L05 The Adrenergic System

Abbreviations

• Adrenaline (ADR) = Epinephrine (EPI)

• Noradrenaline (NA) = Norepinephrine (NE)

• Related to ADR or NA = adrenergic or noradrenergic

• Though ADR and NA share features, they also have important differences

• Our focus is NA, as it is more important to the brain

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• notably, noradrenaline is more important within the brain

ADR + NA

• Monoamine (w/DA + 5-HT) and catecholamine (w/DA only) families

• Catecholamines have a similar structure as well as shared synthesis + metabolism pathways

  • Numerous implications, including shared drug sensitivity

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• in group of DA, which is why it is affected by same compounds

• hence, ADHD drugs affect both dopaminergic + adrenergic systems

ADR + NA Synthesis

• Begins w/dopamine (DA) production (see L04)

• DA then reacts with the enzyme dopamine-B-hydroxylase to produce NA

• Enzymes act on NA to produce ADR

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• tyrosine → DA → NA→ adrenaline

• LHS: fine print where synthesis is occurring → neurons that make DA that don’t have to make NA in their vesicles

  • make DA and if you’re the right type of neuron → you turn that into something else (NA made by vesicles in NA neurons) → NA important in brain

  • in periphery, ADR important, made by adrenal glands → most doesn’t reach the brain

Metabolism

• • Metabolized by COMT (1) and MAO (2)*

  • MAO inhibitors for depression, COMT + MAO inhibitors for Parkinson’s (adjuncts)

• MHPG is a metabolite (surrogate measure of NA)1-4 • Bipolar disorder, eating disorders, gambling disorders, PTSD (recall: weak correlations + not strong enough to be diagnostically useful)

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• catechol-O-methol transferase (COMT) → acts on catecholamines, including DA and NA

• NA also a monoamine and can also be targeted by monoamine oxidase (MAO)

• therefore 2 metabolic routes for NA

• with COMT/MAO inhibitor → will affect breakdown of NA and other NTs → such compounds associated w higher NA levels

• MAO inhibitors used for depression

• COMT + MAO inhibitors used for PD

• MHPG (DNM name) → a metabolite important as index of NA (if lots of metabolite in periphery, it may mean lots of NA in the brain or somewhere else)

Receptors

ADR + NA:

• alpha 1: Excitatory

• alpha 2: Generally inhibitory

  • α2A, PFC = postsynaptic

  • α2 can be pre-synaptic

• beta: Generally excitatory

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• 3 classes of receptors

• a1 and a2 more well studied + better understood

• significance of pre-synaptic receptors = usually inhibitory (often for turning off)

  • lever for shutting things is AP at axon hillock

• presynaptic usually a2

Receptor affinity

• Strength of binding between agent and receptors

• Receptor affinity varies across subtypes

• Some receptors are fully active at low NA levels (high affinity, α2) whereas other require higher levels (low affinity, α1)

  • At low NA concentrations, α2 more active (receptor is high affinity)

  • At high NA concentrations, both α2 and α1 are active

  • Relevant to theories of noradrenergic function (e.g. PFC for working memory)

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• a1 has this affinity for NA = strength of association for those 2 things

• high affinity of receptor for agent = strong bond, meaning a very low concentration of agent is needed to bind all receptors

  • low affinity = need lots of agent for receptors to be bound

• when we know affinity, we know how much agent is needed to bind receptors

• leads to concept that if agent is of low concentration, this means only high affinity receptors are bound

  • if concentration of agent high, we expect low + high affinity receptors to be bound

• stress or arousal = situations where NA and ADR concs vary

Where do we find NA-releasing (adrenergic) neurons?
The NA system

• Widely distributed across PNS and CNS

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• noradrenergic neurons in CNS but also PNS, which branches into autonomic > sympathetic division

NA system (Central) – Main area

• The locus coeruleus (LC) contains most of the NA neurons in your brain

• Small (~30 000 neurons) but has many projections

• LC innervation of the hippocampus, prefrontal cortex and basolateral amygdala is critical (projections to these areas)

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• PFC innervation may be important for attention, hippocampus innervation for memory, etc.

