C N Karson

Central Arkansas Veterans Healthcare System, Washington, Washington, D.C., United States

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Publications (99)585.17 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: It has been hypothesized that schizophrenia arises from cell membrane abnormalities due to changes in phospholipid (PL) composition and metabolism. We have used high resolution, in vitro 31P nuclear magnetic resonance (NMR) to characterize the PLs in left frontal cortex (gray matter) of postmortem brain from four schizophrenics and five controls. High resolution 31P NMR spectra were obtained in an organic-solvent system to resolve PL classes (headgroups) and in a sodium-cholate, aqueous dispersion system to resolve phosphatidylcholine (PC) molecular species. Multivariate analysis which included the major PC molecular species and phosphatidylinositol (PI) showed a significant difference between schizophrenics and controls. Analysis of specific interactions showed that the PI was significantly higher in the schizophrenic group than in the control group. There were no differences between the two groups for other individual PL classes, or for individual PL subclasses determined by the linkage type at the sn-1 position on glycerol. There was a trend for total PL content to be higher in schizophrenics than in controls. There was no evidence for elevated lysophosphatidylcholine or lysophosphatidylethanolamine in schizophrenia. The intensity of the PC peak representing molecular species with one saturated and one unsaturated (one or two double bonds) acyl chain was higher for the schizophrenic group than for the control group. Although these results are not in complete agreement with previous studies, they support the idea that PL abnormalities occur in the brain in schizophrenia and that fatty acid metabolism may be abnormal.
    Psychiatry Research 06/2001; 106(3):171-80. DOI:10.1016/S0925-4927(01)00081-6 · 2.68 Impact Factor
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    S V Kyosseva · S M Owens · AD Elbein · C N Karson
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    ABSTRACT: We have previously demonstrated elevation of the extracellular signal-regulated kinase (ERK) pathway in the cerebellum from patients with schizophrenia, an illness that may involve dysfunction of the N-methyl-D-aspartate (NMDA) receptor. Since the NMDA antagonist, phencyclidine (PCP), produces schizophrenic-like symptoms in humans, and abnormal behavior in animals, we examined the effects of chronic PCP administration in time- and dose-dependent manner on ERK and two other members of mitogen-activated protein kinase family, c-Jun N-terminal protein kinase (JNK) and p38, in rat brain. Osmotic pumps for PCP (18 mg/kg/day) and saline (controls) were implanted subcutaneously in rats for three, 10, and 20 days. Using Western blot analysis, we found no change at three days, but a significant increase in the phosphorylation of ERK1, ERK2 and MEK in the cerebellum at 10- and 20-days of continuous PCP infusion. For the experiments involving various doses of PCP, rats were infused with PCP at concentrations of 2.5, 10, 18, or 25 mg/kg/day, or saline for 10 days. We observed a dose-dependent elevation in the phosphorylation of ERK1 and ERK2 only in the cerebellum but not in brainstem, frontal cortex or hippocampus. The activities of JNK and p38 were unchanged in all investigated brain regions including cerebellum. These results demonstrate that chronic infusion of PCP in rats produces a differential and brain region-specific activation of MAP kinases, suggesting a role for the ERK signaling pathway in PCP abuse and perhaps in schizophrenia.
    Neuropsychopharmacology 04/2001; 24(3):267-77. DOI:10.1016/S0893-133X(00)00180-9 · 7.83 Impact Factor
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    ABSTRACT: The metabolites of the antipsychotic drug trifluoperazine (TFP) were investigated with on-line coupling of high-performance liquid chromatography (HPLC) and NMR spectroscopy. A chromatographic method was developed using a reversed-phase C30 silica gel column. Rats were given a cumulative dose of 90 mg kg−1 TFP dihydrochloride and samples of brain and muscle tissues were extracted after 29 h. The peaks obtained on chromatographic separation were assigned to trifluoperazine and its metabolites. With the help of chromatograms obtained from test mixtures, 1D and 2D HPLC–NMR were used to identify the peaks found for these mixtures. Copyright © 2000 John Wiley & Sons, Ltd.
