (a) pVTA and influence dopaminergic neurons projecting to AcbSh and (b) PVT, from where the secondary neurons may feed into the AcbSh. Excitation of the CARTergic pathway to the pVTA as well as the PVT seems to promote DA release in the AcbSh and contribute to the generation of reward.