About the LC

• Tonic (maintained) and phasic (brief) firing (L04)

  • Tonic correlates with overall arousal state (~ exploration)

    • like states of awake, alert, drowsy, asleep, deep sleep, etc. (like walking around env, taking in sights)

  • Phasic correlates w/specific responses (~ exploitation)

    • interacting intensively for a brief episode

• Controlled stimulation of the LC (e.g. via optogenetics) can have strikingly different effects on the brain1

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• demonstrates tonic firing (maintained all the time but tends to be low) even when nothing special is going on

• potential for great increase in firing rate in short time interval = phasic firing (phasic bursts + tonic over long time)

• theory - activity firing associated w different things

• diagram - stress is associated w change in firing rate of these neurons

  • acute stress = high tonic rate

  • CRF = neuropeptide released by brain to initiate response to acute stress

The NA system (Peripheral)

• The ANS is involved in automatic, involuntary changes in organ function

• The ANS has sympathetic and parasympathetic divisions (SNS + PNS)

• SNS = “fight or flight”]

  • often NA signal is major NT

• PNS = “rest and digest”

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• PNS component where we find these cells → part of sympathetic division (LHS)

  • recall PNS = everything not at the midline + not encased in bone, so NS in contact w organs → in some fibers in sympathetic division, NA signaling happens

The NA system (Peripheral)

• Certain effects – like pupillary diameter – are going to be important later

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• target organ = NA in SNS (contact/signaling to organ is via NA)

• importantly, neurons in brain in LC are noradrenergic → involved in affecting organ function in many stress + arousal-like states + flight/fight (speeding up heart, changing breahting)

  • notably an effect is pupillary diameter → index of SNS activation

Indexing adrenergic function

• Pupillary diameter measures (SNS marker)

  • note: not a LC marker

• Salivary amylase (SNS marker)

  • can measure non-invasively

• Metabolite measurement

  • MHPG

• MRI adapted for the LC (i.e. LC neuromelanin MRI; see L4)

  • MRI signals that pick up certain structures associated w noradrenergic transmission

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• in situations where NA levels are high + noradrenergic transmission is significant → we can see this things as indices

Adrenal Gland releases ADR

• Adrenal gland mixture is 80% ADR, 20% NA

• ADR + NA in the blood does not easily cross the BBB

• Direct effects unlikely but indirect possible

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• almost none of ADR/NA gets to brain bc it cannot cross BBB easily

• large amount at periphery released at certain states has peripheral actins that are significant but central actions in brain less significant bc it can’t penetrate

• peripheral effects can indirectly give rise to central effects via indirect mechanisms downstream, even thought ADR + NA doesn’t enter the brain

  • injected mice w ADR in periphery but were found to be smarter due to indirect effects

Rapid effect of adrenergic signalling

• lots of peripheral effects associated w NA signaling

• DN receptor subtype

• when taking a drug, you could predict the type of physiological effect if you know the receptor type involved

• pupil dilation = rapid effect

PNS, SNS + the adrenergic system

• ADR + NA levels vary w states of consciousness

• lower NA/ADR → anticipate more relaxed state

• higher NA/ADR → anticipate more fight/fight state (stress, arousal, etc.)

  • states where sympathetic NS is likely to be more active = more noradrenergic signaling happening

Lower NA/ADR in PNS dominance

• Meditation is associated with lower NA + ADR (depends on style, genetics) → more parasympathetic activation

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• note: it is not just 1 system being on; there is both to various degrees → so one is more dominant

• noradrenaline + adrenaline levels lower in those that meditate and also low in those that meditate regularly

• note crude proxy → looking at diff substance in diff compartment + drawing inferences about what could be going on in brain

Meaning of basal NA/ADR is complex

• Individual variability is high

• Peripheral measures of metabolites may not reflect central activity of transmitter

• Understanding stress requires measurement of the stress states and coping responses, not just the baseline

• Ignores cortisol

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• hormones often written as ranges because lots of individual variability → eg. log cortisol

  • therefore measurements should also be done at several time points → ideally to capture a change in levels over time bc starting point differs across individuals

Importantly…

• NA + ADR increase during stress and SNS activation

• Though many people might find arousal and SNS activation unappealing (even terrifying), this might not be the case for everyone

• Some might find states exhilarating and actively seek them out

• This brings us to a popular idea…

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“Adrenaline addict”

