精神分裂症5-羟色胺病理生理机制

SEROTONIN MECHANISMS IN THE PATHOPHYSIOLOGY OF SCHIZOPHRENIA Larry Ereshefsky, PharmD, FCCP, BCPP Alexander Miller, MD San Antonio State Hospital, Texas

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

RECEPTOR BINDING PROFILES OF CONVENTIONAL AND ATYPICAL APDS ,[object Object],Haloperidol Clozapine Risperidone Olanzapine

IMPACT OF SCHIZOPHRENIA SYMPTOMS ON FUNCTIONAL OUTCOMES Positive Symptoms Social/Occupational Dysfunction Mood Symptoms Cognitive Symptoms Negative Symptoms ,[object Object],[object Object],[object Object],[object Object]

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

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

EVIDENCE OF SEROTONIN INVOLVEMENT IN SCHIZOPHRENIA PATHOPHYSIOLOGY ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

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)

SEROTONIN-DOPAMINE INTERACTIONS: ELECTROPHYSIOLOGIC AND NEUROCHEMICAL STUDIES ,[object Object],[object Object],[object Object],[object Object]

SEROTONIN-DOPAMINE INTERACTIONS: ELECTROPHYSIOLOGIC AND NEUROCHEMICAL STUDIES ,[object Object],[object Object],J Neurochem 1990;54:1755. * P <.05 vs saline. Time (min) * * * * * * * * * Clozapine 5 mg/kg Clozapine 10 mg/kg Saline 250 200 150 100 50 Dopamine (% preinjection) -40 -20 0 20 40 60 80 100 120 140 Injection

SEROTONIN-DOPAMINE INTERACTIONS: BEHAVIORAL STUDIES ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

NMDA-ANTAGONIST MODEL OF SCHIZOPHRENIA KETAMINE EFFECTS IN HEALTHY HUMAN SUBJECTS ,[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],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],*May be related to sedative effects of ketamine

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

NMDA ANTAGONIST-INDUCED BEHAVIORS ,[object Object],[object Object],[object Object],[object Object]

NMDA ANTAGONIST-INDUCED DISRUPTIONS IN PREPULSE INHIBITION (PPI) ,[object Object],[object Object],[object Object],[object Object],* P <.01 vs SAL/SAL group; † P <.05 vs SAL/PCP group; ‡ P <.01 vs SAL/PCP group. ,[object Object],Prepulse Intensity -20 0 20 40 60 80 %PPI . . . . . . . . . . . . + 3 6 12 _ _ SAL/SAL SAL/PCP 1.25mg/kg CLOZ/PCP 2.5mg/kg CLOZ/PCP 5mg/kg CLOZ/PCP 10mg/kg CLOZ/PCP

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

精神分裂症5-羟色胺病理生理机制

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精神分裂症5-羟色胺病理生理机制