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Cellular and Molecular Substrates of Drug Abuse in Schizophrenia by Alan Lesselyong, M.S. (mentor) Carol Tamminga, M.D.
Schizophrenia and Drug Abuse Drug Use – Any willful exposure to a psychoactive substance in order to achieve a desired fee...
Hypotheses <ul><li>The molecular pathophysiology of schizophrenia can predispose individuals to drug abuse. </li></ul><ul>...
Levels of Analysis <ul><li>Behavior </li></ul><ul><ul><li>Motivation and Drive </li></ul></ul><ul><li>Systems </li></ul><u...
Feasability <ul><li>Good quality tissue available from the Dallas Brain Collection (DBC). </li></ul><ul><li>Patients curre...
Behavioral changes <ul><ul><li>↑   drive for artificial (drug) reward </li></ul></ul><ul><ul><li>↓ drive for natural (sex,...
Prevalence of Drug Abuse (lifetime) A  – Kapplan and Sadock, The Comprehensive Textbook on Psychiatry, 8 th  ed; B  – 2006...
Caffeine <ul><li>Caffeine is an agonist of the beta-adrenergic receptor subtype 2 (ref) </li></ul><ul><li>Caffeine is know...
Neuregulin 1 and Nicotine <ul><li>Activated via ErbB receptors and NMDA/PSD95 activation </li></ul><ul><li>C-terminal is c...
COMT and Cannabinoids <ul><li>The protein product is an enzyme that participates in the clearance of dopamine (DA) from sy...
NPAS3, DISC1 and Neurogenesis <ul><li>Originally discovered in an extended family in Scotland, evidence supports a correla...
To Do (behavioral) <ul><li>Volunteer for endophenotyping experiments </li></ul><ul><li>Develop drug abuse questioner for s...
Systems changes synaptogenesis LTP/LTD Δ in neural excitability Drug Abuse Schizophrenia
Neural Circuitry of Schizophrenia
Glutamatergic Synapse
The hypo-NMDAR hypothesis <ul><li>Symptoms in all three domains are the result of reduced signaling downstream of the NMDA...
Neuropharmacology of Neuroleptics <ul><li>Typical and Atypical antipsychotics function primarily as dopamine (D2) antagoni...
To Do (systems) <ul><li>Integrate Basal Ganglia circuitry </li></ul><ul><li>Zoom in on post-synaptic cell </li></ul><ul><l...
Cellular changes Reduced NSC proliferation Accelerated neuronal integration, resulting in aberrant morphological developin...
Reduced Neural Stem Cell Proliferation in the Posterior, but not the Anterior Hippocampus <ul><li>This experiment will be ...
Preliminary data support methods Lesselyong preliminary data (control only) Harburg Dissertation (control – white; heroin ...
Quantification of human neurogenesis in-vivo <ul><li>Magnetic Resonance Spectroscopy (MRS) identifies neural progenitors i...
To Do (cellular) <ul><li>Quantify Ki-67-IR cells in an entire cohort of schizophrenic hippocampus and their age-matched co...
Molecular changes <ul><ul><li>↑   transcription factors in the NAc (Nestler, 2004) </li></ul></ul>Reduced COMT activity Ch...
NR1 mRNA Expression <ul><li>Insignificant decrease in NR1 expression in the anterior DG in schizophrenia (p=.162) becomes ...
To Do (molecular) <ul><li>Compare expression patterns of molecular targets downstream of NMDAR in schizophrenic and contro...
Acknowledgements <ul><li>The Tamminga Lab </li></ul><ul><ul><li>Carol Tamminga, M.D. </li></ul></ul><ul><ul><li>Subroto Gh...
References <ul><li>Chen, J., Lipska, B., and Weinberger, D., Genetic mouse models of schizophrenia: from hypothesis-based ...
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Molecular Substrates of Drug Abuse in a Schizophrenic Population

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This presentation is a Work In Progress (WIP) covering experiments examining the molecular correlates of drug abuse in human brains diagnosed with schizophrenia

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Transcript of "Molecular Substrates of Drug Abuse in a Schizophrenic Population"

  1. 1. Cellular and Molecular Substrates of Drug Abuse in Schizophrenia by Alan Lesselyong, M.S. (mentor) Carol Tamminga, M.D.