• A person who engages in high-risk, arousing behaviors for pleasure (thrill-seeker)

  • Extreme sports is a common example

  • Exercise addiction considered separate

• Not a clinical term

  • Except gambling, behavioral addictions are controversial

• Studies are very few and almost entirely psychological (i.e. not neurochemical)

  • ADR released during stress does not enter the brain

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• many behavioral problems aren’t considered addictions, except problematic gambling

NA/ADR in risk-taking

• In humans, NA levels are higher in problematic gambling

• In animals, NA levels are correlated with high-risk, exploratory behaviors

• Genes in the NA system are weakly linked to risk-taking

• Drugs affecting NA levels affect decision-making

SNS activation (w/ADR + NA increases) contributes to stress. However, the SNS is not the only system active during stress.

• NA signaling and its association with SNS activation

• but it’s not the only signaling form that changes in those states

Stress + the HPA axis

• cortisol also changes in states of stress/arousal

• cortisol is likely changes around the same time + likely interacts with NA signaling

Stress and the HPA axis

Comparisons – SNS vs. HPA

• The SNS response is…

  • Involved in the orientation to stressors

  • Fast-acting and short-lasting

• The HPA response is…

  • A defeat response for stressors perceived as uncontrollable

  • Associated w/avoidance, withdrawal and mental illness

  • Slow-acting and long-lasting

• SNS and HPA responses overlap and interact

• Activity of these systems may be abnormal in disorders

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• SNS response occurs first, then HPA response kicks in, but may be both in play at same time

Post-traumatic stress disorder

• lots of study into LT effects of these systems being active on your immune system

• PTSD not only associated w military service, it can be associated w any traumatic event (even witnessing one)

  • is one of the few disorders with a clear cause (anticipant event) → but also outcomes are among the more serious ones → but opportunity for treatment

How might NA and cortisol levels be affected in PTSD?

Cortisol and NA levels in PTSD

• In veterans + others w/PTSD, NA may be higher with cortisol + CRF lower

• Weak cortisol responses to a stressor predict future PTSD

• In the treatment of PTSD, increases in salivary cortisol predict recovery

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• NA levels at baseline are higher in PTSD

• changes in baseline cortisol tone = predictor of recovery

Why does this occur?

• Amygdala activity is affected by baseline cortisol tone

• When tone is moderate

  • stress responses are terminated quickly, NA levels lower

• When tone is weak

  • stress responses stronger, NA levels higher

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• certain healthy cortisol level needed for normal functioning

• lower cortisol = circuits involved in stress responses may be tuned improperly

• baseline cortisol if good but it being too low would mean system responds to strongly and strong stressors go on for too long

NA system in stress

• Though we are discussing PTSD here, these findings might apply more generally to many disorders

• Early life stress is a risk factor for multiple mental health disorders, and has been correlated with alterations in the NA system

• Disrupted NA signaling during adolescence might be associated with long-term consequences in adulthood

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• so both PNS and SNS in play at the same time, but NA is higher and cortisol lower in PTSD

Conscious states

Many states of consciousness might exist. We’re always moving from one to another (e.g. wakefulness to sleep, and from one sleep state to another)

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• noradrenergic signaling can change as you move between states (like from REM to light sleep to awake)

Many functions regulated by NA

• different noradrenergic targets

• there are potential functions of connections from LC to other brain areas → like wakefulness associated w transitions across diff states

Modulation of arousal

• Drugs increasing catecholamine signaling ~ stimulants (e.g. amphetamine - they increase arousal, energy, alertness, etc)

  • Mimic catecholamine release during arousal, affect sleep-promoting + reward circuits

• β1 mutations are associated with familial natural short sleep (also mice)

  • certain families where mutation is seen that allows individuals to function normally even with less sleep (5-6 hrs)

• α1 agonists increase arousal (mechanisms indirect)

• Drugs acting on α2 receptors can be sedative

  • dexmedetomidine (adjunct in anesthesia) inhibits LC

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• drugs that target these receptors affect consciousness/arousal

• LC = major source of noradrenergic innervation → may promote wakefulness → any effect to LC may change wakefulness

Many other signaling systems (and drugs targeting them) might affect arousal. Any guesses?

• melatonin, adenosine, etc.

