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Serotonin Mechanisms in the Pathophysiology of Schizophrenia)。更多精彩教程,请访问缤果网(。

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  1. 1. SEROTONIN MECHANISMS IN THE PATHOPHYSIOLOGY OF SCHIZOPHRENIA Larry Ereshefsky, PharmD, FCCP, BCPP Alexander Miller, MD San Antonio State Hospital, Texas
  2. 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
  3. 3. RECEPTOR BINDING PROFILES OF CONVENTIONAL AND ATYPICAL APDS <ul><ul><ul><li>J Pharmacol Exp Ther 1996;277:968; J Clin Pharmacol 1999;39:1S; Psychopharmacology 1993;112:S60; Am J Psychiatry 1997;154:782. </li></ul></ul></ul>Haloperidol Clozapine Risperidone Olanzapine
  4. 4. IMPACT OF SCHIZOPHRENIA SYMPTOMS ON FUNCTIONAL OUTCOMES Positive Symptoms Social/Occupational Dysfunction Mood Symptoms Cognitive Symptoms Negative Symptoms <ul><li>work </li></ul><ul><li>interpersonal relationships </li></ul><ul><li>self-care </li></ul><ul><ul><ul><li>Am J Psychiatry 1997;154:1; Lancet 1995;346:477; Practitioner 1992;236:255. </li></ul></ul></ul>
  5. 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. 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
  7. 7. EVIDENCE OF SEROTONIN INVOLVEMENT IN SCHIZOPHRENIA PATHOPHYSIOLOGY <ul><li>Postmortem Studies in Schizophrenics </li></ul><ul><ul><ul><li>Increase in 5-HT transmission and 5-HT-transporter density in subcortical regions, but no change or decrease in cortical regions </li></ul></ul></ul><ul><ul><ul><li>Decrease or no change in 5-HT 2 -receptor density in prefrontal cortex </li></ul></ul></ul><ul><li>Cerebrospinal Fluid (CSF) Studies of 5-HT Metabolites </li></ul><ul><ul><ul><li>Inconsistent results between studies </li></ul></ul></ul><ul><li>Agonist-Challenge Studies </li></ul><ul><ul><ul><li>Administration of m -chlorophenylpiperazine (mCPP) a partial 5-HT agonist: </li></ul></ul></ul><ul><ul><ul><li>- Exacerbates symptoms in unmedicated schizophrenics </li></ul></ul></ul><ul><ul><ul><li>- Has no effect in healthy volunteers </li></ul></ul></ul>
  8. 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)
  9. 9. SEROTONIN-DOPAMINE INTERACTIONS: ELECTROPHYSIOLOGIC AND NEUROCHEMICAL STUDIES <ul><li>Midbrain </li></ul><ul><ul><li>5-HT inhibits the firing of dopaminergic neurons </li></ul></ul><ul><ul><li>Acute administration of 5-HT2 antagonists increases the firing rate of VTA and SN neurons </li></ul></ul><ul><ul><li>Chronic administration of typical and atypical APDs attenuates the number of spontaneously active neurons </li></ul></ul>
  10. 10. SEROTONIN-DOPAMINE INTERACTIONS: ELECTROPHYSIOLOGIC AND NEUROCHEMICAL STUDIES <ul><li>Prefrontal Cortex </li></ul><ul><ul><li>5-HT2 antagonists increase dopamine release </li></ul></ul>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
