CNS Dopaminergic Neurotransmission - Kelly 5 Flashcards Preview

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Flashcards in CNS Dopaminergic Neurotransmission - Kelly 5 Deck (35)
1

Dopaminergic pathways in the brain

1. Mesolimbic pathway
2. Mesocortical pathway
3. Nigrostriatal pathway
4. Tuberoinfundibular pathway
5. Chemoreceptor trigger zone and regular emesis

2

Mesolimbic pathway

DA neurons in the tegmenjtum synapse at NcAc
Important in reward

3

Mesocortical pathways

Da neurons from tegmenjtum to prefrontal cortex
Important in cognition, motivation

4

Nigrostriatal pathway

DA neurons from Substance nigra synapse in striatum
Important in coordination of movement

5

Tuberinfundibular pathway

DA pathway from hypothalamus to pituitary Inhibits release of prolactin binding to increased serum prolactin

6

Drugs affecting dopaminergic pathways

1. Drugs of abuse (mesolimbic pathways)
2. Antipsychotics (mesolimbic and mesocortical pathways)
3. Drugs for Parkinson's disease (nigrostriatal pathway)

7

DA metabolism

Broken down by COMT and MAO to homovanillic acid

8

D1 receptor family

Increase cAMP via Gs
Increase PIP2 hydrolysis
Ca mobilization, PKC activity

9

D2 receptor family

Decrease cAMP via Gi
Increase K currents
Decrease voltage-gated Ca currents

10

Schizophrenia

1% of the worlds population
Positive, negative and cognitive symptoms

11

Positive symptoms of schizophrenia

Psychosis, with hallucinations and delusions
Caused by increase activity in mesolimbic pathway

12

Negative symptoms of schizophrenia

Social withdrawal, inability to experience pleasure, loss of motivation
Caused by decreased activity in mesocortical pathway

13

Cognitive symptoms of schizophrenia

Disorganization of thought and speech

14

Dopamine hypothesis of schizophrenia

May result from functional excess of dopamine in the CNS
Based on evidence that drugs that block DA receptors can relieves symptoms
Drugs that activate DA receptors aggravate symptoms and cause psychoses

15

Drug action for schizophrenia

Increase activity in mesocortical (5-HT receptor blockers), decrease activity in mesolimbic (D2 receptor blockers)

16

Antipsychotic drugs

Agents that reduce psychotic symptoms and improve behaviour of schizophrenia patients
Also called neuroleptic drugs because they suppress motor activity and emotion
Typical and Atypical

17

Chlorprozamine

First anti-psychotic drug
Anti-histamine being tested as adjunct to anesthesia
Prevents hallucinations and delusions
Blocks D2 receptors

18

Typical anti-psychotic drugs

First generation, or conventional
Phenothiazines (chlorpromazine)
Butyrophenones (haloperidol)
Ability to relieve positive symptoms of schizophrenia correlates with affinity for antagonism of D2 receptors
Block of D2 receptors in striatum results in extra-pyramidal side effects

19

Atypical anti-psychotic drugs

Clozapine, olanezepine
Higher affinity for 5-HT2 than for D2
Acts presynaptically to block DA release in prefrontal cortex
Reduces extrapyramidal side effects
Metabolic dysfunction
More expensive

20

Anti-psychotic drug PK/PD

Well absorbed, with long half life, sequestered in body tissue
Dopamine receptor antagonism
Correlation between effective dose and binding affinity for D2 receptors

21

Extrapyramidal dysfunction

Results from D2 receptor blockade
DA is a NT in the nigrostatial pathway
Stratum is part of the extrapyramidal motor system
Important in initiation and execution of voluntary movements
Management is reducing dose of antipsychotic

22

Acute extrapyramidal side effects

Akathisia, pseudoparkinsonism, dystonia due to antagonism of DA receptors

23

Long term extrapyramidal side effects

Tardive dyskinesia due to increased sensitivity of DA receptors

24

Parkinsons disease

Nigrostriatal pathway
Progressive neurodegenerative disorder that affects motor pathways in the brain
Loss of dopaminergic neurons in the substantial nigra, leading to decreases DA in the striatum
Exact cause unknown
Progressive
Resting tremor, rigidity, akinesia, bradykinesia

25

Treatment for Parkinsons

1. Drugs that increase DA levels in the brain
2. DA receptor agonists
3. Acetylcholine antagonists

26

Drugs that increase DA levels

1. Levodopa
2. Caridopa
3. Catechol-O-methyltransferase inhibitors
4. Selegiline

27

Levodopa

L-DOPA
Biosynthetic precursor of DA
Crosses BBB and taken up by neurons in the substantial nigra
Covered into dopamine by LAAD
Can be metabolized in the periphery by LAAD and COMT to produce DA and 3OMD
Adverse affects due to increase DA in peripheral tissues

28

Caridopa

Analog of L-DOPA
Inhibits conversion of L-DOPA to DA in the peripheral tissue
Does not cross BBB
Combination therapy with L-DOPA to increase the amount of L-DOPA that crosses the BBB, allowing lower amounts of L-DOPA

29

Catechol-O-methyltransferase inhibitors

Block conversion of L-DOPA to 3-OMD
Used in combination with L-DOPA
Inhibits activity of COMT, the peripheral enzyme that metabolites L-DOPA to 3OMD
Maximizes bioavailability of L-DOPA to be transported into the brain

30

DCC inhibitor

Events conversion of L-DOPA into dopamine in periphery

31

Selegiline

Irreversible inhibitor of MAO-B in the stratum
Stratal MAO-B metabolizes DA
Inhibits oxidation of DA to DOPAC
Increases DA levels in stratum

32

Dopamine receptor agonists

Directly activate DA receptors
Can be used in combination with levodopa-carbidopa
Act at most synaptic dopamine receptors
Activation of a specific DA receptor may limit adverse effects of these drugs

33

Antimuscarinic drugs

Block stratal muscarinic receptors
Not as effective as levodopa-carbidopa treatment
Efficient at controlling tremors
Often used in combination therapy, alleviate extra-pyramidal effects caused by older anti-psychotic drugs

34

Amantadine

Often combined with levodopa-carbidopa therapy
Also anti-viral
Used in patients who do not respond well to levodopa
Inhibits dopamine re-uptake
Facilitate presynaptic DA release
Antagonist NMDA receptors

35

Pharmacological strategy in Parkinson's disease

Enhance dopamine functions or antagonize acetylcholine at muscarinic receptors