The role of neuropeptide CART in the lateral hypothalamic-ventral tegmental area (LH-VTA) circuit in motivation

• Intracranial self-stimulation (ICSS) was facilitated by CART.
• ICSS resulted in robust activation of CART cells in the LH.
• ICSS induced synaptic plasticity in CART system in reward circuit.
• Rats can be conditioned to self-administer CART in pVTA.
• CART neurons of LH-MFB may process motivation via the mesolimbic dopamine pathway.

Rats with electrode implanted in the lateral hypothalamus (LH)-medial forebrain bundle (MFB) area actively engage in intracranial self-stimulation (ICSS). However, the neuronal substrate that translates the electrical pulses into the neural signals, and integrates the information with mesolimbic reward system, has remained elusive. We test the hypothesis that the cocaine- and amphetamine-regulated transcript (CART) neurons in the LH-MFB area may support this function. The ICSS activity via an electrode in LH-MFB area was facilitated by CART (55–102) peptide stereotaxically injected in the lateral ventricle or posterior ventral tegmental area (pVTA), but attenuated by CART antibody. While the ICSS experience seems to activate CART cells in the LH, the pVTA showed significant increment in the CART fiber terminals on the dopamine cells, increase in tyrosine hydroxylase (TH)-immunoreactivity, and CART and synaptophysin colabeled elements. Neuronal tracing experiments revealed that CART cells of the LH-MFB region project to the pVTA. The rats with stereotaxically implanted cannulae in pVTA avidly self-infused CART (55–102) suggesting a role for the peptide in motivation, however, CART (1–39) was ineffective. CART self-infusing activity was inhibited by dopamine D1 receptors antagonist, given directly in the nucleus accumbens shell (AcbSh). The rats trained to self-administer CART (55–102) showed enhanced TH immunoreactivity in the cells of pVTA and fibers in AcbSh. We suggest that CART neurons of the LH-MFB area may play a role in conveying reward information to the mesolimbic dopamine neurons, which in turn may arouse the goal directed behavior.