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Neuropharmacology > DA 2 COPY > Flashcards

DA 2 COPY Flashcards

1
Q

Dopamine associated conditions

A 
Schizophrenia; Parkinson’s disease; Reward and Drugs of abuse
//
Attention deficit hyperactivity disorder (ADHD); Tourette's Huntington’s disease; Bipolar disorders; Depression
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2
Q

Which dopamine associated condition is a form of psychosis?

A

Schizophrenia

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3
Q

Epidemiology of schizophrenia

A

Affects about 1% of the population worldwide; more common in men (20 to 30% prevalence in homeless men); cost accounts for 2.5% of total health spending in the US; strong genetic predisposition ( polygenic)

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4
Q

Being born in which season increases the risk of schizophrenia?

A

Winter

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5
Q

Which viruses increase the risk of schizophrenia?

A

Influenza and Zika, as they both affect development

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6
Q

Degree of relatedness and the risk of schizophrenia

A

Diagram

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7
Q

Positive symptoms of schizophrenia

A

Delusions (especially paranoid); prominent hallucinations (usually auditory and often self-critical); disordered thoughts; problems processing sensory input

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8
Q

Negative symptoms of schizophrenia

A

Withdrawal; emotionally unresponsive; unusual posture

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9
Q

Negative symptoms of schizophrenia and antipsychotics

A

Pharmacological treatment of negative symptoms is much less effective, suggesting that the negative symptoms of schizophrenia could actually be a different disease

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10
Q

Prognosis in schizophrenia

A

65% suffer for as many years; remission and recovery in 25% in a five year period; 10% experience total incapacity; early detection and diagnosis is important, young patients respond well, recover better, have fewer relapses

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11
Q

Underlying causes of schizophrenia

A

Prominent anatomical abnormalities in the brain; dopamine theory

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12
Q

Prominent anatomical abnormalities in brain

A

Reduced blood flow to globus pallidus (basal ganglia to frontal lobes)
Reduced blood flow to frontal lobes during memory tests
Cortex of medial temporal lobe is thinner
Enlarged lateral and third ventricles and widening of the sulci.
Enlarged palladium Reduced hippocampus, amygdala, thalamus, nucleus accumbens.

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13
Q

Uncertainty surrounding the anatomical theories of schizophrenia

A

Unclear whether the abnormalities are due to disease or drugs

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14
Q

Which anatomical abnormality is most common in schizophrenia?

A

Enlarged ventricles and widening sulci

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15
Q

Another anatomical feature which is particularly interesting in schizophrenia

A

Is the frontal lobes

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16
Q

Dopamine theory

A

(Carlsson 1960’s)
1951: chlorpromazine calms agitated patients (‘tranquilizer’) - Laborit
1964: chlorpromazine found to mitigate schizophrenic symptoms
1964-: chlorpromazine and other antipsychotics act as dopamine antagonists

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17
Q

Standard antipsychotics used against schizophrenia

A

chlorpromazine (Thorazine) fluphenazine (Prolixin) haloperidol (Haldol)
thiothixene(Navane) trifluoperazine (Stelazine) perphenazine (Trilafon) thioridazine (Mellaril)

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18
Q

Which type of antipsychotics are DA blockers?

A

Standard antipsychotics

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19
Q

Atypical antipsychotics used against schizophrenia

A

risperidone (Risperdal) clozapine (Clozaril) olanzapine (Zyprexa)

20
Q

Which type of antipsychotic are serotonin blockers?

A

Atypical antipsychotics

21
Q

Principal mechanisms of drug action

A

Diagram

22
Q

Which adjective is a technical term to describe the mechanism of action of antipsychotics?

A

Dirty- wide acting thus have far-reaching side-effects

23
Q

Principal side effects of antipsychotics

A

movement: controlled by many neurotransmitters but particularly a balance between dopamine and acetylcholine

24
Q

Name the effect on movement that dopamine blocking drugs often have

A

extrapyramidal effects

25
Q

Acute dystonias (Parkinson-type)

A

involuntary movements (protruding tongue)
quick onset
REVERSIBLE

26
Q

Tardive dyskinesia

A

Disabling involuntary movements; slow onset; IRREVERSIBLE

27
Q

Benefits of antipsychotics that block cholinergic transmission and atypical antipsychotics

A

Fewer extrapyramidal side effects

28
Q

Problems with the D2R hypothesis

A

General Problems: Known antipsychotics take several weeks to work; No good mechanism explaining anti-D2R correlation with
schizophrenia (knockouts, genetics etc)
Positive and Negative Symptoms: D2 antagonists primarily block just +ve symptoms
Clozapine - Atypical antipsychotic: Poor D2R antagonist (5HT) and yet still efficacious against +/-ve
symptoms

29
Q

Why is D4R interesting in relation to schizophrenia?

