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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 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
Hypotheses ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Levels of Analysis ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Feasability ,[object Object],[object Object],Con Com DA Sch DA dx RIN pH age sex cases
Behavioral changes ,[object Object],[object Object],Drug Abuse Schizophrenia
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
Caffeine ,[object Object],[object Object],[object Object],[object Object]
Neuregulin 1 and Nicotine ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
COMT and Cannabinoids ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
NPAS3, DISC1 and Neurogenesis ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
To Do (behavioral) ,[object Object],[object Object]
Systems changes synaptogenesis LTP/LTD Δ in neural excitability Drug Abuse Schizophrenia
Neural Circuitry of Schizophrenia
Glutamatergic Synapse
The hypo-NMDAR hypothesis ,[object Object],[object Object],[object Object],[object Object]
Neuropharmacology of Neuroleptics ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
To Do (systems) ,[object Object],[object Object],[object Object],[object Object],[object Object]
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
Reduced Neural Stem Cell Proliferation in the Posterior, but not the Anterior Hippocampus ,[object Object]
Preliminary data support methods Lesselyong preliminary data (control only) Harburg Dissertation (control – white; heroin – black)
Quantification of human neurogenesis in-vivo ,[object Object],[object Object],[object Object]
To Do (cellular) ,[object Object],[object Object]
Molecular changes ,[object Object],Reduced COMT activity Changes in BDNF in mPFC and in Hippocampus ?!? ,[object Object],[object Object],[object Object],[object Object],Reduced NR1 expression in the anterior, but not posterior hippocampus Drug Abuse Schizophrenia
NR1 mRNA Expression ,[object Object],[object Object],[object Object]
To Do (molecular) ,[object Object],[object Object],[object Object],[object Object]
Acknowledgements ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
References ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

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Molecular Substrates of Drug Abuse in a Schizophrenic Population

  • 1. Cellular and Molecular Substrates of Drug Abuse in Schizophrenia by Alan Lesselyong, M.S. (mentor) Carol Tamminga, M.D.
  • 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.
  • 4.
  • 5.
  • 6.
  • 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.
  • 9.
  • 10.
  • 11.
  • 12.
  • 13. Systems changes synaptogenesis LTP/LTD Δ in neural excitability Drug Abuse Schizophrenia
  • 14. Neural Circuitry of Schizophrenia
  • 16.
  • 17.
  • 18.
  • 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.
  • 21. Preliminary data support methods Lesselyong preliminary data (control only) Harburg Dissertation (control – white; heroin – black)
  • 22.
  • 23.
  • 24.
  • 25.
  • 26.
  • 27.
  • 28.