UTMB - The University of Texas Medical Branch

Research Interests

This laboratory is interested in the mechanisms of drugs abuse that support addiction or model psychiatric illness. Our work in the last several years has largely focused on the neurochemical mechanisms by which phencyclidine (PCP, angel dust) causes behavioral changes in rats that mimic schizophrenia following administration in developing rat pups. One of the senior scientists in the lab found PCP causes apoptotic death of both principal neurons and parvalbumin-containing interneurons in the frontal cortex and other important regions of the developing rat brain.

Neurodegeneration can be prevented by administration of antischizophrenic drugs. Similarly, the consequent behavioral abnormalities can also be blocked by these drugs. Our goal is to understand the detailed mechanism of neuronal death and to use this model to develop novel treatments for schizophrenia.

Thus far, one of our students and a research scientist have determined that PCP blocks a cell survival pathway that involves inhibition of phosphoinositol-3 kinase (PI-3K) and Akt, which ultimately activates glycogen synthase kinase-3β (3GSK-3β) which in turn, causes the activation of a neuronal caspase-3-dependent “suicide” pathway. In addition, we observed that blockade of GSK-3β with the antimanic agent, lithium, is neuroprotective. More recently, we have determined that activation of synaptic neurotransmission by blocking inhibition by GABAergic neurons also can prevent neuronal death, particularly when calcium influx is increased through non-NMDA channels. This may suggest that schizophrenia, in broad terms, is a result of diminished neurotransmission in critical brain regions during a critical period of development (postnatal day 5-14 in rat, late second-early third trimester in humans). Importantly, this also suggest that treatments that overcome this deficit may be valuable in treating schizophrenia.

Our laboratory has recently discovered that activation of dopamine D1 receptors can prevent PCP-induced neurotoxicity in neuronal cultures by activation of protein kinase A (PKA) and the src kinase family, which in turn phosphorylates two of the NMDA receptor subunits, NR1 and NR2B. This phosphorylation causes these receptors to be transported from the extrasynaptic region of the neuron into the synaptic region, thereby overcoming the PCP-induced blockade of synaptic NMDA receptors. We propose that PCP-induced cell death models the pathological and behavioral hypofrontality observed in schizophrenia, including learning, sensorimotor gating deficits as well as diminished social interaction. Another student in the lab is working to understand the relationship between NMDA receptor blockade and altered behavior by using NMDA receptor subunit-selective drugs to measure their effect on apoptotic neuronal death and subsequent development of altered behaviors. She has recently found that acute treatment on PN7 results in a different pattern of behavior and receptor regulation than administration on PN7, 9 and 11. Preliminary results indicate that block of synaptic (NR1-NR2A) receptors causes caspase-3 activation, but blockade of NR1-NR2B (extrasynaptic). Behavioral studies are underway to determine the relationship between degeneration and behavioral alterations.

A second area of investigation involves collaboration with Dr. Alan Kozikowski at the University of Illinois-Chicago. These projects have synthesized and tested new tropane or piperidine analogs of cocaine as potential therapeutic drugs for treatment of cocaine abuse. A new project also involves Dr. K.A. Cunningham and is designed to find novel 5-HT2C receptor agonists that we believe could be beneficial in cocaine abuse.

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 a NIDA grant on the neurochemical pharmacology of phencyclidine. Dr. Johnson directs a pre- and post-doctoral training grant on the Neural and Pharmacological Mechanisms of Abused Drugs. 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 150 peer-reviewed research papers and is listed as one of the world's most highly cited pharmacologists (www.isihighlycited.com). Dr. Johnson currently serves on the editorial boards of the Journal of Pharmacology and Experimental Therapeutics and Drug and Alcohol Dependence and in the past has served on a pharmacology review panel for NIDA (1988-1992). He is currently the Director of the Graduate Program in Pharmacology and Toxicology and the Associate Director of the Center for Addiction Research at UTMB.

Selected Publications

Lei, G., Xia, Y. and Johnson, K.M. The role of Akt-GSK-3β signaling and synaptic strength in phencyclidine-induced neurodegeneration. Neuropsychopharmacology (2007 Jul 18; [Epub ahead of print]).

