L4 - L5 Catecholamines - 4 IRL flashcards
Difference in mechanism of action between Amphetamines and Cocaine
Amphetamine is an indirectly acting sympathomimetic - displacing NA from vesicles so more is present in the junction
-Independent on nerve stimulation
Cocoaine blocks neuronal re-uptake of NA -> more present in the junction
-Requires NA to be present in the junction to have an effect
6-OH dopamine leads to?
Selective degen of catecholaminergic nerve terminals and all transmitters stored within via the formation of reactive metabolite (toxic quinone)
Degen of terminals leads to diseases such as?
Parkinsonian signs and depression
!Reserpine - effects? Depletion takes ___. It ___ BP but also causes ____ (mental illness).
Irreversibly blocks the vesicular monoamine transporter (VMAT)
Depletion takes 24-48 hours. It lowers BP but also causes depression.
Effect of guanethidine on NA nerves?
Releases NA like amphetamine and depletes NA like reserpine
Guanethidine is transported by uptake 1 into the presynaptic terminal transported by norepinephrine transporter (NET). This leads to a gradual depletion of norepinephrine stores in the nerve endings. Once inside the terminal it blocks the release of NA in response to arrival of an AP by preventing exocytotic release by blocking Ca2+ channel intracellularly.
Spontaneous release is not affected!
__% of NA goes into neuronal uptake _% goes extraneuronal uptake
90, 10
!Desipramine
Similar to cocaine - inhibits reuptake of NA. It is a tricyclic antidepressant (TCA).
List a MAO-A Inhibitor and a MAO B isoform inhibitor
MAO-A Inhibitor - Moclobemide
MAO-B Inhibitor (DA selectivity) - Selegiline (used as adjunct with L-DOPA)
List a COMT inhibitor. COMT inhibitors are used as adjunct therapy in ___
Entacapone. Parkinsons
Role of MAO
Enzymes that catalyze the oxidation of monoamines - breaking down NA, 5-HT, Dop
_% of brain catecholamine content is dopamine
50
CNS dopamine neurons have several discrete cell groups. What areas are they linked to? a) Nigrostriatal pathway b) Mesolimbic pathway c) Mesocortical/hypothalamic cell groups !d) Tuberoinfundibular pathway
a) Nigrostriatal pathway - motor control
b) Mesolimbic pathway - emotion, addiction
c) Mesocortical/hypothalamic cell groups - temperature control, behavioural
d) Tuberoinfundibular pathway - hormone regulation: prolactin, GH
!How is parkinsons treated pharmacologically?
Dopamine does not pass from blood to brain, so it cannot be given directly as a medicine.
1) Instead, levo-dopa (L-dopa) is used, which does enter the brain and is converted there into dopamine
2) Carbidopa (inhibits DDC peripherally!) is used to allow more L-DOPA to enter CNS (it also suppresses nausea from L-DOPA - as a lower dose of L-DOPA is used when carbidopa is present)
OPTIONAL: alpha methyl para tyrosine (AMPT) - Tyrosine hydroxylase inhibitor, Dopamanergic pathways can be excit or inhibit – Subset of motor disorders (some dystonias/dyskinesias) where there is overactivation of pathway SE: causes depression
Chemically, what does COMT do? MAO?
COMT adds methyl groups
MAO gets ride of amine groups
Dopamine is affected by MAO and COMT and Aldehyde dehydrogenase converts these affected intermediates into DOPAC (Dihydroxyphenyl acetic acid) or Homovanillic acid (HVA). It is where potential for reactive metabolities forming comes in. It can make dopamergic nerves more sensitive due to oxidative stress
Dopamine is affected by MAO and COMT and Aldehyde dehydrogenase converts these affected intermediates into DOPAC (Dihydroxyphenyl acetic acid) or Homovanillic acid (HVA). It is where potential for reactive metabolities forming comes in. It can make dopamergic nerves more sensitive due to oxidative stress
What happens to individuals with the DA transporter KO?
Hyperactivity, insensitivity to cocaine
DA transporter is __ fold more selective for DA than NA and vice versa
10
Dopamine transporter has _ aa _ TMS domains
620 aa 12 TMS domains
Drugs of dependence increase dopamine in the __ and has propensity for psychotic-like symptoms
nucleus accumbens
Symptoms of Schizophrenia in the brain
Dysfunctional PFC, ventricular enlargement, defective DA transmission (and other transmitters)
What kind of drugs worsen schizophrenia symptoms?
- Amphetamine / cocaine
- D2 receptor agonists BUT also used for Parkinson’s
This is because both these methods increase DA which increase propensity for psychotic symptoms
What kind of activity do antipsychotic drugs have?
- D2 receptor blocking activity
BUT may induce extrapyramidal side-effects: tardive dyskinaesia ( involuntary movements of the face and jaw)
D2 receptor ag and antag
Agonist: bromocriptine
(Parkinson’s, restless leg syndrome, prolactinoma)
Antagonist: haloperidol
(antipsychotics, antiemetics)
Rate limiting step in DA synthesis?
Tyrosine Hydroxylase
