Research Focus

The following is a list of many of the research topics that I have been involved with during my career. I thank all of my mentors, colleagues, fellows and students who made it all possible. I also thank all of the sources who provided financial support during those many years, especially the National Institute on Drug Abuse.

research11. The brain produces very powerful molecules used for transmitting signals among the nerve cells. The distribution of these “neurotransmitters” are tightly controlled, and transporters exist in the brain to remove them from open spaces where they might create erroneous signals. The transporters are the brain’s vacuum cleaners (although they are very selective in what they pick up), and they play a major role in the action of antidepressants and psychostimulants such as amphetamine. For many years we studied these transporters and found that some transporters also move building blocks (precursors) of neurotransmitters. A major finding was how nerve impulses increased the activity of some of these transporters. (1-3)

research22. The 1970s and 80s were an amazing time when receptors for drugs and neurotransmitters were being identified in the brain. It was possible to attach a radioactive molecule to a given receptor and then find the location of the radioactivity which in turn gave the location of the receptor. The location of the receptor was important because different parts of the brain do different things, and finding out where the receptors are tells us how drugs cause their actions when they bind to those receptors. The technical approach that we used and further developed was called receptor autoradiography. These studies were pioneered in animals and could be used with slices of human brain obtained at autopsy. (4-8)

The image on left shows the distribution of opiate receptors in a slice of spinal cord. The brighter colors (Yellow, orange) indicate higher densities of receptors.

research33. In the 1980s, localizing receptors in living human beings was developed using PET scanning (PET = positron emission tomography). The same attachment/localization approach described in #2 above was used, and greatly extended the autoradiography approach used earlier. Studies in living humans are the ultimate in being able to understand the brain. I was a senior member of the team that accomplished this. My experience in localizing receptors by binding/autoradiography was key for this development. PET scanning of receptors opened up an enormous number of studies of the brain in both health and disease. (9-11)

The image on the right is the first PET scan of dopamine brain receptors. Henry Wagner is the subject. The mat around the image is autographed by key members of the PET team. The lighter color (yellow) shows higher densities of receptors.

research44. Cocaine has many actions that are based on cocaine’s binding to its “receptors”. While it was known that cocaine is addicting, the precise molecule that cocaine bound with to produce addiction wasn’t clear. Studies in our lab identified the dopamine transporter as the binding site for cocaine addiction. The study involved correlating the potency of various molecules in binding to the transporter with their potency in producing addictive behavior in monkeys. This finding stimulated a host of studies on the dopamine transporter including PET scanning studies that helped clarify the effects of cocaine on the biochemistry of the brain during addiction. (12-14) The figure on the left is the key data from Ref # 12. It shows that the compounds most effective in blocking the transporter are most effective in drug taking in animals and humans.

research55. Part of the power and magic of studying receptors is that the approach can be used to identify new medicines. Potential medications for cocaine and amphetamine abusers evolved from a detailed study of the cocaine molecule and its targets in the brain. Several cocaine-like compounds are considered as medications for reducing craving for the drugs. These compounds lack many of the toxic problems of cocaine and have properties desirable in medications. One of compounds can be used as a diagnostic imaging agent for Parkinson’s disease. Another, RTI-336, has been considered for treating human cocaine addicts, and this potential medicine has passed preliminary trials in humans. (15-17)

research66. In an effort to further understand how drugs produce addiction in the brain, we examined neurotransmitters called CART peptides. These peptides modulate dopamine in areas of the brain associated with addiction, particularly addiction to psychostimulants like cocaine and amphetamine. Topics of research included: the CART gene and its regulation, the effects of mutations in the gene in humans, how CART peptides help control the actions of drugs, and the possibility of using the CART system in the brain to develop new medications for drug addicts. (18-22)

The image on the left is a view of a brain slice through a microscope, and the CART containing nerve cells are stained light brown.

research77. It is amazing that separating rat babies (pups) from their mothers for a few hours a day around their birth changes them for life! Early maternal separation of rat pups (a stressful experience) increases their likelihood to use drugs when they are adults. We have identified many of the changes induced in the brain by the maternal separation procedure. This helps explain the molecular mechanisms of the increase in vulnerability, and helps produce a strategy to treat these animals (and humans) so they have less interest in drugs. (23-24)

research88. In a departure from regular scientific studies, I have been working on an ethical topic called collegial ethics. It is more or less a life’s experience topic. Collegial ethics proposes that we practice fairness and support with our colleagues, and develop and practice ways to do so. While this is an important topic/skill for everyone working with colleagues and friends, there is little practical training in it – hence the need to develop collegial ethics! There have been several publications and a website (collegialethics.com) devoted to this important topic. (25-29)

References

(These are a few of the publications. See the CV for a full list.)

