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Schizophrenia (Neurobiology (Dopamine Hypothesis (version 3) The Final…

- - - - regional specificity, cortical-subcortical interactions, dopamine receptors showing different brain distributions
      - negative & cognitive symptoms from frontal hypodopaminergia (no direct evidence)
        
        Val/Val genotype vulnerable(poorer cognitive performance)
      - positive symptoms from striatal hyperdopaminergia
    - - no link to genetics, dopamine thought of in isolation
  - - - why its onset was in the late teens and early twenties
      - why the disorder appeared to be associated with structural brain changes and cognitive deficits
      - why schizophrenia was characterized by treatment-resistant negative symptoms
    - - prevent Calcium ion flux into the cell
      - lead to effects that mimic those seen in schizophrenia
      - lead to a relapse of psychotic symptoms
      - primary site of action: NMDA receptors expressed on GABAergic interneurons in the thalamus and basal forebrain
      - net effect of NMDA receptor blockade --> disinhibition of projection neurons, resulting in elevated cortical glutamate and acetylcholine release
      - also have effects at other receptor populations
      - psychotomimetic actions of PCP and ketamine could arise through agonism of high affinity dopamine D2 receptors
      - distinct from other psychomimetic drugs in that they induce prominent emotional blunting, anhedonia and social withdrawal, similar to the negative symptoms of schizophrenia
      - The only direct or downstream action of ketamine and PCP that distinguishes them from other psychoactive drugs is their blockade of the NMDA receptor
        
        suggests that NMDA receptor dysfunction may be central to the formation of negative, rather than positive, psychotic symptoms
    - - neurodegeneration in rats following NMDA receptor blockade leads to a transient gliosis
      - glutamate-mediated excitotoxicity has been found to induce apoptotic loss of dendrites and synapses without cell-body death or gliosis
      - chronic schizophrenia: risk of neuronal loss through apoptosis
      - mitochondrial chain abnormalities, which would be expected to increase the tendency towards apoptosis
      - lower levels of superoxide dismutase and other enzymes that protect against oxidative insults
      - GABAergic interneurons could potentially arise as a result of excitotoxicity secondary to excess cortical glutamate
    - - Ketamine causes elevation of cortical glutamate in animals & humans
- - - - block dopamine D2 receptors
      - BUT little evidence of dopamine receptor abnormality in schizophrenia
    - - Despite recent interest in other neurotransmitter systems, dopamine D2 receptors are still the primary target for recently developed second generation antipsychotic drugs
    - - patients relapse rapidly and more severity after discontinuation of treatment
      - antipsychotic drugs used on the basis of dopamine hypothesis