    Magnetic Resonance in Chemistry 11/2000; 38(11):951 - 956. DOI:10.1002/1097-458X(200011)38:11<951::AID-MRC762>3.0.CO;2-6 · 1.56 Impact Factor
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    ABSTRACT: We investigated the levels of transcription factors associated with activation of the mitogen-activated protein (MAP) kinase pathway in schizophrenics using postmortem brain samples. These studies were done to determine whether our previous findings of abnormal levels of the MAP kinases in the cerebellar vermis were linked to additional downstream targets of this signal transduction pathway. We measured the protein levels of 3 transcription factors in nuclear fractions of postmortem samples from cerebellar vermis of 10 patients with schizophrenia and 13 control subjects: Elk-1, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), and activating transcription factor 2 (ATF-2). Studies in rats examined the postmortem stability and effect of haloperidol and risperidone on levels of Elk-1, cAMP, and ATF-2 proteins. We found a significant increase in the protein levels of Elk-1 (mean+SD, 4489+/-659 vs 2915+/-583 arbitrary densitometric units [P<.001]), CREB (mean +/- SD, 2149 1061 vs 904+/-711 arbitrary densitometric units [P=.003]) and ATF-2 (mean+/-SD, 1421 854 vs 512+/-394 arbitrary densitometric units [P=.003]) in the cerebellar vermis of schizophrenic subjects. Complementary studies in rats indicate that these findings can not be attributed to subacute treatment with antipsychotic medications. Taken together with the alterations of MAP kinases previously reported, and the findings of elevations of downstream transcription targets, we suggest that the MAP kinase signal transduction pathway contributes to the cerebellar abnormalities in schizophrenia.
    Archives of General Psychiatry 08/2000; 57(7):685-91. · 13.75 Impact Factor
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    ABSTRACT: Fluorine-19 NMR spectra were acquired from extracts of tissues from heads of rats given the antipsychotic drug trifluoperazine (TFP). Contributions to the in vivo (19)F spectra from tissues other than brain were negligible. The in vivo (19)F resonance at -62.3 ppm from CCl(3)F consisted of 6-8 resolved resonances in vitro. Some in vitro resonances were assigned to previously identified TFP metabolites. Multiple resonances in vitro partially explain the relatively large line width seen in vivo for TFP. Unidentified metabolites were observed at about -74 to -75 ppm in a number of spectra of extracts of brain and muscle.
    Magnetic Resonance in Medicine 06/2000; 43(5):756-9. · 3.40 Impact Factor
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    ABSTRACT: Fluorine-19 NMR spectra were acquired from extracts of tissues from heads of rats given the antipsychotic drug trifluoperazine (TFP). Contributions to the in vivo 19F spectra from tissues other than brain were negligible. The in vivo 19F resonance at -62.3 ppm from CCl3F consisted of 6–8 resolved resonances in vitro. Some in vitro resonances were assigned to previously identified TFP metabolites. Multiple resonances in vitro partially explain the relatively large line width seen in vivo for TFP. Unidentified metabolites were observed at about -74 to -75 ppm in a number of spectra of extracts of brain and muscle. Magn Reson Med 43:756–759, 2000. © 2000 Wiley-Liss, Inc.
    Magnetic Resonance in Medicine 05/2000; 43(5):756 - 759. DOI:10.1002/(SICI)1522-2594(200005)43:5<756::AID-MRM19>3.0.CO;2-U · 3.40 Impact Factor
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    ABSTRACT: Localized in vivo proton magnetic resonance spectroscopy at 4.7 T was used to examine the brains of rats that were given the antipsychotic drugs haloperidol, clozapine, or olanzapine for 1 week. Spectra were collected before and during treatment. The ratios of N-acetylaspartate (NAA) to creatine (Cr) and choline to Cr were determined from the spectra. No significant differences in these ratios were seen among the rats given the various antipsychotic medications or between the control rats and the treated rats. No significant time-dependent changes were seen in most cases, except for a small reduction of NAA/Cr after 7 days of olanzapine administration. These results suggest that differences in brain metabolite ratios in vivo in schizophrenics relative to controls, at least for short-term treatment, arise from the disease, and not as a metabolic effect of the medication.