  2. 2. Schizophrenia and Drug Abuse Drug Use – Any willful exposure to a psychoactive substance in order to achieve a desired feeling or behavior. Drug Abuse – The repeated use of a substance to the extent that it interferes with adequate social, vocational, or self-care functioning. Drug Dependence (Addiction) – The development of tolerance to a particular substance and the experience of withdrawal symptoms and craving after a period of abstinence. Symptom Domains Of Schizophrenia Positive Hallucinations Delusions Cognitive Attention Working Memory Negative Anhedonia Asociality
  3. 3. Hypotheses <ul><li>The molecular pathophysiology of schizophrenia can predispose individuals to drug abuse. </li></ul><ul><li>The cellular pathophysiology of schizophrenia can predispose individuals to drug abuse. </li></ul><ul><li>“ Self-medication” - Patients use psychotropic drugs to treat symptoms of their disorder or the side-effects of their antipsychotic medication. This implies that persons with distinct symptoms will be motivated to use particular drugs (different symptoms, different drugs). </li></ul><ul><ul><li>negative symptoms  stimulant use </li></ul></ul><ul><ul><li>psychosis  depressant or opiate use </li></ul></ul><ul><li>“ Additive or Synergistic Degeneration” – The combined effect of schizophrenia and drug abuse magnify molecular changes associated with the addictive or psychotic state. </li></ul>
  4. 4. Levels of Analysis <ul><li>Behavior </li></ul><ul><ul><li>Motivation and Drive </li></ul></ul><ul><li>Systems </li></ul><ul><ul><li>Synaptogenesis </li></ul></ul><ul><ul><li>Long-term potentiation / depression </li></ul></ul><ul><ul><li>Neural Excitability </li></ul></ul><ul><li>Cellular </li></ul><ul><ul><li>Proliferation of neural stem cells (NSCs) </li></ul></ul><ul><ul><li>Fate Decision </li></ul></ul><ul><ul><li>Survival </li></ul></ul><ul><ul><li>Maturation </li></ul></ul><ul><li>Molecular </li></ul><ul><ul><li>Neurotrophin levels </li></ul></ul><ul><ul><li>Enzyme activity </li></ul></ul><ul><ul><li>Gene transcription (epigenetics) </li></ul></ul><ul><ul><li>Gene translation </li></ul></ul>
  5. 5. Feasability <ul><li>Good quality tissue available from the Dallas Brain Collection (DBC). </li></ul><ul><li>Patients currently undergoing treatment may represent a population for further study. </li></ul>Con Com DA Sch DA dx RIN pH age sex cases
  6. 6. Behavioral changes <ul><ul><li>↑ drive for artificial (drug) reward </li></ul></ul><ul><ul><li>↓ drive for natural (sex, chocolate) reward </li></ul></ul>Drug Abuse Schizophrenia
  7. 7. Prevalence of Drug Abuse (lifetime) A – Kapplan and Sadock, The Comprehensive Textbook on Psychiatry, 8 th ed; B – 2006 National Survey on Drug Abuse; C – Mueser, et al., 1990 2.7% B 14.3% B 1.5% B 3.6% B 5.0% B 5.8% B 14.3% B ? 82.7% B 39.8% B 29.7% B 70.7% B Control PCP Hallucinogens Opiates Sedatives Ecstasy Amphetamine Cocaine Stimulants (any) Ethanol Cannabinoids Nicotine Caffeine Drug 1.40X 20% C ? ? 4.00X 6% C 1.67X 6% C ? ? 4.36X 25.3% C 0.88X 12.6% C ? 29% C 0.60X 50% C 1.08X 43% C 2.86X > 85% A 1.27X >90% A Fold Increase Schizophrenia
  8. 8. Caffeine <ul><li>Caffeine is an agonist of the beta-adrenergic receptor subtype 2 (ref) </li></ul><ul><li>Caffeine is known to increase PKA activation (ref) </li></ul><ul><li>At higher doses, caffeine is a phosphodiesterase (PDE) inhibitor </li></ul><ul><li>Caffeine has short-term beneficial effects on memory, motivation, and attention (ref) </li></ul>