  1. Kuhar, M.J. Neurotransmitter Uptake: A Tool in Identifying Neurotransmitter Specific Pathways. Life Sci. 13: 1623 1634, 1973.
  2. Kuhar, M.J. and Murrin, L.C. Sodium Dependent High Affinity Choline Uptake (A Review). J. Neurochem. 30: 15 21, 1978.
  3. Atweh, S., Simon, J.R., and Kuhar, M.J. Utilization of Sodium Dependent High Affinity Choline Uptake in vitro as a Measure of the Activity of Cholinergic Neurons in vivo. Life Sci. 17: 1535 1544, 1975.
  4. Kuhar, M.J. and Yamamura, H.I. Light Autoradiographic Localization of Cholinergic Muscarinic Receptors in Rat Brain by Specific Binding of a Potent Antagonist. Nature 253: 560 561, 1975.
  5. Pert, C.B., Kuhar, M.J., and Snyder, S.H. Autoradiographic Localization of the Opiate Receptor in Rat Brain. Life Sci. 16: 1849 1854, 1975.
  6. Atweh, S.F. and Kuhar, M.J. Autoradiographic Localization of Opiate Receptors in Rat. Brain. I. Spinal Cord and Lower Medulla. Brain Res. 124: 53 67, 1977.
  7. Young, W.S., III, and Kuhar, M.J. A New Method for Receptor Autoradiography: [3H]Opioid Receptors in Rat Brain. Brain Res. 179: 255 273, 1979
  8. Kuhar, M.J., De Souza, E.B., and Unnerstall, J.R. Neurotransmitter Receptor Mapping by Autoradiography and Other Methods. Ann. Rev. Neurosci. 9: 27 59, 1986.
  9. Wagner, Jr., H.N., Burns, H.D., Dannals, R.F., Wong, D.F., Langstrom, B., Duelfer, T., Frost, J.J., Ravert, H.T., Links, J.M., Rosenbloom, S.B., Lukas, S.E., Kramer A.V., and Kuhar, M.J. Imaging Dopamine Receptors in the Human Brain by Positron Tomography. Science 221(4617): 1264 1266, 1983.
  10. Wong, D.F., Wagner, H.N., Jr., Dannals, R.F., Links, J.M., Frost, J.J., Ravert, H.T., Wilson, A.A., Rosenbaum, A.E., Gjedde, A., Douglass, K.H., Petronis, J.D., Folstein, M.F., Thomas Toung, J.K., Burns H.D., and Kuhar, M.J. Effects of Age on Dopamine and Serotonin Receptors Measured by Positron Tomography in the Living Human Brain. Science 226: 1393 1396, 1984.
  11. Wong, D.F., Wagner, H.N., Jr., Pearlson, G., Dannals, R.F., Links, J.M., Ravert, H.T., Wilson, A.A., Suneja, S., Bjorvvinssen, E., Kuhar, M.J., and Tune, L. Dopamine Receptor Binding of C 11 2 N Methylspiperone in the Caudate in Schizophrenia and Bipolar Disorder: A Preliminary Report. Psychopharmacol. Bull. 21(3): 595 598, 1985.
  12. Ritz, M.C., Lamb, R.J., Goldberg S.R., and Kuhar, M.J. Cocaine Receptors on Dopamine Transporters are Related to Self administration of Cocaine. Science 237: 1219 1223, 1987.
  13. Hume, S.P., Luthra, S.K., Brown, D.J., Opacka-Juffry, J., Osman, S., Ashworth, S., Myers, R., Brady, F., Carroll, F.I., Kuhar, M.J., and Brooks, D.J. Evaluation of [11C]RTI-121 as a Selective Radioligand for PET Studies of the Dopamine Transporter. Nucl. Med. Biol. 23: 377-384, 1996.
