Dopamine Transporter Immunoreactivity in Monkey Cerebral Cortex: Regional, Laminar, and Ultrastructural Localization DAVID A. LEWIS, 1,2 * DARLENE S. MELCHITZKY, 1 SUSAN R. SESACK, 1,2 RICHARD E. WHITEHEAD, 1 SUNGYOUNG AUH, 3 AND ALLAN SAMPSON 3 1 Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania 15213 2 Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania 15213 3 Department of Statistics, University of Pittsburgh, Pittsburgh, Pennsylvania 15213 ABSTRACT Dopamine (DA) influences a number of cognitive and motor functions that are mediated by the primate cerebral cortex, and the DA membrane transporter (DAT) is known to be a critical regulator of DA neurotransmission in subcortical structures in rodents. To gain insight into the possible functional role of cortical DAT, we compared the regional, laminar, and ultrastructural distribution of DAT immunoreactivity to that of tyrosine hydroxylase (TH), the rate-limiting enzyme in DA synthesis, in the cerebral cortex of macaque monkeys. DAT-immunoreactive (DAT-IR) axons were present throughout the cortical mantle, with substantial differences in density and laminar distribution across cytoarchitectonic areas. In particular, high densities of DAT-IR axons were present in certain regions (e.g., posterior parietal cortex, dentate gyrus) not previously thought to receive a substantial DA input. The laminar distribution of DAT-IR axons ranged from a restricted localization of labeled axons to layer 1 in lightly innervated regions to the presence of axons in all six cortical layers, with a particularly dense plexus in deep layer 3, in highly innervated regions. These regional and laminar patterns paralleled those of TH-IR axons, but several differences in fiber morphology and ultrastructural localization of DAT were observed. For example, in contrast to TH, DAT immunoreactivity in the cortex was localized predominantly to small-diameter profiles, whereas, in the dorsolateral caudate nucleus, DAT and TH immunoreactivities were present in both large-diameter and small-diameter profiles, which may represent varicose and intervaricose axon segments, respectively. Overall, the distribution of DAT-IR axons confirms and extends the results of previous reports, using other markers of DA axons, that the DA innervation of the primate cerebral cortex is global but specialized on both a regional basis and a laminar basis. In particular, these observations reveal an anatomical substrate for a direct and potent influence of DA over neuronal activity in posterior parietal cortex and in certain regions of the temporal lobe. However, due to its predominant distribution to small-diameter profiles, immunoreactivity for DAT may not be an appropriate ultrastructural marker for larger DA varicosities in the primate cortex. Moreover, this distribution of DAT suggests that cortical DA fibers may permit greater neurotransmitter diffusion than subcortical DA axons. J. Comp. Neurol. 432:119 –136, 2001. © 2001 Wiley-Liss, Inc. Indexing terms: cynomolgus monkey; dentate gyrus; dopamine; neocortex; tyrosine hydroxylase Grant sponsor: U.S. Public Health Service: Grant numbers: MH43784, MH45156, and MH50314. *Correspondence to: David A. Lewis, M.D., Western Psychiatric Institute and Clinic, Biomedical Science Tower, W1651, 3811 O’Hara Street, Pitts- burgh, PA 15213. E-mail: lewisda@msx.upmc.edu Received 3 December 1999; Revised 10 August 2000; Accepted 22 De- cember 2000 THE JOURNAL OF COMPARATIVE NEUROLOGY 432:119 –136 (2001) © 2001 WILEY-LISS, INC.