  9. 9. Neuregulin 1 and Nicotine <ul><li>Activated via ErbB receptors and NMDA/PSD95 activation </li></ul><ul><li>C-terminal is capable of translocation to the nucleus and direct interaction with transcription factors (ref?) </li></ul><ul><li>Enhanced expression in schizophrenia leads to suppression of NMDAR function (Hahn et al., 2006) </li></ul><ul><li>Heterozygous deletion of the transmembrane domain alters activity and pre-pulse inhibition (PPI; Chen et al., 2006) </li></ul><ul><li>Altered expression due to alternative splice variants? </li></ul><ul><li>Nicotine is an agonist for the nicotinic acetylcholine receptor (nAchR) </li></ul><ul><li>Neuregulin (NRG1) expression is disrupted in schizophrenia and may be responsible for the reduced expression of α7 nicotinic acetylcholine receptor in the frontal cortex (Mathew, et al., 2007) </li></ul>
  10. 10. COMT and Cannabinoids <ul><li>The protein product is an enzyme that participates in the clearance of dopamine (DA) from synapses (Craddock et al., 2006; Turnbridge et al., 2006) </li></ul><ul><li>A functional polymorphism (Val  Met) at codon 108 (in soluble isoform) or 158 (in membrane-bound isoform) alters enzyme activity (ref?) </li></ul><ul><li>Val158Met is associated with cannabis-induced psychosis (ref?) </li></ul><ul><li>Exogenous cannabinoids (THC) act by displacing endogenous cannabinoids (anandamide) at the cannabinoid (CB1) receptor </li></ul><ul><li>Endogenous cannabinoids promote embryonic and adult neurogenesis (Jiang, et al., 2005) </li></ul><ul><li>Delta9-tetrahydrocannabinol (THC) does not affect proliferation in the adult dentate gyrus (Kochman, 2006) </li></ul>
  11. 11. NPAS3, DISC1 and Neurogenesis <ul><li>Originally discovered in an extended family in Scotland, evidence supports a correlation between DISC1 and more general forms of mental illness such as bipolar disorder and autism (Marx, J., Science 318, 1062, 2007) </li></ul><ul><li>Binds to NudE-like 1 (NDEL1), phosphodiesterase 4B (PDE4B), FEZ1, LIS1, dynein, and tubulin, all known to be important in neuronal migration </li></ul><ul><li>DISC1 KO’s display hyperactivity and social and cogitive impairement, similar to humans with schizophrenia (Sawa et al., PNAS, 2007; Pletnikov, Molecular Psychiatry, 2007) </li></ul><ul><li>NPAS3 is disrupted by chromosomal translocation in two related individuals with schizophrenia (Pickard et al., 2005), likely producing a dominant negative form of the transcription factor </li></ul><ul><li>Deletions of NPAS3 alter neurogenesis? (Peiper, ?) </li></ul><ul><li>Neurogenesis is known to be reduced in patients with schizophrenia (although evidence is limited, Reif et al., 2006) </li></ul><ul><li>Neurogenesis is reduced as a result of the use of drugs of abuse, including alcohol (Nixon, 2006), opiates (Eisch et al., 2000), and ecstasy (Hernandez-Rabaza et al., 2006) </li></ul><ul><li>Downregulation of DISC1 leads to accelerated neuronal integration, resulting in aberrant morphological developing and mispositioning of new granule cells in a cell-autonomous fashion. </li></ul>
  12. 12. To Do (behavioral) <ul><li>Volunteer for endophenotyping experiments </li></ul><ul><li>Develop drug abuse questioner for schizophrenia clinic patients </li></ul>
  13. 13. Systems changes synaptogenesis LTP/LTD Δ in neural excitability Drug Abuse Schizophrenia
