Cholecystokinin and neurotensin mRNAs are differentially expressed in subnuclei of the ventral tegmental area.

Immunohistochemical studies of ventral tegmental area (VTA) neurons indicate that individual cells can contain dopamine as well as the neuropeptide neurotransmitters cholecystokinin (CCK) and neurotensin (NT). We have defined the distribution of the cells expressing the mRNAs encoding these two dopamine cotransmitter peptides in each of the subnuclei of the ventral tegmental area, and quantitated the extent of expression of each gene by using in situ hybridization methods. These studies reveal significant differences in the patterns of expression of each of these two genes within various subdivisions of the VTA. The rostral linear nucleus contained numerous CCK positive cells, some of which appeared to express preproCCK-mRNA at a very high level, but this nucleus contained relatively few NT-expressing cells. The parabrachialis pigmentosus contained numerous NT and CCK positive cells. The paranigralis and interfascicularis nuclei displayed positive CCK cells but with expression at only modest levels. NT cells were very few in these nuclei. The caudal linear nuclei contained the highest number of NT-expressing neurons and these cells expressed very high levels of NT mRNA. The selective distribution of these peptide genes within the VTA subnuclei may have specific consequences. Studies of the connectivity of neurons in the VTA show that the different subnuclei of this region project to several functionally and architectonically different regions of the cerebral cortex and subcortically to nuclei related to the limbic system. Results from our study show very prominent expression of CCK mRNAs in those subnuclei that project heavily to the prefrontal, other cortical areas, and the amygdaloid complex. The NT gene is expressed prominently in those subnuclei of VTA that project heavily to the entorhinal cortex and amygdaloid complex. These results provide support for a differential role for the NT-expressing neurons than that of CCK-expressing neurons of VTA in "reward" mechanisms and in drug-seeking and motivational behavior. These observations could be applied to create working hypotheses and experimental paradigms to test the differential functional activity of the subdivisions of VTA and their potential roles in the pathogenesis and treatment of drug-seeking behavior and other neuropsychiatric disorders.