• biggest one is acetylcholine signaling (cholinergic signaling)

NA signaling in other states

• flow states - state you experience where you are doing well at a challenging activity (time is distorted, you feel fantastic)

Psychological flow

• A subjective experience generated from intense engagement in an activity

  • Loss of self-awareness, sense of surroundings

  • Distorted passage of time

  • Positive valence (i.e. enjoyable)

• Associated with performance and well-being

• Originally proposed based on expert interviews

• Relatively little is known about its neural basis

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• little known about its neural basis → but might have to do something with noradrenergic signaling

Flow + NA signaling

• Subjective flow is related to subjective task difficulty on the n-back

  • U-shaped

• Subjective task difficulty is related to pupil diameter

• U-shaped

• Pupil diameter ~ LC-NA tone (proxy) and other factors

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• correlates of noradrenergic are correlated w flow reports

• pupil diameter associated w subjective reports

• measured both difficulty + measures associated w "flow”

Many functions of NA

• function of NA signaling in attention → in PFC + sensory cortices

NA and attention

• In each environment, we must use the correct cues (relevant stimuli) to guide our behavior

• An attentional set is a set of rules used to determine which stimuli are relevant (in the current env)

  • diff attentional sets across diff envs

• As our environment changes, we must shift between attentional sets

• A model of attentional set shifting in humans is the Wisconsin Card Sorting Task

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Wisconsin Card Sorting Task

• Cards w/symbols varying in shape, color and number

• Subjects must sort the cards according to rules

• Rules change; set shifting is required to perform

• Set shifting is impaired in certain disorders (neurodegenerative disease, depression, SZ + ADHD)

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• task - sort cards according to rules that will be changed throughout game (shape, colour, number)

• this is impaired in disorders

Set shifting involves the PFC…

• …and PFC neurons have receptors for NA

• Trade-off: α1Rs facilitate set-shifting but inhibit working memory

• NA signaling is associated with performance

  • Reduced NA levels are associated w/impairments

  • Adrenergic agonists can affect memory performance

  • Blockers of NA transport associated with improved set shifting

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• neural basis of set shifting → PFC plays a role (PFC neurons sensitive to NA inputs)

• two things to consider: flexibility (shifting b/w sets) + working memory capacity (trade off b/w the two)

  • people good at shifting may have poor memory

  • people poor at shifting may have good memory

In ADHD treatment

• First-line drugs are stimulants; while these work they have side effects and are not suitable in every case

  • DAT + NAT blockers (Methylphenidate)

  • DAT/NAT reversal + release (Amphetamine) → not blockade, reversing how they work

• Also non-stimulant drugs → not associated w arousal/alertness (more focused on effects of NA transport/receptors rather than DA transport)

  • NAT blockers (atomoxetine), ADR receptor agonists (guanfacine, clonidine)

• Recently, centanafadine has attracted interest

  • Blocks NA transport strongly, blocks DA transport moderately

  • Possibly less abuse liability while still having beneficial effects

Many functions of NA

• NA signaling in PFC + amygdala + HPC

Memory

• Process whereby information is stored, consolidated + retrieved

• Several types (or stores) with different properties: sensory, short-term/working + long-term

WM test – monkeys (L02)

• mild food deprivation leads to strong motivation to perform for food

• then shown two wells, one is empty, the other food

• wall is lowered over cage and wells are covered → in order to remember where food is, monkey must maintain mental representation of its location

• this is delay period across memory assays (period where original stimulus removed and monkey can’t see it, so representation is maintained)

• then leave time for response phase

Task-relevant PFC neurons

• To complete the task, the animal must maintain a representation of the stimulus (food in well) and focus on the goal (point to well) during delay

• PFC neurons might fire during the delay period (task-relevant neurons) and such cells could be responsive to NA stimulation*

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• there is representation of information in its absence (during delay period) that allows this task to work

• PFC neurons still fire even when visuals are removed (they are responsive to NA signals)

How does NA affect memory? Does NA make memory better or worse?

WM and NA and Yerkes Dodson Theory

• NA levels vary (e.g. during states of stress/arousal)

• In humans and animals, very low and very high NA levels are associated with impaired WM

• Moderate NA levels appear to be optimal for WM

• If this relationship sounds familiar, it should – you have seen it before!