    Magnetic Resonance in Medicine 04/2000; 43(3):355-8. DOI:10.1002/(SICI)1522-2594(200003)43:33.0.CO;2-R · 3.40 Impact Factor
  • Biological Psychiatry 04/2000; 47(8). DOI:10.1016/S0006-3223(00)00327-9 · 10.25 Impact Factor
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    ABSTRACT: Phencyclidine-induced activation of MAP kinases in rat cerebellum. We have previously demonstrated that several intermediates of the Mitogen Activated Protein (MAP) kinase pathway are elevated in postmortem cerebellum from patients with schizophrenia, an illness that may involve dysfunction of the N-methyl-D-aspartate (NMDA) receptors. The NMDA antagonist, phencyclidine (PCP) produces schizophrenia-like symptoms in humans and abnormal behavior in animals. Therefore, in this study we examined the effect of chronic PCP administration on ERK1, ERK2 and MEK in rat brain. Osmotic pumps for PCP (18 mg/kg/day) and saline (controls) were implanted subcutaneously in rats for 3, 10, and 20 days. Using Western blot analysis, we found no change at 3 days, but a significant (p<0.05) increase in the phosphorylation state of ERK1 and ERK2 in the cerebellum, and not in the brainstem at 10-and 20-days of continuos PCP infusion. We also found an elevation of the upstream activator of ERK, i.e., MEK after 20 days of PCP infusion in the cerebellum. These data demonstrated that chronic infusion of PCP for up to 20 days in rats produces a time-dependent and brain region-specific activation of ERKs and MEK, which suggest s a role for the ERK signaling pathway in the pathology of PCP-induced brain changes in the rat.
    Society for Neuroscience, 1999 Meeting, Miami, Florida; 10/1999
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    Karson C.N. · Kiosseva S.V. · Hutton T.L. · Lyon M. · Elbein A.D.
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    ABSTRACT: Presentation Number: 830.9. Abstract Title: Effect of antipsychotic drugs on MAP kinases in cerebellum. In our previous studies we have demonstrated that several intermediates of the MAP kinase pathway are altered in the cerebellum of schizophrenic patients but not in other brain regions, including mesopontine tegmentum and prefrontal cortex. We found increased protein levels of ERK2, MEK, Raf, and transcription factors Elk-1, CREB and ATF-2. In these studies, all patients with schizophrenia had an extensive lifetime exposure to antipsychotic medications. Our aim was to determine whether the previously observed alteration in the signaling pathway was due to the pathology of schizophrenia or the effects of antipsychotic drugs. To accomplish this we made use of two antipsychotic drugs, haloperidol and resperidone. In order to simulate chronic human use of these drugs, they were administered to rats for 21 days in different doses – high and low. The drug doses were 1.5 mg/kg (high dose) and 0.15 mg/kg (low dose) for haloperidol and 0.5 mg/kg (high dose) and 0.05 mg/kg (low dose) for resperidone. Using immunoblotting techniques, we examined the cerebellum for alterations in the protein levels and of MAP kinases in brain extracts. The blots were quantified by densitometry and it was found that there were no significant differences in MAP kinases for either drug and any dose compared to saline controls. These findings support our idea that the changes in the MAP kinase pathway we reported previously in patients with schizophrenia cannot be due to the chronic treatment with antipsychotic medications and suggest that these alterations may represent intrinsic manifestation of the disease itself.