  14. 14. Neural Circuitry of Schizophrenia
  15. 15. Glutamatergic Synapse
  16. 16. The hypo-NMDAR hypothesis <ul><li>Symptoms in all three domains are the result of reduced signaling downstream of the NMDA receptor </li></ul><ul><li>Currently the most widely accepted hypothesis </li></ul><ul><li>Supported by in-situ, histology, as well as PET and fMRI data </li></ul><ul><li>Interactions between glutamate and dopamine may explain antipsychotic effects of neuroleptics </li></ul>
  17. 17. Neuropharmacology of Neuroleptics <ul><li>Typical and Atypical antipsychotics function primarily as dopamine (D2) antagonists. </li></ul><ul><li>Treatment with NMDAR coagonists </li></ul><ul><ul><li>D-serine (DAOA activates DAO which oxidizes D-serine) </li></ul></ul><ul><ul><li>glycine </li></ul></ul><ul><li>Treatment with mGluR2/3 agonists (LY2140023) </li></ul><ul><li>Treatment with rolipram, a PDE4B inhibitor (DISC1 binding partner) </li></ul><ul><li>Histamine agonist? </li></ul>
  18. 18. To Do (systems) <ul><li>Integrate Basal Ganglia circuitry </li></ul><ul><li>Zoom in on post-synaptic cell </li></ul><ul><li>Illustrate cell-signaling cascade, including pCREB activation and gene transcription </li></ul><ul><li>Research glutamatergic / dopaminergic interactions </li></ul><ul><li>Complete list of experimental pharmacology treatments </li></ul>
  19. 19. Cellular changes Reduced NSC proliferation Accelerated neuronal integration, resulting in aberrant morphological developing and mispositioning of new granule cells in a cell-autonomous fashion Reduced neurotrophin expression leads to delays in cell differentiation and maturation Drug Abuse Schizophrenia
  20. 20. Reduced Neural Stem Cell Proliferation in the Posterior, but not the Anterior Hippocampus <ul><li>This experiment will be repeated using updated techniques </li></ul>
  21. 21. Preliminary data support methods Lesselyong preliminary data (control only) Harburg Dissertation (control – white; heroin – black)
  22. 22. Quantification of human neurogenesis in-vivo <ul><li>Magnetic Resonance Spectroscopy (MRS) identifies neural progenitors in the live human brain (Manganas, et al., 2007) </li></ul><ul><li>Uses Single Voxel Decomposition (SVD), a type of post-scan ‘filter’. </li></ul><ul><li>Compare Control, Schizophrenia, Drug Abuse, Comorbid </li></ul>
  23. 23. To Do (cellular) <ul><li>Quantify Ki-67-IR cells in an entire cohort of schizophrenic hippocampus and their age-matched control group </li></ul><ul><li>Develop in-vivo imaging technique for measuring neurogenesis (validate using cultured NSCs from postmortem SVZ/SGZ) </li></ul>
  24. 24. Molecular changes <ul><ul><li>↑ transcription factors in the NAc (Nestler, 2004) </li></ul></ul>Reduced COMT activity Changes in BDNF in mPFC and in Hippocampus ?!? <ul><ul><ul><ul><li>CREB (cAMP response element binding protein) mediates a form of tolerance and dependence </li></ul></ul></ul></ul><ul><ul><ul><ul><li>2. Δ FosB mediates a state of relatively prolonged sensitization to drug exposure and may drive drug seeking behavior </li></ul></ul></ul></ul><ul><ul><li>↑ NAc BDNF is a marker of susceptibility to drug abuse (Krishnan, et al., 2007) </li></ul></ul><ul><ul><li>↓ expression of HDAC5 in NAc controls behavioral adaptations to chronic stimuli (Renthal, et al., 2007) </li></ul></ul>Reduced NR1 expression in the anterior, but not posterior hippocampus Drug Abuse Schizophrenia