  • Inverted U-shaped relationship between arousal and performance also appears to exist for WM

WM + the PFC

• The bell shape may be due to receptor affinity

• Only weak α2 at low NA levels; strong α1/α2 at very high NA levels

• Targeting adrenergic receptors to treat cognitive dysfunction (with aging, in ADHD)1-3 ; many studies focusing on guanfacine

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• concentration variation matters bc it reflects a pattern + receptor activation

• in certain individuals, drugs may be helpful bc they push them closer to a sweet spot where' there’s the right proportion of activation of a1 and a2 receptors

Role in asversive/emotional memories

• Memories of arousing experiences tend to be stronger*

  • We are more likely to remember major events (which are arousing) and major details of these events

• Enhanced memory for arousing experiences might involve adrenergic signaling and the amygdala

  • Amygdala damage impairs fear conditioning

  • β-adrenergic antagonists in the amygdala impair fear memories

  • β3-KO mice also show impairments, results in β1/ β2 KO mice more complex

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• NA signaling may play role in aversive memories

  • disrupt such signaling in animals w damage to amygdala → we don’t see such strong memories + no fear conditioning

Therapeutic relevance

• β-adrenergic receptor blocker (propranolol) in PTSD

  • Exposure after trauma may lower risk (inconsistent)

  • If used during memory reactivation, may reduce symptoms

• α1R blocker prasozin used to treat nightmares in PTSD

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• altering emotional character of traumatic memory may be useful in PTSD → target neural basis of memory (target with antagonist + treatment during memory → improvement over time)

• study where those who got into accidents got surgery with anesthetic compounds had lower PTSD risk → perhaps the drug affected the likelihood of PTSD

Adrenergic theory of cognition

• Many different theories

• Effects of NA on memory and attention (psychological processes) are likely the result of effects of NA on neuronal function (physiological processes)

• Roles of adrenergic signaling in cognition might exist due to many effects, including energy metabolism, synaptic plasticity + gain control

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• NA signaling does not just facilitate memory → it may have a role in energy metabolism indirectly, or facilitating synaptic plasticity, gain control (doesn’t just contribute to neural activity)

• not as fleshed out theories though

Adrenergic signaling + mood

• Many mental health disorders are related to stress

  • risk of Anxiety, depression and post-traumatic stress disorder goes up w more stressful life events

• As part of the effects of stress might be due to NA, ADR and cortisol levels, modulating signaling may be therapeutic

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1 – Anxiety

• LC activity likely contributes to the anxiety of stress (due to being primary source of noradrenergic signaling)

• Activating the LC (e.g. w/optogenetics study) increases anxiety-like behavior in the EPM (see L03)

  • less active LC cells would show less anxiety

• Reduced LC activity with therapeutic drugs (e.g. benzodiazepines, SSRIs and MAOis in some cases)

2 – Depression

• Mixed evidence for lower NA levels in depression

• Decreases in NA release (also other NTs) (i.e. with reserpine) are associated with depression-like behavior

• Many antidepressants affect NA metabolism and transport

  • MAOis + SSRIs

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• every signaling compound associated w depression in some way

MAOIs + depression

• Antidepressant action may require long-term adaptations that take place over several weeks

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• antidepressants don’t work right away but may involve long-term changes in NS

• why not right away - because they slowly change your brain

• MAOi → less metabolism → more monoamines → less receptors***

Role of cortisol in depression

• higher cortisol associated w depression

• can be on exam → describe the association of all NTs with depression

Memory, cognition and aging

• cognitive peak likely to come earlier in life

• why? noradrenergic changes

NA system in aging

• Early studies suggested a loss of LC neurons w/aging

• NA levels are lower with age

• These changes may contribute to age-related cognitive decline + disorders such as Alzheimer’s Disease (AD)

• Targeting adrenergic signaling may help with cognitive decline and apathy in AD (more on this later)

  • not usually done, but notably for ADHD where we use drugs to affect noradrenergic signaling to enhance cognition

With aging

• Increase in positive emotions + decrease in negative emotions → due to NA signaling

• Original theories proposed a role for cognitive control + more

• Recent studies propose changes in the CNS (i.e. in the LC) contribute

  • theory = different mechanisms for cog control develop as you age → how you experience emotions become different