Cocaine- and amphetamine-regulated transcript peptide projections in the ventral midbrain: colocalization with gamma-aminobutyric acid, melanin-concentrating hormone, dynorphin, and synaptic interactions with dopamine neurons.

To date, cocaine- and amphetamine-regulated transcript (CART) peptides have been found to influence feeding, locomotor activity, and conditioned place preference. A common brain structure that could mediate these effects is the ventral tegmental area (VTA). For a better understanding of the anatomical substrates that might 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 VTA. Double-labeling immunofluorescence revealed that approximately 15% of CARTir terminals in the VTA contain the hypothalamic neuropeptide, melanin-concentrating hormone (MCH). Furthermore, CART peptides were also found to colocalize with GABA and, to a small extent, with dynorphin in nerve terminals in both the VTA and the substantia nigra (SN). In the VTA, CARTir terminals form both symmetric and asymmetric synapses onto dopaminergic and nondopaminergic distal dendrites, suggesting that various sources contribute to this innervation. About 30% of CARTir terminals in the VTA and only 15% in the SN appose or form synaptic contact with DA neurons, which support our previous data showing that GABAergic basal ganglia output neurons in the substantia nigra pars reticulata (SNr) receive strong CARTir input from the accumbens core. Results of these studies suggest that the most significant behavioral states influenced by CART peptides, feeding and locomotion, may be mediated by direct and/or indirect modulation of VTA dopaminergic neuronal activity.