Anastasio NC, Johnson KM. Differential regulation of the NMDA receptor by acute and sub-chronic phencyclidine administration in the developing rat. J Neurochem. 2008 Mar;104(5):1210-8. Epub 2007 Nov 6. - Additional Information

Wang CZ, Yang SF, Xia Y, Johnson KM. Postnatal phencyclidine administration selectively reduces adult cortical parvalbumin-containing interneurons. Neuropsychopharmacology. 2008 Sep:33(10):2442-55. Epub 2007 Dec 5. - Additional Information

Anastasio NC, Johnson KM. Atypical anti-schizophrenic drugs prevent changes in cortical N-methyl-D-aspartate receptors and behavior following sub-chronic phencyclidine administration in developing rat pups. Pharmacol Biochem Behav. 2008 Oct;90(4):569-77. - Additional Information

Xia Y, Wang CZ, Liu J, Anastasio NC, Johnson KM. Lithium protection of phencyclidine-induced neurotoxicity in developing brain: the role of phosphatidylinositol-3 kinase/Akt and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase signaling pathways. J Pharmacol Exp Ther. 2008 Sep;326(3):838-48. Epub 2008 June 10. - Additional Information

Lei G, Anastasio NC, Fu Y, Neugebauer V, Johnson KM. Activation of dopamine D1 receptors blocks phencyclidine-induced neurotoxicity by enhancing N-methyl-D-aspartate receptor-mediated synaptic strength. J Neurochem. 2009 May;109(4):1017-30. Epub 2009 Mar 10. - Additional Information

Wang, C.Z. and Johnson, K.M. The role of caspase-3 activation in phencyclidine-induced neuronal death in postnatal rats. Neuropsychopharmacology 32: 1178-1194, 2007. - Additional Information

Iso, Y., Grajkowska, E., Wroblewski, J., Davis, J., Goedders, N. E. Johnson, K.M., Sankaer, S., Roth, B.L., Tuecckmantel, W., and Kozikowski, A.P. Synthesis and structure-activity relationships of 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) analogues as potent, non-competitive metabotropic glutamate receptor subtype 5 (mGluR5) antagonists; search for cocaine medications. J. Med. Chem. 49:1080-1100, 2006. - Additional Information

Kozikowski, A.P., Zhao, L. Zhang, A., Wang, Cheng Z., Flippen-Anderson, J. and Johnson, K. M. Structural remodeling of cocaine - design and synthesis of novel trisubstituted cyclopropanes: serotonin-selective reuptake inhibitors. ChemMedChem 1: 58-65, 2006. - Additional Information

Wang, C., Fridley, J., and Johnson, K.M. The role of NMDA receptor upregulation in phencyclidine-induced cortical apoptosis in organotypic culture. Biochemical Pharmacology 69: 1373�1383, 2005. - Additional Information

Wang, C.Z. and Johnson, K. M. Differential effects of acute and subchronic administration on phencyclidine-induced neurodegeneration in the perinatal rat. J Neuroscience Res 81: 284-292, 2005. - Additional Information

He R, Kurome T, Giberson KM, Johnson KM, Kozikowski AP. Further structure-activity relationship studies of piperidine-based monoamine transporter inhibitors: effects of piperidine ring stereochemistry on potency. Identification of norepinephrine transporter selective ligands and broad-spectrum transporter inhibitors. J Med Chem.48: 7970-7979, 2005. - Additional Information

Ahmed, A. E., Campbell, G.B., Harirah, H.M., Jacob, S. and Johnson, K.M. Fetal origin of adverse pregnancy outcome: the water disinfectant byproduct chloroacetonitrile induces oxidative stress and apoptosis in mouse fetal brain. Brain Res Dev Brain Res. 159: 1-11, 2005.  - Additional Information

Zhou, J., Kla��, T., Johnson, K.M., Giberson, K.M. and Kozikowski, A.P. Discovery of novel conformationally constrained tropane-based biaryl and arylacetylene ligands as potent and selective norepinephrine transporter inhibitors and potential antidepressants. Bioorg Med Chem Lett. 15:2461-2465, 2005. - Additional Information