  25. 25. NR1 mRNA Expression <ul><li>Insignificant decrease in NR1 expression in the anterior DG in schizophrenia (p=.162) becomes significant (p=.040) when considering comorbid cases. </li></ul><ul><li>Significant decrease in the anterior CA3 in cases of schizophrenia (p=.028) and a return to baseline when considering comorbid cases (p=.734). </li></ul><ul><li>No changes in the posterior hippocampus (yet). </li></ul>
  26. 26. To Do (molecular) <ul><li>Compare expression patterns of molecular targets downstream of NMDAR in schizophrenic and control hippocampal subregions using qRT-PCR </li></ul><ul><li>Perform Western Blots for Δ FosB in schizophrenic and control NAc </li></ul><ul><li>Perform ELISA for BDNF in schizophrenic and control NAc </li></ul><ul><li>Perform qRT-PCR for HDAC5 in schizophrenic and control NAc </li></ul>
  27. 27. Acknowledgements <ul><li>The Tamminga Lab </li></ul><ul><ul><li>Carol Tamminga, M.D. </li></ul></ul><ul><ul><li>Subroto Ghose, M.D., Ph.D. </li></ul></ul><ul><ul><li>Ana Stan, M.D. </li></ul></ul><ul><ul><li>Masaya Yanagi, M.D., Ph.D. </li></ul></ul><ul><ul><li>Kelly Lewis-Amezcua </li></ul></ul><ul><ul><li>Brian Potts </li></ul></ul><ul><li>Special Thanks </li></ul><ul><ul><li>Eric Nestler, M.D., Ph.D. </li></ul></ul><ul><ul><li>Amelia Eisch, Ph.D. </li></ul></ul><ul><ul><li>Toshiro Kishi, M.D., Ph.D. </li></ul></ul><ul><ul><li>Amelia Russo-Neustadt, M.D., Ph.D. </li></ul></ul><ul><li>Funding Sources: </li></ul><ul><ul><li>“ Basic Science Training Program” of the National Institute of Drug Abuse (NIDA), grant #T32-DA007290. </li></ul></ul>
  28. 28. References <ul><li>Chen, J., Lipska, B., and Weinberger, D., Genetic mouse models of schizophrenia: from hypothesis-based to succeptability gene-based models. Biological Psychiatry 59, 1180-1188, 2006 </li></ul><ul><li>Craddock, N., Owen, M., O’Donovan, M., The catechol-O-methyl transferase (COMT) gene as a candidate for psychiatric phenotypes: evidence and lessons. Molecular Psychiatry 11, 446-458, 2006 </li></ul><ul><li>Hahn, C., Wang, H., Cho, D., Talbot, K., Gur, E., Berrettini, W., Bakshi, K., Kamins, J., Borgmann-Winter, K., Siegel, S., et al., Altered neuregulin1-ErbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia. Nature Medicine 12, 824-828, 2006 </li></ul><ul><li>Jiang, W., Zhang, Y., Xiao, L., Van Cleemput, J., Ji, S., Bai, G., Zhang, X., Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects. Journal of Clinical Investigation 115 (11), 3104-3116, 2005 </li></ul><ul><li>Kockman, L., dos Santos, A., Formal, C., Jacobs, B., Despite strong behavioral disruption, Delta9-tetrahydrocannabinol does not affect cell proliferation in the adult dentate gyrus. Brain Research 1113 (1), 86-93, 2006 </li></ul><ul><li>Mathew, S., et al., Human Molecular Genetics 16 (23), 2921-2932, 2007 </li></ul><ul><li>Nestler, E., Molecular Mechanisms of Drug Addiction; Neuropharmacology 47, 24-32, 2004 </li></ul><ul><li>Nixon, K., Alcohol and Adult Neurogenesis: Roles in Neurodegeneration and Recovery in Chronic Alcoholism. Hippocampus 16, 287-295, 2006 </li></ul><ul><li>Straub, R., and Weinberger, D., Schizophrenia genes – famine to feast. Biological Psychiatry 60, 81-83, 2006 </li></ul><ul><li>Turnbridge, E., Harrison, P., and Weinberger, D., Catechol-O-methyl transferase, cognition, and psychosis: Val(158)Met and beyond. Biological Psychiatry 60, 141-151, 2006 </li></ul>

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