Catecholamines Flashcards
What are catecholamines?
DA, NE and EPI and are all monoamines (5ht is a monoamine but not a catecholamine)
- NE and EPI released from adrenal medullla, EPI is not very big in the brain
NE and EPI are also adrenaline in the british world
Functions
- Motor (DA) -striatum - Learning Memory - Attention - Motivation - Emotional Responses - Rewards
Dysfunction linked to catecholamine transmission (Parkinson’s, schizophrenia, depression, ADHD, drug addiction)
Do so many things and disruption leads to interesting things
How are catecholamines synthesized?
- Tyrosine, Tyrosine Hydroxalade (TH) (slowest enzyme-rate limiting) turns into
- DOPA (same as L-dopa), it’s a precursor. Dopamine decarboxylase (ADDC)
- Dopamine: Amine and catachol group. This
Everything you need happens in the terminals! (but can be produced at cell body too
TH: marker for catecholamines: its how you label them
Can also label dopamine decarboxylase. (antibodies)
If its just dopamine: stops there! But if not…
4. Noepinephrine by Dopa beta hydroxylase. (DBH) (also enzymes for this)
Dopamine and NE are very similar in chemical structure. (OH group) Effects how transporters differentiate between the two of them.
How is the activity of TH and other catepholamine production regulated?
TH is rate limiting step BUT the Rate at which is produces Ldopa and other things is not fixed
1. Negative feedback (increase in levels, inhibits TH activity) 2. Rate of cell firing (depleted levels in the terminal, acts faster to convert) - L-dopa: precursor to dopamine and noadrenaline (oral) taken up by terminals. Quickly make it NE and DA depending on enyzmes ○ Increase in transmitter levels - AMPT (alpha methyl para tyrosine): block TH, prevent synthesis ○ Sedation (reducing NE levels, reduce BP (systemic effect) These effects can be reversed by given L-dopa.
How are catecholamines packaged?
DA/NE packaged by transporter proteins
- VMAT (vesicular monoamine transporter)
Reserpine: blocks VMAT transporter prevents packing
- They will get borken down by other enzymes - Reduction in transmitter levels - Reduce transmission - Causes: Sedation, Depression, Systemic effects (reducing BP and heart rate by reducing noadrenaline)
Describe catecholamine enzyme degradation?
Catecholamiens are metabolized by MOA (monoamine oxidase) and or COMT (catechol_o_methyltransferate)
DA metabolite: HVA (homovaniliic acid)
NE metabolites (MHPG)
Intermediary steps:
- DA produced DOPAC or 3MT but both converted to HVA.
These metabolites enter CSF and be elimated in urine.
Levels of these in the CSF indicated levels of activity
Drugs can block enzymes, this increases NT levels.
1. Phenelzine (Nardil) treats depression, lots of side effects MAO inhibitor 2. Tolcapone (Tasmar) used with L-dopa to enhance Ldopa when treating parkinson's disease. COMT inhibitor.
PFC: not a lot of reuptake transporters of dopmaine, so dopamine metabolism can be done with COMT very effectivly.
How are catecholamines wired?
- Along lengths of axons there are varicosities along it
- Some of the varicosities make tight synaptic contact onto dentrites, and some don’t.
- These make IN PASSING (EN PASSANT) synapes.
○ This allows for VOLUME TRANSMISSION on EXTRASYNAPTIC receptors.
○ EACH ONE can get depolarized and get diffused away from the release site. Effects that neuron or multiple neurons in multiple regions at once.
○ Broadcast signal.
How are catecholamines reuptaken and what’s some pharmacology?
Transmitter is then sucked into varicosities by transporters. DAT or NET
This is how catecholamines are cleared (some enzyme but not much - except for DOP in frontal lobes)
SLOPPY: each of these can pick up each other (DAT and NET are not selective)
- IN frontal lobes, DAT is cleared through some enzyme degradation and MOSTLY by NET.
Pharmacology
A lot of drugs target these transporters (block them)
- Cause increased in free floating DA and NE.
- IMPULSE DEPENDENT RELEASE.
○ In order to get an accumulation, the 2nd action potential needs to happen and more and more. Gradual buildup of transmitter molecules.
