| Cocaine and amphetamine regulated transcript (CART) was identified as an mRNA which increases in the striatum after acute cocaine or amphetamine administration in rats. Subsequent to this discovery, CART peptide immunoreactivity (CARTir) has been localized in discrete nuclei throughout the brain. CART peptides have been found to influence feeding and locomotor behaviors. To better understand the anatomical substrates that underlie CART peptides' role in these behaviors, we performed a series of experiments to elucidate the source, synaptic connectivity and neurochemical content of CART peptide immunoreactive (CARTir) terminals in the rat substantia nigra (SN) and ventral tegmental area (VTA).; CARTir varicosities provide a dense innervation of the rostrocaudal SN. Double immunolabeling of CART peptides and TH revealed that CARTir terminals were abundant in the dorsomedial SN reticulata (SNr). To characterize the postsynaptic targets and potential sources of CARTir terminals in the SNr, electron microscopic (EM) observations were conducted; which revealed that CARTir terminals in this region form both symmetric and asymmetric synapses onto nondopaminergic (85%) and dopaminergic (15%) distal dendrites. To determine the source of CARTir terminals in the SN, unilateral excitotoxic lesions directed to the core of the nucleus accumbens (Acc) were produced and a dramatic, almost complete loss of CARTir terminal staining in the SN was observed.; CARTir varicosities moderately innervate the rostrocaudal VTA. EM observations revealed that CARTir terminals form both symmetric and asymmetric synapses onto dopaminergic (30%) and nondopaminergic (70%) distal dendrites. To determine the sources of CARTir terminals in the VTA, the retrograde tracer, cholera toxin (CTb), was injected and analysis of double labeled sections revealed that 80% of hypothalamic retrogradely labeled CARTir neurons were found in the ipsilateral and contralateral LH and Pef. Some double labeled neurons were also identified in the shell of the Acc.; Confocal and EM studies were conducted to elucidate the neurochemical content of CARTir terminals in the VTA and SN where CART peptides were found to colocalize with GABA and, to a small extent, dynorphin. In the VTA, 15% of CARTir terminals contain the hypothalamic neuropeptide, melanin-concentrating hormone.; These studies provide a rational basis for understanding CART peptides mechanism of action in nigral and VTA circuits involved in drug abuse pathways. |
