Pharmacology and Toxicology - Research

Kenneth M. Johnson, Ph.D.

Professor and Graduate Program Director

Research Interests

This laboratory is interested in developing novel therapeutic approaches to the treatment of schizophrenia. We have developed a rat model in which young rats are administered phencyclidine (PCP) on postnatal (PN) days 7, 9 and 11. Behaviors relevant to schizophrenia are measured from PN 25 to late adolescence (~PN70). Examples of behavioral techniques include the analysis of pre-pulse inhibition of acoustic startle as well as social and play behavior following acute and repeated PCP administration. We have discovered that this treatment causes changes in these behaviors, as well as apoptotic death of layer II-IV cortical principle neurons and parvalbumin-containing interneurons in the cortex. One student has recently found that treatment with newer atypical antischizophrenic drugs prevents neuronal death and behavioral deficits. She has also reported that PCP treatment causes a compensatory upregulation in a class of glutamate receptors that are inhibited by PCP treatment. Others in the lab have found that PCP kills cortical neurons via a caspase-3-dependent apoptotic mechanism that involves activation of GSK-3β through inhibition of the PI-3K/Akt pathway. Another student found that PCP-induced neuronal death in cortical slice cultures can be prevented by BDNF, nicotine and lithium, a GSK-3β inhibitor. We propose that PCP-induced cell death models the pathological and behavioral hypofrontality observed in schizophrenia, including learning and sensorimotor gating deficits. We are now developing the use of fluorescence activated cell sorting (FACS) to identify various cell types that are most sensitive to PCP. Other examples of prominent techniques in the lab include immunochemical staining of specific neuronal markers, including enzymes critical to apoptosis such as caspase-3, terminal dUTP nick-end labeling (TUNEL) of fragmented DNA, pull-down assays for assessing protein-protein interaction, immunoblot analysis of proteins and transcription factors in the apoptosis pathway. We are now developing potential new therapeutic approaches by testing newly synthesized excitatory glutamate-like drugs against PCP-induced apoptosis.

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]).

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.

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.

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.

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.

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.

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.

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.

Zhou, J., Kla¨ß, 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.