○ If you stop catecholamine neuron from firing, then a reuptake blocker WILL NOT WORK. Need them to fire to lead to accumulation.
○ Neuron has to be active.
○ If a neuron is super active, it might cause MORE accumulation
1. Cocaine: nonselective transporter blocker 2. Tricyclic antidepressatns: inhibit reuptake of NE and 5HT 3. Methyphenidate (Fritalin) treats ADHD, catecholamines (DA, NE)
How do amphetamines effect release and reuptake?
NORMAL TRANSMISSION: NA/DA release, exocytosis and transporters take it back up.
Drugs target these transporters
AMPHETAMINE: REVERSE the transporter. (monoamine) More potent than the other ones.
Prevent transporter from taking it back in, but also a source of transmitter release.
In addition to the normal transmission.
INDEPENDENT OF CELL FIRING. IMPULSE INDEPENDENT.
- No need for AP. They can take the molecules and shoot them into synaptic space.
- Relative selectivity. Mostly nonselective - Adderal: more preferential for catecholamines - MDMA (ecstasy) higher affinity for seratonin but effects the other ones too.
What are the behavioral effects of taking amphetamines?
Vertebrates: DA in nucleus accumbens
Drugs that block reuptake too have this (cocaine).
Dose response curve:
Low dose: increase lotomotion
Higher doses effect other aspects of motor activity. STEROTOPY; instead of moving bodies, sit in one place and move their LIMBS. More localized activity instead of whole body around.
- Seen in humans as well (meth tweaking)
- Change in TYPE of activity.
VTA= Nucleus accumpens makes forward locomotin
SUB nigra= dorsal striatum (fine movements of upper body) starting to stimulate other brain structures at higher doses.
Ex: nucleus accumbens is saturated at lower dose
Dorsal striatum is a bigger structure so it takes more to saturate it and then it becomes dominant (limb, trunk, orofacial) prevents them from normal locomotor movement.
AT HIGHER DOSES YOU EFFECT LARGER BRAIN STRUCTURES. (amphetamine or even cocaine)
What is sensitization?
(reverse tolerance)
Repeated exposure increases sensitivity to effects of drug at teh same dose.
Tested on locomotor effects, animals that got a repeated dose had a higher locomotor response to the same drug as the 1st day.
- For any drug, this has multiple effects. - Some effects can sensitize, increase effects on dopamine system, some induce tolerance.
Drugs with high addictive potential: produce some sensitization.
How do amphetamines work at lower doses?
Lower doses: medicinal effects
- Promote wakefulness
○ During WWII to fight longer
○ Reduces REM sleep. Even at lower doses. (lingering effects)
- Cognitive enhancer
○ Attention, working memory memory encoding
○ In healthy ppl and AHD, schizophrenia.
○ In the FRONTAL LOBES
○ Sacrifice other functions (like creative thoughts, new ideas) Amphetamines enhances attention is different than being creative (gotta lose focus). Using as study aid
○ Prolonged used can led to bad shit.
Neuroethics: drug that makes you smarter, how do we say that only ppl with medical condition.
- They are supposed to help unhealthy ppl, but some people will just want to use it to get smarter even tho theyre otherwise healthy
What are catecholamine autoreceptors?
DA:D2 is the autoreceptor
NE: Alpha 2 subtype is the autoreceptor.
Open potassium channels.
- Hyperpolarizes the cell. - Shortens duration of AP. - Reduces how long calcium channels stay open (cause they're voltage gated)
Terminals: reduces ca influx
Cell bodies: reduces firing (somatodendritic autoreceptors)
Common for all monoamiens but not every neuron does it!
Where can D2/Alpha2 receptors reside?
As autoreceptors OR as possynaptic receptors.
Ex: quinpriole: stimulates D2 receptors
At low doses: reduces locomotion via autoreceptors to decrease catecholamine release
At high doses: activates postsynaptic receptors to increase locomotion
A selective D2 autoreceptor knockout increase DA and increase locomotion (same for NE)
What is AMPT?
- AMPT (alpha methyl para tyrosine): blocks TH, prevent synthesis of De and NE)
○ Sedation (reducing NE levels, reduce BP (systemic effect)
These effects can be reversed by given L-dopa.
