CART peptide‐immunoreactive projection from the nucleus accumbens targets substantia nigra pars reticulata neurons in the rat

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Abstract
Cocaine and amphetamine regulated transcript (CART) was originally identified as a mRNA which increases in the striatum after acute cocaine or amphetamine administration in rats. In addition, intra‐ventral tegmental (VTA) area injections of CART peptides produce psychostimulant‐like behavioral effects. CART peptide immunoreactivity (CARTir) has been localized in discrete nuclei throughout the brain, and, within the striatum, it is located only ventrally in a subpopulation of medium spiny projection neurons in the shell and core of the nucleus accumbens. To better understand the potential role of CART peptides in the mechanism of action of psychomotor stimulants, we analyzed the distribution and synaptic connectivity of CARTir terminals in the ventral midbrain. CARTir terminal‐like varicosities were located throughout the rostrocaudal extent of the substantia nigra (SN), VTA, and retrorubral field (RRF). They were particularly abundant in the dorsomedial SN where they overlapped with non‐dopaminergic substantia nigra pars reticulata (SNr) neurons and proximal dendrites of dopaminergic substantia nigra pars compacta (SNc) neurons. CARTir terminals were also in register with dopaminergic perikarya in the ventromedial part of the rostral SNc. In many instances, CARTir terminals ensheathed dendrites of SNr neurons. To characterize the postsynaptic targets and potential sources of CARTir terminals in the SN, electron microscopic observations were conducted. Ninety percent of the CARTir terminals examined displayed the ultrastructural features of boutons of striatal origin and 80% of them formed symmetric synapses with distal dendrites of SNr neurons. To further elucidate the source of CARTir terminals in the SN, unilateral excitotoxic lesions directed to the core of the nucleus accumbens (Acc) were produced; this led to a dramatic, almost complete loss of CARTir terminal staining in the ipsilateral SN, whereas the density of CARTir terminals was relatively unchanged in the VTA. In conclusion, this study demonstrates the presence of CART peptides in a direct pathway from the accumbens to the SNr, thus illustrating a unique feature of CART peptides in that they delineate a specific anatomical circuit of the basal ganglia. J. Comp. Neurol. 434:29–39, 2001.