OCB03-2009 DOPAMINE Flashcards
Where are the monoaminergic neurons found in the CNS?
Cell bodies in brainstem and basal forebrain with diffuse projections
What is the general function of monoaminergic neurons?
Modify effects of major excitatory (glutamate) and inhibitory (GABA) neurotransmitters
What diseases is dopamine implicated in?
Schizophrenia
Parkinson’s disease
Restless leg syndrome
What is dopamine a precursor for?
Noradrenaline
What dopaminergic pathways are there in the CNS?
Nigrostriatal pathway
Mesolimbic pathway
Mesocortical pathway
Tuberoinfundibular pathway
Retina
Olfactory tubercle
Describe the dopaminergic nigrostriatal pathway.
From substantia nigra to caudate nucleus/putamen (striatum)
Control of movement
What dopaminergic pathway is compromised in Parkinson’s disease?
Nigrostriatal pathway
Describe the mesolimbic pathway.
From ventral tegmental area to nucleus accumbens (frontal part of caudate nucleus)
Increases responsiveness to external and internal stimuli
Involved in motivation, motor activity and reward
What dopaminergic pathway is important in drug addiction and positive symptoms of schizophrenia?
Mesolimbic pathway
Describe the mesocortical pathway.
From ventral tegmental area to frontal cortex
Involved in normal cognition, motivation, emotion
What dopaminergic is dysfunctional in psychoses and ADHD?
Mesocortical pathway
Describe the tuberoinfundibular pathway.
From arcuate nucleus (in hypothalamus) to the median eminence
Important in control (inhibition) of prolactin release from adenohypophysis
What is the pathway of synthesis of dopamine?
L-tyrosine –> L-DOPA by tyrosine hydroxylase
L-DOPA –> dopamine by L-DOPA decarboxylase (aromatic amino acid decarboxylase)
Which enzyme catalyses the reaction L-tyrosine –> L-DOPA?
Tyrosine hydroxylase
Which enzyme catalyses the reaction L-DOPA –> dopamine?
L-DOPA decarboxylase
What is the pathway of dopamine degradation in neurons?
Dopamine –> dihydroxy-phenyl acetic acid (DOPAC) by MAOa/b
DOPAC –> homovanillic acid (HVA) by COMT
What is the final metabolite of dopamine?
Homovanillic acid
What does COMT stand for?
Catechol-O-methyl transferase
What is the pathway of dopamine degradation in glial cells?
Dopamine –> 3-methoxy-tyramine (3MT) by COMT
3MT –> to homovanillic acid by MAOa/b
Where is MAO found?
In outer mitochondrial membranes in presynaptic terminal and other cells
What can MAOa metabolise?
Dopamine, NA, serotonin
What can MAOb metabolise?
Dopamine
Where is COMT found?
Extraneuronal, intracellular areas
What can be measured to determine dopaminergic brain activity?
Homovanillic acid in CSF
Describe general dopaminergic transmission.
DA taken up into vesicles by VMAT and stored in an acidic environment
AP = DA exocytosed into synaptic cleft
DA stimulates post (D1, 2) and pre (D2) synaptic receptors
DA leaves by diffusion and is taken up by DAT or ENT to be stored or metabolised
Where is DAT found?
Presynaptic neuronal cell membrane
Where is ENT found?
Glial cell membrane
What does ENT mean?
Extraneuronal transporter
What does VMAT mean?
Vesicular monoamine transporter
Which type of transporter removes most of the dopamine after transmission?
DAT
What are the two main groups of dopamine receptors?
D1 and D2
How many dopamine receptors are there in total?
5
Which dopamine receptors are part of the D1 family?
D1
D5
Which dopamine receptors are part of the D2 family?
D2, 3, 4
Which dopamine receptors are the most abundant in the brain?
D1 and D2
Which family of dopamine receptors are involved in prolactin secretion?
D2 (D2 and 3)
Which dopamine receptors are involved in motor control?
All of them (mostly D1 and D2)
Which dopamine receptors are involved in emotion?
All of them (mostly D1 and D2)
Which dopamine receptors are involved in arousal and mood?
D1 > D2 > D4
What G protein is the D1 receptor family coupled to?
Gs
Where are the D1 receptor family mainly found?
Postsynaptically
What G protein is the D2 receptor family coupled to?
Gi/o (open K channels)
Where are the D2 receptor family found?
Pre and postsynaptically
Which receptor family does DA have a higher potency with?
D2
What are some dopamine antagonists?
Chlorpromazine
Haloperidol
Sulpiride
Clozapine
What are some dopamine agonists?
Apomorphine
Bromocripine
What are the consequences of degeneration of the nigrostriatal pathway?
(Parkinson’s disease)
Tremor
Akinesia
Postural instability
Rigidity
Why may hyperprolactinaemia be a side effect of D2 antagonists for schizophrenia treatment?
Inhibits the tuberoinfundibular pathway so prolactin release is uncontrolled
How does cocaine affect DA transmission and what is the result of this?
Inhibits DAT = increased extracellular DA so increases receptor stimulation
Stimulant and addictive; psychoses
How does amphetamine and methylphenidate affect DA transmission and what is the result of this?
Increase DA release and inhibit DAT to increase extracellular DA
Stimulant and addictive; psychoses
Calming in ADHD
How does L-DOPA administration affect DA transmission?
Increases DA formation so increased transmission
How does selegiline administration affect DA transmission?
Inhibits MAOb so decreased DA metabolism to increase transmission
What does entacapone do?
Inhibits COMT to decrease L-DOPA metabolism
What drugs can be used to treat Parkinson’s disease?
(Increases DA transmission) L-DOPA Selegiline Entacapone Apomorphine Rotigotine Ropinirole Pramipexole
What are the D2 antagonists and what do they treat?
Sulpiride
Clozapine
Antipsychotics for schizophrenia