    Society for Neuroscience 1999, 29 Annual Meeting, Miami, Florida; 10/1999
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    ABSTRACT: Mitogen-activated protein kinases (MAPKs) are important mediators of signal transduction from the cell surface to the nucleus and have been implicated in the integration of a variety of physiologic processes in most cells, including neurons. To investigate the possible involvement of MAPKs in schizophrenia, we compared the levels of the MAPK intermediates in postmortem brain tissue obtained from schizophrenic and control subjects. Our focus was on the cerebellar vermis because of evidence suggesting that schizophrenia is associated with abnormalities of structure, function, and signal transduction in this brain region. Cytosolic proteins were fractionated by gel electrophoresis and subjected to Western blot analysis using polyclonal MAPK antibody, which detects total extracellular signal-regulated kinases (ERKs) 1 and 2 levels, and monoclonal MAP kinase phosphatase (MKP) 2 antibody. Schizophrenic subjects had increased levels of ERK2 [2763 +/- (SD) 203 vs. 2286 +/- 607 arbitrary units, U = 17, p < .05] in cerebellar vermis. The levels of a dual specificity tyrosine phosphatase, MKP2, were significantly decreased in cerebellar vermis (1716 +/- 465 versus 2372 +/- 429 arbitrary units, U = 12, p < .02) from schizophrenic patients. ERK1/MKP2 and ERK2/MKP2 ratios in cerebellar vermis, but not in other brain regions, were significantly different in schizophrenic subjects as compared to control subjects (U = 15, p < or = .027; U = 3, p < .001, respectively). MAPK levels are elevated in the cerebellar vermis of schizophrenic subjects. This could result from a protein dephosphorylation defect in vivo and might be involved in the pathology of the disease.
    Biological Psychiatry 09/1999; 46(5):689-96. DOI:10.1016/S0006-3223(99)00104-3 · 10.25 Impact Factor
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    ABSTRACT: Localized, in vivo H-1 magnetic resonance spectroscopy has been performed in a number of brain regions of neuropsychiatric interest in male and female control subjects to determine if gender and region affect the measured metabolite ratios. In contrast to some previous reports, no significant differences mere seen in any region for any metabolite ratio between males and females. As expected, significant variations,vith brain region were seen for metabolite ratios for the total group of subjects. (C) 1999 Elsevier Science Inc.
    Magnetic Resonance Imaging 05/1999; 17(3):427-33. DOI:10.1016/S0730-725X(98)00186-6 · 2.02 Impact Factor
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    ABSTRACT: Background: In neurons, mitogen-activated protein kinases (MAPKs) transduce extracellular signal (at surface receptors) into intracellular responses. Previous reports that schizophrenics have higher NOS activity in the cerebellar vermis could suggest aberrations of signal transduction are involved in the disorder. Methods: Using immunoblotting techniques in postmortem cerebellum from 9 schizophrenic patients and a like number of age-matched controls, we studied the levels of MAPK 1 and MAPK 2 and other related elements to see if a MAPK mediated signal transduction pathway might play a role in schizophrenia. We also studied the levels of transcription factors ELK-l and CAMP response element binding protein (CREB) in nuclear extracts from postmortem cerebellum using Western blot analysis (10 schizophrenics and 13 controls). Results: Schizophrenics had increased levels of MAPK 2 (2763+ 203 versus 2285 + 607 absorbance units, p < 0.05) and decreased levels of the related phosphotase (1716 + 465 versus 2372 + 429 absorbance units, p < 0.01). A nonsignificant tendency in the same direction for MAPK 1 was also observed. More impressively, we have found a significant, 2-fold increase in the levels of transcription factors ELK-l (4489 + 659 [SD] versus 2915 +583 arbitrary units, p <0.0001) and CREB (2149 + 1061 [SD] versus 904 + 711 arbitrary units, p < 0.03) in schizophrenics. Conclusions: These data suggest that extracellular to intracellular transduction may be disrupted in the cerebellum in schizophrenia. Several signal channels, such as NMDA, can initiate MAPK-mediated signal transduction, suggesting that future studies need to pinpoint whether selective signal channels are involved in schizophrenia. Moreover, it remains to be determined whether the more impressive increase of the corresponding transcription factors is a primary or secondary phenomenon.