  11. 11. SEROTONIN-DOPAMINE INTERACTIONS: BEHAVIORAL STUDIES <ul><li>Amphetamine-Induced and Spontaneous Locomotor Activity </li></ul><ul><ul><li>Serotonin depletion via pCPA, a tryptophan-free diet, or lesions by 5,6-dihydroxytryptamine administration enhances amphetamine-induced hyperlocomotion </li></ul></ul><ul><ul><li>Serotonin depletion or lesions of midbrain raphe increase spontaneous locomotor activity </li></ul></ul><ul><li>Catalepsy </li></ul><ul><ul><li>Inhibition of serotonin induced by electrolytic lesions of the raphe, administration of pCPA or 5-HT antagonists decreases neuroleptic-induced catalepsy </li></ul></ul><ul><ul><li>Serotonergic enhancement via the addition of 5-HT agonists, precursors, and uptake inhibitors increases neuroleptic-induced catalepsy </li></ul></ul>
  12. 12. NMDA-ANTAGONIST MODEL OF SCHIZOPHRENIA KETAMINE EFFECTS IN HEALTHY HUMAN SUBJECTS <ul><li>Positive Symptoms </li></ul><ul><ul><ul><li>Grandiose/paranoid delusions </li></ul></ul></ul><ul><ul><ul><li>Bizarre ideation </li></ul></ul></ul><ul><ul><ul><li>Profound perceptual alterations </li></ul></ul></ul><ul><ul><ul><li>Hallucinations (less frequently) </li></ul></ul></ul><ul><li>Negative Symptoms* </li></ul><ul><ul><ul><li>Blunted affect </li></ul></ul></ul><ul><ul><ul><li>Emotional withdrawal </li></ul></ul></ul><ul><ul><ul><li>Psychomotor retardation </li></ul></ul></ul><ul><li>Mood Effects </li></ul><ul><ul><ul><li>Euphoria </li></ul></ul></ul><ul><ul><ul><li>Anxiolysis (low dose) </li></ul></ul></ul><ul><ul><ul><li>Anxiety (high dose) </li></ul></ul></ul><ul><li>Cognitive Deficits – Frontal Cortex Circuits </li></ul><ul><ul><ul><li>Distractibility </li></ul></ul></ul><ul><ul><ul><li>Reduced verbal fluency </li></ul></ul></ul><ul><ul><ul><li>Working memory deficits </li></ul></ul></ul><ul><ul><ul><li>Impairment of smooth pursuit eye-tracking </li></ul></ul></ul><ul><ul><ul><li>Reduced cortical activation while performing the oddball task </li></ul></ul></ul><ul><li>Cognitive Deficits – Temporo-Hippocampal Circuits </li></ul><ul><ul><ul><li>Disruption of new learning </li></ul></ul></ul><ul><ul><ul><li>Reduced prepulse inhibition of the startle response </li></ul></ul></ul>*May be related to sedative effects of ketamine
  13. 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
  14. 14. NMDA ANTAGONIST-INDUCED BEHAVIORS <ul><li>NMDA Antagonist-Stimulated Hyperlocomotion </li></ul><ul><ul><li>MK-801 and PCP induce a behavioral syndrome that includes hyperlocomotion, head-weaving, body-rolling, ataxia, reduced rearing, and stereotypes </li></ul></ul><ul><ul><li>Conventional and atypical APDs reduce MK-801-stimulated hyperlocomotion </li></ul></ul><ul><ul><ul><li>- Clozapine is more potent at decreasing locomotor behavior than stereotypic movements </li></ul></ul></ul>
  15. 15. NMDA ANTAGONIST-INDUCED DISRUPTIONS IN PREPULSE INHIBITION (PPI) <ul><li>PPI is used as a model of attentional processes, and disruptions in PPI </li></ul><ul><ul><ul><li>- Have been observed in schizophrenic patients, </li></ul></ul></ul><ul><ul><ul><li>- Can be induced by NMDA antagonists, such as PCP, ketamine, and MK-801, and </li></ul></ul></ul><ul><ul><ul><li>- Are prevented by atypical APDs, including clozapine, risperidone, quetiapine, and olanzapine </li></ul></ul></ul>* P <.01 vs SAL/SAL group; † P <.05 vs SAL/PCP group; ‡ P <.01 vs SAL/PCP group. <ul><ul><ul><li>J Pharmacol Exp Ther 1994;271:787. </li></ul></ul></ul>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
  16. 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