WIDESPREAD ORIGIN OF THE PRIMATE MESOFRONTAL DOPAMINE SYSTEM

The dopaminergic innervation of the frontal cortex, commonly implicate d in psychiatric and neurological disorders, has traditionally been as sociated with a circumscribed midline group of ventral tegmental area (VTA) neurons. We have employed a combination of retrograde tracing, u sing fluorescent dyes, and tyrosine hydroxylase (TH) immunohistochemis try to amplify knowledge of frontal cortex projecting dopamine (DA) ne urons in non-human primates, Injections of retrograde fluorochromes we re made in areas 46, 8B/6M, 12, 4, 24, and the prelimbic (PL) and infr alimbic areas (IL) of the rhesus monkey. The mesencephalic distributio n of neurons exhibiting both retrograde labeling and TH immunoreactivi ty or retrograde labeling alone was examined from the level of the mam millary bodies to the locus coeruleus. DA afferents innervating the ma caque frontal cortex as a whole originate from an unexpectedly widespr ead continuum of neurons distributed in the dorsal aspects of all thre e of the mesencephalic DA cell groups [A9, A10 and A8; generally corre sponding to the DA cells of the substantia nigra (SN), VTA, and the re trorubral area (RRA) respectively]. A large number of these retrograde ly labeled neurons are non-dopaminergic. The dorsal frontal cortex (ar eas 46, 8B/6M and 4) receive DA projections primarily from the full me dial-lateral extent of A9 cells dorsal to the SN pars compacta (i.e. A 9 dorsalis), the RRA and to a lesser extent from the A10 parabrachial pigmented nucleus (PBPG) and linear nuclei, the latter of which have b een associated with the mesocortical DA system. In contrast, the ventr omedial PL and IL exhibit a significantly more robust input from the P BPG and midline linear VTA nuclei than from the lateral groups. The an terior cingulate cortex (area 24) is innervated by a group of DA neuro ns primarily located between these laterally and medially concentrated populations. These findings demonstrate a degree of compartmentalizat ion of the mesofrontal DA system in primates, and suggest that this pr ojection should no longer be viewed as a unitary midline system.