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1. SEROTONIN MECHANISMS IN THE PATHOPHYSIOLOGY OF SCHIZOPHRENIA Larry Ereshefsky, PharmD, FCCP, BCPP Alexander Miller, MD San Antonio State Hospital, Texas
2. SCHIZOPHRENIA PATHOPHYSIOLOGY AND PHARMACOLOGIC PROFILE OF ANTIPSYCHOTIC DRUGS (APDS) Schizophrenia Pharmacologic Pathophysiology Profile of APDs Past Excess dopaminergic Dopamine D2-receptor activity antagonists Present Renewed interest in the Combined 5-HT2/D2 role of serotonin (5-HT) antagonists Future Imbalance in cortical More selective antagonists communication and Mixed agonist/antagonists cortical-midbrain Neuropeptide analogs integration, involving multiple neurotransmitters
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5. SEROTONERGIC PATHWAYS AND INNERVATION Manter and Gatz’s Essentials of Clinical Neuroanatomy and Neurophysiology. Edition 8. F.A. Davis Co.:Philadelphia; 1992. Hypo = hypothalamus SN = substantia nigra Thal = thalamus
6. DOPAMINERGIC PATHWAYS AND INNERVATION Manter and Gatz’s Essentials of Clinical Neuroanatomy and Neurophysiology. Edition 8. F.A. Davis Co.:Philadelphia; 1992. Nuc Acc = nucleus accumbens SN = substantia nigra VTA = ventral tegmental area
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8. SEROTONIN-DOPAMINE INTERACTIONS Prefrontal Cortex Limbic System GABA/ACh Striatum Ventral Tegmental Area (A10) Substantia Nigra (A9) Dorsal Raphe Median Raphe 5-HT 2A antagonists release dopamine from inhibition and decrease EPS Blockade of D 2 receptors by conventional APDs causes EPS Motor Outputs GABA Glutamate Dopamine (DA) Serotonin (5-HT)
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13. SEROTONIN-GLUTAMATE-DOPAMINE INTERACTIONS Limbic System Ventral Tegmental Area (A10) Substantia Nigra (A9) Dorsal Raphe Median Raphe Prefrontal Cortex Striatum NMDA antagonists elevate extracellular brain levels of 5-HT in the prefrontal cortex NMDA antagonists reduce burst firing of VTA DA neurons NMDA antagonists increase the firing of DA in limbic areas 5-HT2A antagonists restore dopaminergic function in the prefrontal cortex 5-HT2 antagonists block the effects of NMDA antagonists Dopamine (DA) Glutamate Serotonin (5-HT) GABA
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16. AN INTEGRATIVE MODEL OF SCHIZOPHRENIA Serotonin 5-HT 2A Dopamine D 1 , D 2 A9/A10 Striatal Complex Dopamine Sense Organs Limbic System Prefrontal Cortex Glutamate Thalamus SN/VTA 5-HT 2A selectively targets A10