  14. Wong, D.F., Harris, J.C., Naidu, S., Yokoi, F., Marenco, S., Dannals, R.F., Ravert, H.T., Yaster, M., Evans, A., Rousset, O., Bryan, R.N., Gjedde, A., Kuhar, M.J. and Breese, G.R. Dopamine Transporters are Markedly Reduced in Lesch-Nyhan Disease in vivo. Proc. Natl. Acad. Sci. USA 93: 5539-5543, 1996
  15. Carroll, F.I., Gao, Y., Abraham, P., Lewin, A.H., Lew, R., Patel, A., Boja, J.W., and Kuhar, M.J. Probes for the Cocaine Receptor. Potentially Irreversible Ligands for the Dopamine Transporter. J. Med. Chem. 35: 1813-1817, 1992.
  16. Scheffel, U., Lever, J.R., Abraham, P., Parham, K.R., Mathews, W.B., Kopajtic, T., Carroll, F.I., and Kuhar, M.J. N-Substituted Phenyltropanes as in vivo Binding Ligands for Rapid Imaging Studies of the Dopamine Transporter. Synapse 25: 345-349, 1997.
  17. Carroll, F.I., Howard, J.L., Howell, L.L., Fox, B.S., and Kuhar, M.J. Development of the Dopamine Transporter Selective RTI-336 as a Pharmacotherapy for Cocaine Abuse. AAPS J. 8: E196-E203, 2006.
  18. Jaworski JN, Hansen ST, Kuhar MJ, Mark GP. Injection of CART peptide into the nucleus accumbens reduces cocaine self-administration in the rat. Behav Brain Res 191:266-271, 2008. PMID: 18485497.
  19. del Giudice, EM, E., Santoro, N., Fiumani, P., Dominguez, G., Kuhar, M.J., and Perrone, L. Adolescents Carrying a Missense Mutation in the CART Gene Exhibit Increased Anxiety and Depression. Depress. Anxiety 23: 90-92, 2006.
  20. Rogge, G., Jones, D., Hubert, G.W., Lin, Y and Kuhar, MJ. CART peptides: regulators of body weight, reward and other functions. Nat Rev Neurosci, 9(10):747-58. 2008. PMID: 18802445.
  21. Hunter, R.G., Philpot, K., Vicentic, A., Dominguez, G., Hubert, G.W., and Kuhar, M.J. CART in Feeding and Obesity. Trends Endocrinol. Metab. 15: 454-459, 2004.
  22. Brennan DJ, O’Connor DP, Laursen H, McGee SF, McCarthy S, Zagozdzon R, Rexhepaj E, Culhane AC, Martin FM, Duffy MJ, Landberg G, Ryden L, Hewitt SM, Kuhar MJ, Bernards R, Millikan RC, Crown JP, Jirström K, Gallagher WM. The cocaine- and amphetamine-regulated transcript mediates ligand-independent activation of ER?, and is an independent prognostic factor in node-negative breast cancer. Oncogene. 2012 Jul 26;31(30):3483-94. doi: 10.1038/onc.2011.519. Epub 2011 Dec 5. PMID: 22139072
  23. Moffett, M.C., Vicentic, A., Kozel, M., Plotsky, P., Francis, D.D., and Kuhar, M.J. Maternal Separation Alters Drug Intake Patterns in Adulthood in Rats. Biochem. Pharmacol. 73: 321-330, 2007.
  24. Jaworski, J.N., Francis, D.D., Brommer, C.L., Morgan, E.T., and Kuhar, M.J. Effects of Early Maternal Separation on Ethanol Intake, GABA Receptors and Metabolizing Enzymes in Adult Rats. Psychopharmacology (Berl.) 181: 8-15, 2005.
  25. Kuhar, M.J. Should Codes of Ethics Include Expectations of Others? (Letter to the Editor). Sci. Eng. Ethics 12: 413-414, 2006.
  26. Kuhar, M.J. On Blacklisting in Science. Sci Eng Ethics 14:301-303, 2008. PMID 18668347
  27. Kuhar, M.J. Blacklisting Whistleblowers. ORI Newsletter, 17(1): 6, Dec 2008