Your SlideShare is downloading. ×
精神分裂症5-羟色胺病理生理机制
Upcoming SlideShare
Loading in...5
×

Thanks for flagging this SlideShare!

Oops! An error has occurred.

×

Saving this for later?

Get the SlideShare app to save on your phone or tablet. Read anywhere, anytime - even offline.

Text the download link to your phone

Standard text messaging rates apply

精神分裂症5-羟色胺病理生理机制

791
views

Published on

精神分裂症5-羟色胺病理生理机制( …

精神分裂症5-羟色胺病理生理机制(
Serotonin Mechanisms in the Pathophysiology of Schizophrenia)。更多精彩教程,请访问缤果网(http://www.bingomed.com)。

Published in: Health & Medicine

0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total Views
791
On Slideshare
0
From Embeds
0
Number of Embeds
0
Actions
Shares
0
Downloads
0
Comments
0
Likes
0
Embeds 0
No embeds

Report content
Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
No notes for slide

Transcript

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