CNS Dopaminergic Neurotransmission - Kelly 5 Flashcards
Dopaminergic pathways in the brain
- Mesolimbic pathway
- Mesocortical pathway
- Nigrostriatal pathway
- Tuberoinfundibular pathway
- Chemoreceptor trigger zone and regular emesis
Mesolimbic pathway
DA neurons in the tegmenjtum synapse at NcAc
Important in reward
Mesocortical pathways
Da neurons from tegmenjtum to prefrontal cortex
Important in cognition, motivation
Nigrostriatal pathway
DA neurons from Substance nigra synapse in striatum
Important in coordination of movement
Tuberinfundibular pathway
DA pathway from hypothalamus to pituitary Inhibits release of prolactin binding to increased serum prolactin
Drugs affecting dopaminergic pathways
- Drugs of abuse (mesolimbic pathways)
- Antipsychotics (mesolimbic and mesocortical pathways)
- Drugs for Parkinson’s disease (nigrostriatal pathway)
DA metabolism
Broken down by COMT and MAO to homovanillic acid
D1 receptor family
Increase cAMP via Gs
Increase PIP2 hydrolysis
Ca mobilization, PKC activity
D2 receptor family
Decrease cAMP via Gi
Increase K currents
Decrease voltage-gated Ca currents
Schizophrenia
1% of the worlds population
Positive, negative and cognitive symptoms
Positive symptoms of schizophrenia
Psychosis, with hallucinations and delusions
Caused by increase activity in mesolimbic pathway
Negative symptoms of schizophrenia
Social withdrawal, inability to experience pleasure, loss of motivation
Caused by decreased activity in mesocortical pathway
Cognitive symptoms of schizophrenia
Disorganization of thought and speech
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
Drug action for schizophrenia
Increase activity in mesocortical (5-HT receptor blockers), decrease activity in mesolimbic (D2 receptor blockers)
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
Chlorprozamine
First anti-psychotic drug
Anti-histamine being tested as adjunct to anesthesia
Prevents hallucinations and delusions
Blocks D2 receptors
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
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
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
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
Acute extrapyramidal side effects
Akathisia, pseudoparkinsonism, dystonia due to antagonism of DA receptors
Long term extrapyramidal side effects
Tardive dyskinesia due to increased sensitivity of DA receptors
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
Treatment for Parkinsons
- Drugs that increase DA levels in the brain
- DA receptor agonists
- Acetylcholine antagonists
Drugs that increase DA levels
- Levodopa
- Caridopa
- Catechol-O-methyltransferase inhibitors
- Selegiline
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
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
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
DCC inhibitor
Events conversion of L-DOPA into dopamine in periphery
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
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
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
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
Pharmacological strategy in Parkinson’s disease
Enhance dopamine functions or antagonize acetylcholine at muscarinic receptors
