Dopamine and Noradrenaline Flashcards
Where are the DA and NE cell groups
- Noadrenergic: A1-A7
- Dopaminergic A8-A16
What is the nigrostriatal pathway
A9
Caudate putamen (dorsal stiatum)
- dopmaine oxidizes it turns black
- voluntary movement
- neurotoxins 60Hda and MPTP damage this path and look like parkinsons
- Parkinson’s disease is a loss of these neurons (progressive, so over time therapies stop working cause they don’t have enough dopamine to boost signal or you must increase drug so much that it interferes with other shit)
Dopamine helps you select an action to obtain a goal. Promote one and inhibit another through D1/D2
- Shakin in parkinsons cause hard to focus on on signal.
but REFLEXIVE movements are fine: react and think quickly cause bypassing striatum
Whats the mesolimbic pathway
Part of A10 cell group in VTA (ventral tegmental area)
Mesolimbic dopamine pathway: projects to things within the limbic system (Nucleus accumbens (ventral striatum) amygdala, (hippocampus)
○ Forwards locomotion towards something
○ Reward and motivational functions
○ Rewarding: pleasureable sensations (HEDONIA) OR motivational aspects (drive our behavior to obtain rewards) the WANTING
§ All rewards increase dopamine increase, but dopmaine dones’t cause the pleasurableness
§ Mesolimbic dopamien does not mediate pleasure
§ It’s the WANTING. It helps you obtain goals, to direct behavior.
§ Also learning to get away from bad things, avoiding things.
What is the mesocortical pathway
2nd VTA pathway
Mesocortical regions: go to PFC
Distinctions
- Project to different targets AND
- Dopamine terminals have fewer reuptake transporters than the other path
○ It hangs out in the cleft of space longer
○ NET, COMT or other enzymes reuptake it.
- PFC: more D1 receptor than D2
- Nucleus accumbnes: Lots of D1 and D2
Cortical dopmaine transmission: cognitive executive function
- Execute behaviors (uses info from everywhere to make complex behavior)
○ Working memory (manipulating lots of info to make plans)
○ Selective attention
○ Cognitive flexibility
○ If its blocked, you get impairments.
- Biphasic (NE too) ○ Optimal range for executive function (to little or too much is bad)
What are the dopamine receptor subtpes?
5 basic dop receptor subtypes
- All metabotropic
- Two families
○ D1D5: similar in structure and pharm (D1-like) both drugs stimulate both
○ D2 like family (D2,3,4) slightly different effects
D1: adenylinc cylase and cAMP synthesis INCREASES (to activeate things like pKA) - there may be other cascades too.
D2: opposite effect
Find d1 and d2 that have all regions that has dopmaine innervation
D345, are more regional variation
D4: cortex prominent
D3: mesolimbic pathways (nucacc amyg)
D5 in cortex but kinda unclear
Neuron might have more than one receptor, but in places like dorsal striatum you have areas that only have 1 type (NACc too)
Describe some differences in D1 and D2 receptors subtypes
D2: both autoreceptors and postsynaptic receptors
- Antagonist: block post synapic signalling and also block autoreceptors. - Increase overall dopamine levels, but post synaptic cells are also blocked and it still won't have an effect - You might get activation of D1 tho. - D2 have higher affinity for dopmaine. ○ High concentrations needed for D1 activation ○ Brain uses different concentrations to do different activites and behaviors.
Some dopammine receptors are heteroreceptors (D2 on glutamate and gaba to mediate)
- Prefrontal cortical glutamate terminals in striatum have D2 recpeotrs, hyperpolarize glutamate terminals to reduce glutamate release - D2 can also be on GABA interneruons which disinhibit pyramidal preftonral projection cells* always think about network level.
What are some non selective dopamine receptor drgus.
Non selective:
Agnoist: apomorphine: all dop receptors
- Like cocaine and amphetamine, induces behavioral activation, increase in locomotor activity. (same if you give more selective for d1 or d2 ex: quinthrole?* for d2)
Antagonist: flupenthixol block all dop receptor (D1D2)
- Reduction on motivated responding
- Higher doses: catalepsy (lack of spontaneous movement)
○ Animal freezes up.
We don’t have a lot of drugs can be selective within a family (D1 same as D5)
Haloperiodol: selective for D2 like family, but binds equally to D2,3,4 (within that family)
Hard to show differences within families
Preferential for some things is super dose dependent!! (not preferential at different oses)
Verydifficult to see effects of the drug!
Always factor in lack of movement (we infer cognition behaviors, its not just cause the animals can’t perform the test as much, not that they have less cognition)
Describe an experiment that shows dopmaine supersentisitivty
How effects change over time
- Repeated use: supersensitivity
- Like antipsychotics.
D2 antagonist (HAL)
Initially Hal blocks effects of the DA agonist (like AMPH)
12th day: no sensitization of AMPH but animals with haloperidol no longer blocked the effects.
