CNS Dopaminergic Neurotransmission - Kelly 5

Question 1

Dopaminergic pathways in the brain

Answer 1

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

Question 2

Mesolimbic pathway

Answer 2

DA neurons in the tegmenjtum synapse at NcAc

Important in reward

Question 3

Mesocortical pathways

Answer 3

Da neurons from tegmenjtum to prefrontal cortex

Important in cognition, motivation

Question 4

Nigrostriatal pathway

Answer 4

DA neurons from Substance nigra synapse in striatum

Important in coordination of movement

Question 5

Tuberinfundibular pathway

Answer 5

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

Question 6

Drugs affecting dopaminergic pathways

Answer 6

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

Question 7

DA metabolism

Answer 7

Broken down by COMT and MAO to homovanillic acid

Question 8

D1 receptor family

Answer 8

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

Question 9

D2 receptor family

Answer 9

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

Question 10

Schizophrenia

Answer 10

1% of the worlds population

Positive, negative and cognitive symptoms

Question 11

Positive symptoms of schizophrenia

Answer 11

Psychosis, with hallucinations and delusions

Caused by increase activity in mesolimbic pathway

Question 12

Negative symptoms of schizophrenia

Answer 12

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

Question 13

Cognitive symptoms of schizophrenia

Answer 13

Disorganization of thought and speech

Question 14

Dopamine hypothesis of schizophrenia

Answer 14

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

Question 15

Drug action for schizophrenia

Answer 15

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

Question 16

Antipsychotic drugs

Answer 16

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

Question 17

Chlorprozamine

Answer 17

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

Question 18

Typical anti-psychotic drugs

Answer 18

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

Question 19

Atypical anti-psychotic drugs

Answer 19

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

Question 20

Anti-psychotic drug PK/PD

Answer 20

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

Question 21

Extrapyramidal dysfunction

Answer 21

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

Question 22

Acute extrapyramidal side effects

Answer 22

Akathisia, pseudoparkinsonism, dystonia due to antagonism of DA receptors

Question 23

Long term extrapyramidal side effects

Answer 23

Tardive dyskinesia due to increased sensitivity of DA receptors

Question 24

Parkinsons disease

Answer 24

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

Question 25

Treatment for Parkinsons

Answer 25

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

Question 26

Drugs that increase DA levels

Answer 26

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

Question 27

Levodopa

Answer 27

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

Question 28

Caridopa

Answer 28

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

Question 29

Catechol-O-methyltransferase inhibitors

Answer 29

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

Question 30

DCC inhibitor

Answer 30

Events conversion of L-DOPA into dopamine in periphery

Question 31

Selegiline

Answer 31

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

Question 32

Dopamine receptor agonists

Answer 32

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

Question 33

Antimuscarinic drugs

Answer 33

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

Question 34

Amantadine

Answer 34

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

Question 35

Pharmacological strategy in Parkinson's disease

Answer 35

Enhance dopamine functions or antagonize acetylcholine at muscarinic receptors