Term
| pharmacological evidence supporting excess dopamine (DA) in the positive symptoms of schizophrenia |
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Definition
increasing dopamine worsens psychosis (amphetamine, cocaine)
decreasing dopamine ameliorates psychosis - blockade of DA receptors or DA synthesis |
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Term
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Definition
Tyrosine-->DOPA-->DA
(uses same decarboxylase as SER, NE)
stored/released from vesicles
degraded by MAO |
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Term
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Definition
presynaptic membrane:
-DA tranporter (amphetamine reverses to put DA into extracellular space; cocaine blocks reuptake of DA into presynaptic terminal)
*D2 autoreceptor limits the amoutn of DA being released
postsynaptic membrane:
*DA receptors here are the site of blockage in psychosis treatment |
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Term
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Definition
DA receptors are G-protein coupled metabotropic receptors
two families, in psychosis treatment, block **D2 receptor family** |
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Term
| *source of dopamine in the brain* |
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Definition
DA cell bodies are located in the *MIDBRAIN*
**ventral tegmentum
**substantia nigra |
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Term
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Definition
*mesocortical
*msolimbic
*nigrostriatal
*tuberoinfundibular
*chemoreceptor trigger zone |
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Term
| *mesocortical DA pathway* |
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Definition
midbrain-->prefrontal cortex
involved in cognition, thoughts and actions orchestrate with internal goals |
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Term
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Definition
midbrain-> limbic system
complex reward-oriented behavior, integrating emotional responses
emotional tone, affective behavior |
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Term
| *nigrostriatal DA pathway* |
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Definition
substantia nigra-->striatum/caudate
motor planning and executions, habit formation, memory
*involved in troublesome side effects of antipsychotic drugs; motor SE |
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Term
| *tuberoinfundibular DA pathway* |
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Definition
DA release from hypothalamus-->portal vein-->PITUITARY
DA in the pituitary decreases prolactin release |
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Term
| chemoreceptor trigger zone |
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Definition
many DA receptor located here
role in emesis and nausea |
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Term
| role of dopaminergic activity in schizophrenia |
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Definition
pathway of DA projection from ventral tegmentum to cortex is UNDER wokring
pathway of DA projection from ventral tegmentum to limbic region is OVER active |
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Term
| dopamine-glutamate model of schizophrenia |
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Definition
communication system between dopamine and GABA
glutamatergic pathway from cortex to limbic region and DA cell bodies is decreased |
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Term
| characteristics of antipsychotic drugs |
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Definition
active against psychosis of any origin: idiopathic, metabolic, drug-induced
more active against positive symptoms
**antipsychotic drugs interfere with dopamine transmission**
start to work relatively quickly, but take months to reach maximum effect |
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Term
| antipsychotic drugs used today in modern course of treatment |
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Definition
1st gen (old-line):
**Haloperidol
2nd gen/atypicals:
**Olanzapine, aripiprazole, risperidone
Clozapine |
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Term
| *relationship between potency and toxicity of antipsychotics* |
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Definition
**high specificity for D2 receptors leads to more motor side effects**
do need at least 60% binding to D2 for the drug to be effective |
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Term
| potency/toxicity of 1st generation antipsychotics |
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Definition
1st gen: good D2 specificity, so get substantial motor side effects ("extrapyramidal toxicity")
*Haloperidol is highest for both D2R specificity and EPS effects*
*Chlorpromazine block H1 histamine receptors and blocks alpha-adrenergic receptors so it has sedation and hypotensive side effects as well |
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Term
| potency/toxicity of 2nd generation antipsychotics |
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Definition
most 2nd gen (olanzapine, risperdone) have low D2R specificity and thus do NOT have motor side effects (EPS effects)
aripiprazole has partial D2R agonist activity and so even though it has high D2R specificity, it does NOT have EPS effects |
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Term
| factors that play a role in reduces EPS (extrapyramidal symptoms) for 2nd generation antipsychotics |
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Definition
Receptor Occupancy:
~60% of D2R's need to be occupied to get a therapeutic effect
>80% --> EPS
-2nd gen's occupy between 60-80%
-aripiprazole occupies ~85% but because it is a partial agonist, still get some activity and not EPS
Receptor Binding Profile:
-most 2nd gens have high affinity for a number of serotonin receptors subtypes as well
-this helps reduce EPS, but the reason is unknown |
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Term
| dependence of antipsychotics |
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Definition
NOT addicting
get RELAPSE in psychosis if drug is discontinues ABRUPTLY |
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Term
| tolerance development in antipsychotics |
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Definition
NO tolerance to antipsychotic effect
NO tolerance to prolactin secretion
YES tolerance to seadtion effects |
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Term
pharmacokinetics of antipsychotics
-absorption
-distribution
-elimination |
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Definition
erratic absorption
highly lipophilic
half life = 6-40 hours (take 1x/day)
**P450 metabolism**
clearance from brain bay be slower that clearance from plasma |
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Term
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Definition
antipsychotics are CNS depressants
will potentiate actions of other CNS depressants
blocks effects of L-Dopa and dopaminergic agonists
affected by drugs that alter P450 |
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Term
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Definition
mostly with 2nd gen
weight gain, high lipids, high glucose, DB
**Olanzapine has mega weight gain** |
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Term
types of extrapyramidal side effects
EPS |
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Definition
acute dystonia
akathisia
parkinsonism
tardive dyskinesia |
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Term
| NMDA hypothesis of schizophrenia |
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Definition
NMDA = certain glutamate receptor; a lidand-gated ion channel for Ca (important for signaling) and Na
reducing glutamate worsens symptoms
NMDA agonists improve symptoms in schizophrenia
NMDA receptor ligands have a role in synaptic plasticity and are important in maintaining the strength of the synapse
drugs PCP and ketamine are noncompetitive antagonists --> can cause psychotic effects |
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