- Shows that antipsychotics might stop working over time!
Now you stop giving anything.
AMPH animals have less locomotion than animals that were given HAL for 12 days. Dopamine SUPERSENSITIVITY.
- Is it dopmaine release or change in dopmaine receptors.
- It looks like you get an upregulation
Repeated treatment: show more receptors after chronic antagonist treatment
Drugs like HAL change over time, ability to increase DA over time decreases.
Describe central vs peripheral NE
Central NE in medulla and pons Locus Coeruleus (LC) A6, small nucleus - Sends broad projections throughout the brain - Blue hue (name)
Peripheral: sympatheic system uses this
- Sympatheic ganglia with synaptic ganglia (heart, lungs, gastro) - Hormonal like signal from adrenal glands in the bloodstream
Does not cross due to BBB
Things that activate these systems are similar (stress or arousal of body and brain)
Describe noadrenertic receptor subtypes
We thought DOP was a precursor for NE
- We know more bout NE
All NE are metaobtropic
- Alpha
- Beta
- Distributed widely.
○ Receptors subtype
§ A1: phosphoinostitive system (post syaptic receptors)
□ Agonist: phenlyephrine
□ Antagonist: prazosin
® Effects in body and brain
§ A2: (like D2 receptors) reduce CAMP synthesis
□ Presynaptic (somatodendtritic) autoreceptors and post synaptic receptors) might be a little different. But most drugs will hit both types of autoreceptors
□ Agonist: clonidine (increase NT release)
□ Antagonist: yohimbine
○ Beta: like dop d1 recpetors: enhance cAMP
§ Post synaptic
§ In periphery: on cardiac cells (b1)
□ Non selective
® Agonist: isoprotenerol
Antagnoist: propanolol
◊ Used to treat blood pressure stuff
Describe the role NE plays in arousal
LC neurons when animal is asleep vs awake.
Slow wave: long, corticals synchrony and non rem sleep
Faster irregular: awake, different cortex and different patterns.
LC neurons don’t fire much during sleep.
Rem sleep: LC are totallly off
Medial septum and preoptic area to promote wakefulness.
- Alpha1 or beta injections in these regions, increase time being awake.
Blocked alpha2 or beta receptors with antagnoists: cause sedation.
Describe the role NE plays in cognition
Cognition, pfc
- Attention and working memory - Reduction of NE, impairments (i.e. with reserpine, depletes in whole brain) - With normal aging: slow reduction in noadernergic neurons so these functions are reduced - A2 receptors (presyaptic and postsynaptic in pyramidal cells in pFC)
Working memory experiment: guanfacine: Alpha 2 receptor agonist, more for postsynaptic than presynaptic. It actually stimulates it at the right dose.
- When animals distracted from concentration, old animals lose focus, but with GFC, they did better than normal!
Blocking this gets impairments in working memory.
Giving A2 reception agonist that stimulates postsynaptic receptors MORE like GFC increases NE release and helps working memory. When this is blocked, Working memory is impaired.
Describe how NE works with STRESS.
Inverted U-shaped curve. Can interfere with cognitive functions - STRESS!! - Increase in NE release, detrimental effects - Changes in noadrenaline release.
Experiment: restrained animals, incrase in NE in prefrontal cortex
- Perturbs prefrontal functioning - So that you can FOCUS. Pfc offline. Emergency response, you just want sensory motor affective regions. Shuts down PFC
Driven by activation postsyaptic alpha 1 receptors (postsyanptic in pFC)
- Impairs cognitive functions (same as the way stress impairs it) - Excessive activation of alpha 1 (with agnoist) look similar as restraint or stressful. - Antagonizing it can help stress induced impairments!! - Ne has higher affininty for PFC alpha 2 receptors vs alpha 1 (so only at a higher release will 1 get activated) (same as D2 to D1) ○ At low levels it alpha 2 ○ At higher levels, alpha 1 is activated and overrides alpha 2.
Describe how NE modulates memory. Describe an experiment and a clinical implication.
Memory modulation: enhance memory consolidatoion
- Strong emotional states
- Emotional stories have recollection
- Dinner a few weeks ago vs concert, a sad time
○ Bad things you wanna avoid (how to get out of it)
○ Good things you wanna repeat
Experiment
Ones with emotional narrative: showed better recall
Beta Blocker group: even though these subjects had the same experience, neutral story: do not impair memory formation in general, but blocked NE transmission did NOT show enhanced memory.
- Ability to enhance memories was reduced
- Must to happen DURING THE EVENT!! Not hours after.
- Increase in the amygdala, this enhances other types of memories (emotional/fear memories) but wired to other memories (hippocampal declarative memoreis) ○ By turning on amy with NE, causes other brain regions to encode memory better
Might underlie PTSD : supermemories of bad events.
- Disaster, violence, war: intrusive, trigger same fear as in the same situation - In the future: traumatic event, give Beta blockers help offset enhanced consolidation during stressful events.
