Kenneth M. Johnson, Jr., Ph.D.

Professor

Affiliations: Department of Pharmacology & Toxicology; Department of Psychiatry and Behavioral Sciences, Graduate Program in Neuroscience

Phone: (409) 772-1561
Fax: (409) 772-9642
Email: kmjohnso@utmb.edu

Education

• B.S. 1963-1967 Stephen F. Austin University (Nacogdoches, TX)
• Ph.D. 1969-1974 University of Houston
• Postdoctoral Fellowship 1975-1977 Medical College of Virginia

research interests

This laboratory is investigating the mechanisms responsible for apoptotic death following either over-excitation of neurons in vitro by glutamate or the administration of glutamate antagonists in vivo. The former is relevant to neuronal death in stroke and the latter is most relevant to developing an animal model of schizophrenia. Both projects involve the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor and the actions of phencyclidine (PCP, angel dust) as an NMDA antagonist. We have recently demonstrated that perinatal administration (PN7-11) of PCP kills cortical neurons via an apoptotic mechanism that requires upregulation of critical NMDA receptor subunits. Cell death, as well as the behavioral deficits that occur in these animals later in life (PN25-60), can be prevented by administration of atypical antipsychotic drugs. We propose that PCP-induced cell death models the hypofrontality observed in schizophrenia as well as certain behavioral aspects of this disease, including learning and sensorimotor gating deficits. We are approaching this problem using behavioral, anatomical, biochemical and molecular techniques. Examples of behavioral techniques include the analysis of locomotor activity and prepulse inhibition of acoustic startle following acute and repeated PCP administration. We use in vivo administration of antischizophrenic drugs as well as selective pharmacological antagonists to characterize the role of dopaminergic, muscarinic, GABAergic and serotonergic receptors in the long-term behavioral and biochemical changes induced by chronic administration of PCP. Other examples of prominent techniques in the lab include immunochemical staining of apoptosis-specific antigens, terminal dUTP nick-end labeling (TUNEL) of fragmented DNA, immunoblot analysis of proteins and transcription factors in the apoptosis pathway and in situ hybridization of mRNA for glutamate receptor subunits. We also carry out studies at a more functional level. For example, we have found that chronic PCP administration results in an increase in the NMDA NR1 and NR2A subunits, while acute administration increases cortical NR1 and 2B. These effects are quite different in the striatum and correspond to the differential toxicity observed in this region. In order to answer more detailed mechanistic questions at the cellular and molecular level, we have established a primary cortical cell culture model in which we have observed that chronic administration of PCP results in upregulation of specific NMDA receptor subunits, increased NMDA-induced apoptosis and necrosis and changes in enzymes such as poly(ADPribose) polymerase-1 and caspase-3 as well as apoptotic proteins and transcription factors such as Bax and NF-kB. It is thought that such a multilevel approach is necessary to understand a berrant behavior at a cellular and molecular level.

Biographical Information

Kenneth M. Johnson earned a Ph.D. in biophysical and biochemical sciences from the University of Houston (1974) and completed postdoctoral training in pharmacology at the Medical College of Virginia (1977). Dr. Johnson is currently the P.I. of NIH grants on the neurochemical pharmacology of phencyclidine and perinatal neurodegeneration as a model of schizophrenia. He also has collaborative studies with the University of Illinois and Acenta Discovery scientists that are focused on the discovery of medications for the treatment of cocaine addiction and depression. He lectures on the principles of receptor and enzyme mechanisms, various aspects of catecholamine and glutamate neurochemistry and pharmacology, and the pharmacotherapy of pain, depression and schizophrenia. His research is supported by the National Institute on Drug Abuse (NIDA). He is the author of over 145 peer-reviewed research papers and currently serves on the editorial boards of the Journal of Pharmacology and Experimental Therapeutics and Drug and Alcohol Dependence. Dr. Johnson served on a pharmacology review panel for NIDA (1988-1992) and is currently the Graduate Program Director in Pharmacology and Toxicology and the Associate Director of the UTMB Center for Addiction Research at UTMB.

Selected Publications

Yu, B., Wang, C., Liu, J., Johnson, K.M. and Gallagher, J.P. Adaptation to chronic PCP results in hyperfunctional NMDA and hypofunctional GABAA synaptic receptors. Neuroscience (In Press, 2002).

Petukhov, Pavel A., Wang, Cheng Z., Ye, Yan Ping, Johnson, K.M., Tella, Srihari R. and Kozikowski, Alan P. SAR Studies of Piperidine-Based Analogues of Cocaine. 4: Effect of N-Modification and Ester Replacement. J. Med. Chem. (2002, In Press).

McInnis, J., Wang, C., Anatasio, N., Hultman, M., Ye, Y-P, Salvemini, D. and Johnson, K.M. The role of superoxide and NF-KB signaling in N-methyl-D-aspartate-induced necrosis and apoptosis. J. Pharmacol. Exp. Ther. 301:1-10, 2002.

Wang, C., McInnis, J., Ross-Sanchez, M., Patricia Shinnick-Gallagher, Wiley, J.L. and Johnson, K.M. Long-term behavioral and neurodegenerative effects of perinatal phencyclidine adminstration: implications of schizophrenia. Neuroscience 107:535-550, 2001.

Tamiz, A.P., Bandyopadhyay B.C., Zhang, J., Flippen-Anderson, F.L., Zhang, M., Wang, C.Z., Johnson, K.M., Tella, S. and Dozikowski, A.P. Pharmaoclogical and behavioral analysis of sopme bivalent ligand-based monoamine reuptake inhibitors. J. Med. Chem. 44:1615-1622, 2001.

Phillips, M., Wang, C. and Johnson, K.M. Pharmacological characterization of locomotor sensitization induced by chronic phencyclidine administration. J Pharmacol Exp Ther 296:905-913, 2001.