    Viith International Congress on Schizophrenia Research; Schizophrenia Research 36(1-3) 1999; 04/1999
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    ABSTRACT: An impairment of prefrontal cortical functioning in schizophrenia ('hypofrontality') has been suggested by clinical, neuroimaging, and postmortem brain tissue studies. We used Western immunoblot and Northern hybridization analyses of postmortem brain tissue obtained from 14 schizophrenic patients and 12 control patients of similar ages to measure tissue levels of synaptophysin (a structural synaptic vesicle protein) and of SNAP-25 (a 25-kDa presynaptic protein), and their encoding mRNAs, in Brodmann's area 10 of prefrontal cortex. There were significant decreases in tissue levels of both of these proteins in prefrontal cortex of schizophrenic patients relative to controls. In contrast, tissue levels for the mRNAs encoding these proteins were not decreased in schizophrenic patients. Subsequent labeling of the same Western immunoblots showed no difference in tissue levels of glial fibrillary acidic protein (GFAP) in schizophrenic and control patients. Similarly, subsequent hybridization of the same Northern hybridization membranes showed no difference in tissue levels of GFAP mRNA or of 28S rRNA in schizophrenic and control patients. These alterations in tissue levels of synaptophysin and SNAP-25 are consistent with the idea that the clinically observed 'hypofrontality' of schizophrenia arises from abnormalities of synaptic number or structural integrity in prefrontal cortex.
    Molecular Psychiatry 02/1999; 4(1):39-45. DOI:10.1038/sj.mp.4000459 · 15.15 Impact Factor
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    ABSTRACT: The P1 midlatency auditory evoked potential was studied in female rape victims with Posttraumatic Stress Disorder (PTSD) and compared to an age-matched female control group; and in male combat veterans with PTSD and compared to three groups of age-matched male control subjects. Sensory gating of the P1 potential was determined using a paired click stimulus paradigm in which the stimuli were presented at 250, 500 and 1000 msec interstimulus intervals (ISI). Results showed that sensory gating of the P1 potential was significantly decreased at the 250 msec ISI, and that there was a numerical, but not a statistically significant, decrease in sensory gating at the other intervals tested in both male and female PTSD subjects compared to all control groups. Since the P1 potential may be generated, at least in part, by the reticular activating system, dysregulation of sensory processing by elements of this system may be present in PTSD.
    Depression and Anxiety 02/1999; 9(3):122-30. DOI:10.1002/(SICI)1520-6394(1999)9:33.0.CO;2-M · 4.29 Impact Factor
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    ABSTRACT: In neurons, mitogen-activated protein kinases (MAPKs) transduce extracellular signal (at surface receptors) into intracellular responses. Previous reports that schizophrenics have higher NOS activity in the cerebellar vermis could suggest abberations of signal transduction are involved in the disorder.Using immunoblotting techniques in postmortem cerebellum from 9 schizophrenic patients and a like number of age-matched controls, we studied the levels of MAPK 1 and MAPK 2 and other related elements to see if a MAPK mediated signal transduction pathway might play a role in schizophrenia. We also studied the levels of transcription factors ELK-l and CAMP response element binding protein (CREB) in nuclear extracts from postmortem cerebellum using Western blot analysis (10 schizophrenics and 13 controls). Schizophrenics had increased levels of MAPK 2 (2763+ 203 versus 2285 + 607 absorbance units, p < 0.05) and decreased levels of the related phosphotase (1716 + 465 versus 2372 + 429 absorbance units, p < 0.01). A nonsignificant tendancy in the same direction for MAPK 1 was also observed. More impressively, we have found a significant, 2-fold increase in the levels of transcription factors ELK-l (4489 + 659 [SD] versus 2915 +583 arbitrary units, p <0.0001) and CREB (2149 + 1061 [SD] versus 904 + 711 arbitrary units, p < 0.03) in schizophrenics. These data suggest that extracellular to intracellular transduction may be disrupted in the cerebellum in schizophrenia. Several signal channels, such as NMDA, can initiate MAPK-mediated signal transduction, suggesting that future studies need to pinpoint whether selective signal channels are involved in schizophrenia. Moreover, it remains to be determined whether the more impressive increase of the corresponding transcription factors is a primary or secondary phenomenon.