A

Expressed in the meso-cortico/limbic systems: cortex; amygdala; hippocampus; hypothalamus; mesencephalon;

30
Q

D4Rs and Schizophrenia

A

D4 receptors increased in brains from schizophrenia patients;
Cloned/expressed human D4 receptors -> Clozapine 10X higher affinity human D4Rs vs. D2Rs;
Potential benefits of targeting D4Rs vs. D2Rs -> Reduced extrapyramidal side-effects (Parkinsonism);
Drug companies launched improved D4 antagonists e.g. L745870 which is x103 D4 vs. D2 (Merck)

31
Q

Problems with the D4R hypothesis of schizophrenia

A

Animal models:
Beneficial effects D4 antags occur at doses&raquo_space;
than D4R blockade
Patients: Random, double blind trial: no improvement even
at 4wks

32
Q

Other systems in schizophrenia

A

Glutamate transmission: decreased NMDA transmission –> psychosis; e.g. PCP (Angel dust) – psychotogenic – blocks NMDARs; conversely D2R antagonist (haloperidol) blocks PCP effects
Other transmitter systems: 5HT – evidence LSD (partial agonist (high doses)); but again ‘selective’ drugs found to act on D2Rs!

33
Q

glutamate and schizophrenia

A

Brains from schizophrenia patients show reduced NMDAR in forebrain at
post-mortem (agrees with effect of PCP)-> thus: NMDA agonists might be beneficial.
D-Cycloserine: NMDA agonist (binds to the glycine site of R); used as adjunct in treatment (results mixed).
mGluR2/3 agonists also being trialled (decreased Glu release in prefrontal cortex)

34
Q

dopamine hypothesis of. schizophrenia version 3

A

Imaging studies consistently show increased uptake of L-Dopa and synthesis to DA in presynaptic terminals in striatal DA-neurons.
Imaging also shows increased release of DA from these neurons
D2-blockers (antipsychotics) also block presynapatic D2 receptors that regulate DA release → promotes increase in DA synthesis
Should drug development focus on modulating presynaptic DA synthesis
and/or release?

35
Q

The drug deadlock

A

Drugs developed since 1990 no better than older drugs

36
Q

Early diagnosis

A

Diagnose predisposition for Schizophrenia before symptoms
Approach: Machine learning coupled to functional imaging
E.g. fMRI to measure emotional response images then algorithms to compare individual activity with those of library standards

37
Q

Candidate genes in schizophrenia

A

DISC1 Disrupted in schizophrenia
DTNBP1 Dysbindin (dystrobrevin binding protein 1)
NRG1 Neuregulin 1
AKT1 Protein Kinase B
DAOA D amino acid oxidase activator
COMT Catechol-O-methyl transferase
RGS4 Regulator of G-protein signalling 4
VMAT2 Vesicular monoamine transporter
ARC Cytoskeleton
NMDAR glutamate signalling CACNA1C Ca channel

38
Q

Why is D4R interesting in relation to schizophrenia?

A

Expressed in the meso-cortico/limbic systems: cortex; amygdala; hippocampus; hypothalamus; mesencephalon;

39
Q

D4Rs and Schizophrenia

A

D4 receptors increased in brains from schizophrenia patients;
Cloned/expressed human D4 receptors -> Clozapine 10X higher affinity human D4Rs vs. D2Rs;
Potential benefits of targeting D4Rs vs. D2Rs -> Reduced extrapyramidal side-effects (Parkinsonism);
Drug companies launched improved D4 antagonists e.g. L745870 which is x103 D4 vs. D2 (Merck)

40
Q

Problems with the D4R hypothesis of schizophrenia

A

Animal models:
Beneficial effects D4 antags occur at doses&raquo_space;
than D4R blockade
Patients: Random, double blind trial: no improvement even
at 4wks

41
Q

Other systems in schizophrenia

A

Glutamate transmission: decreased NMDA transmission –> psychosis; e.g. PCP (Angel dust) – psychotogenic – blocks NMDARs; conversely D2R antagonist (haloperidol) blocks PCP effects
Other transmitter systems: 5HT – evidence LSD (partial agonist (high doses)); but again ‘selective’ drugs found to act on D2Rs!

42
Q

glutamate and schizophrenia

A

Brains from schizophrenia patients show reduced NMDAR in forebrain at
post-mortem (agrees with effect of PCP)-> thus: NMDA agonists might be beneficial.
D-Cycloserine: NMDA agonist (binds to the glycine site of R); used as adjunct in treatment (results mixed).
mGluR2/3 agonists also being trialled (decreased Glu release in prefrontal cortex)

43
Q

dopamine hypothesis of. schizophrenia version 3

A

Imaging studies consistently show increased uptake of L-Dopa and synthesis to DA in presynaptic terminals in striatal DA-neurons.
Imaging also shows increased release of DA from these neurons
D2-blockers (antipsychotics) also block presynapatic D2 receptors that regulate DA release → promotes increase in DA synthesis
Should drug development focus on modulating presynaptic DA synthesis
and/or release?

44
Q

The drug deadlock

A

Drugs developed since 1990 no better than older drugs

45
Q

Early diagnosis

A

Diagnose predisposition for Schizophrenia before symptoms
Approach: Machine learning coupled to functional imaging
E.g. fMRI to measure emotional response images then algorithms to compare individual activity with those of library standards

46
Q

Candidate genes in. schizophrenia

A

DISC1 Disrupted in schizophrenia
DTNBP1 Dysbindin (dystrobrevin binding protein 1)
NRG1 Neuregulin 1
AKT1 Protein Kinase B
DAOA D amino acid oxidase activator
COMT Catechol-O-methyl transferase
RGS4 Regulator of G-protein signalling 4
VMAT2 Vesicular monoamine transporter
ARC Cytoskeleton
NMDAR glutamate signalling CACNA1C Ca channel

Neuropharmacology (20 decks)

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