    Society for Neuroscience, 1998 Meeting, Los Angeles, CA; 10/1998
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    ABSTRACT: Schizophrenia is a disorder with an unclear pathophysiology, despite numerous attempts to elucidate its etiology. We have employed proton magnetic resonance spectroscopy in vivo to explore the neurochemistry of several brain regions (left frontal and temporal cortices, left basal ganglia, and left and right thalamus) in patients with schizophrenia and in normal control subjects. We have also examined patients in different medication states. A trend toward a decreased level of inositol/creatine was found in the left temporal lobe of patients with schizophrenia, as was a trend toward a reduced level of N-acetylaspartate/creatine in the left thalamus of patients. In schizophrenic patients treated with atypical antipsychotics, decreased levels of choline were found in the left basal ganglia, while increased levels of N-acetylaspartate were found in the left frontal cortex. These results suggest altered metabolism in patients with schizophrenia, and imply that further study is needed to clarify the effects of the more recently available antipsychotics.
    Psychiatry Research 09/1998; 83(2):105-15. DOI:10.1016/S0925-4927(98)00034-1 · 2.68 Impact Factor
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    ABSTRACT: Recent findings using volumetric MRI techniques have revealed that patients with combat-related and noncombat-related posttraumatic stress disorder (PTSD) have reductions in right hippocampal volume. Twenty-one veterans with PTSD and eight age-matched control veterans were studied using proton magnetic resonance spectroscopy to test the hypothesis that the N-acetyl-L-aspartic acid/creatine (NAA/Cr) ratio would be decreased in the right medial temporal lobe structures of patients with PTSD compared to controls. Patients with PTSD displayed significantly lower NAA/Cr ratio for the right medial temporal lobe relative to the left (P < or = 0.011). Patients with PTSD also had lower NAA/Cr in right medial temporal lobe (P < or = 0.013) and lower choline/Cr in left medial temporal lobe (P < or = 0.030) compared to control subjects. Because NAA is regarded as an indicator of neuronal density, this finding suggests that the neuronal density of right-sided medial temporal structures in patients with combat-related PTSD may be decreased.
    Magnetic Resonance in Medicine 07/1998; 40(1):66-71. DOI:10.1002/mrm.1910400110 · 3.40 Impact Factor
  • J. Alexander · R. Pruitt · M. Lyon · A. B. Whitehead · C. N. Karson
    Biological Psychiatry 04/1998; 43(8). DOI:10.1016/S0006-3223(98)90563-7 · 10.25 Impact Factor

Publication Stats

3k Citations
585.17 Total Impact Points

Institutions

  • 2000–2001
    • Central Arkansas Veterans Healthcare System
      Washington, Washington, D.C., United States
  • 1988–2000
    • University of Arkansas at Little Rock
      Little Rock, Arkansas, United States
    • District of Columbia Department of Mental Health
      Washington, Washington, D.C., United States
  • 1998
    • Philander Smith College
      Little Rock, Arkansas, United States
  • 1991–1994
    • University of Arkansas for Medical Sciences
      • Department of Psychiatry
      Little Rock, Arkansas, United States
  • 1982–1988
    • National Institute of Mental Health (NIMH)
      • • Clinical Brain Disorders Branch
      • • Laboratory of Neuropsychology
      베서스다, Maryland, United States
  • 1986
    • Wayne State University
      Detroit, Michigan, United States