Lecture 3 - Noradrenaline

Noradrenaline (NA) called norepinepherine (NE) in U.S. acts as a hormone outside the central nervous system (produced by adrenal glands & released into bloodstream) acts as a neurotransmitter within CNS (produced by noradrenergic neurons & released into synaptic cleft) broadly similar behavioural functions in each – physiological activation, arousal, stress responses, anxiety

Noradrenergic systems

Noradrenaline (NA) noradrenergic projections from locus coeruleus (in brain stem) to many different brain areas these diffuse projections reflect the role of NA in determining the general level of behavioural activation & arousal important role in alertness & attention increased activity in locus coeruleus associated with stress, anxiety & panic

Drugs that reduce NA levels in the brain often have sedative (alertness reducing) & anxiolytic (anxiety reducing) effects alpha blockers (e.g. clonidine) beta blockers (e.g. propranolol) mainly prescribed as antihypertensives (i.e. to reduce blood pressure) and for management of heart conditions (arrhythmias, angina) – because these drugs also block noradrenaline receptors in the heart and blood vessels

Clonidine & cognitive performance 0.2 mg = twice typical clinical dose for high blood pressure (hypertension) reduces levels of NA in the brain mimics effects of naturally occurring low arousal states (e.g. sleep deprivation) increases feelings of fatigue & reduces alertness impairs performance on a wide range of tasks increases mean response time on simple reaction time tasks by about 20% occasional very long responses on tasks = attention lapses

Effect of 0.2 mg clonidine on a simple reaction time (SRT) task – Smith et al 2003, Journal of Psychopharmacology 17, 283-292

Beta blockers beta blockers have been used to reduce ‘performance anxiety’ (or ‘stage fright’) by professional musicians, and in some sports (especially shooting) reduction of NA levels in the brain by the beta blocker propranolol has also been shown to specifically reduce memory for emotionally arousing stimuli, while leaving non-emotional memories relatively unaffected -

Propranolol & emotional memory van Stegeren et al (1998) 75 subjects randomly allocated to one of 3 drug groups – either received placebo, propranolol, or nadolol (a drug that mainly reduces peripheral, rather than central, noradrenergic activity) in a double-blind procedure all subjects then watched identical slide-show, but auditory commentary was manipulated within groups (either ‘neutral’ or ‘arousing’)

Narratives accompanying slide presentation Neutral version Phase 1 1. A mother and her son are leaving home in the morning. 2. She is taking him to visit his father's workplace. 3. The father is the chief laboratory technician at the nearby hospital. 4. They check before crossing a busy road. Phase 2 5. While walking along, they pass the scene of a minor accident, which the boy finds interesting. 6. At the hospital, the staff are preparing for a practice emergency drill, which the boy will watch. 7. All morning long, surgeons practised the standard emergency drill procedures. 8. Special make-up artists were able to create realistic looking injuries on actors for the drill. Phase 3 9. After the drill, while the father stayed with the boy, the mother left to phone her other child's pre-school. 10. Running late, she phones the pre-school to tell them she will soon pick up her child. 11. Heading to pick up her child, she hails a taxi at the number nine bus stop. Arousing version Phase 1 1. A mother and her son are leaving home in the morning. 2. She is taking him to visit his father's workplace. 3. The father is the chief laboratory technician at the nearby hospital. 4. They check before crossing a busy road. Phase 2 5. While crossing the road, the boy is struck by a runaway car, which critically injures him. 6. At the hospital, the staff prepare the emergency room, to which the boy is rushed. 7. All morning long, surgeons struggled to save the boy's life. 8. Specialized surgeons were able to successfully reattach the boy's severed legs. Phase 3 9. After the surgery, while the father stayed with the boy, the mother left to phone her other child's preschool. 10. Feeling distraught, she phones the pre-school to tell them she will soon pick up her child. 11. Heading to pick up her child, she hails a taxi at the number nine bus stop.

On a scale of 0 to 10, how emotionally arousing was the story?

Memory for story was tested one week later free recall test – subjects given ‘arousing’ version recalled more details from phase 2 of the story than subjects given ‘neutral’ version no difference between different drug groups for ‘neutral’ story for ‘arousing’ story, propranolol group recalled significantly fewer details than either of the other two groups (difference between placebo and nadolol was not significant) -

Free recall – arousing story

recognition memory test – 76 multiple choice questions relating to visual information from slides & narrative story elements no difference between different drug groups for ‘neutral’ story for ‘arousing’ version, scores were significantly higher for questions relating to phase 2 than either phase 1 or 3, but only in subjects given placebo or nadolol

for subjects given propranolol, effect of story phase was not significant memory scores for phase 2 (where arousal was induced) were significantly lower for subjects given propranolol compared to the other two groups scores in nadolol group did not differ significantly from placebo i.e. lowering brain NA with propranolol specifically impaired memory for the emotionally arousing phase of story

Recognition – arousing story

Post-traumatic stress disorder (PTSD) pharmacological manipulation of NA may allow possible treatment and/or prevention of PTSD (e.g. van Stegeren, 2005) PTSD is characterized by enhanced & intrusive memories following a traumatic experience it has been suggested that emergency workers (and military personnel) could be given drugs such as propranolol to reduce the impact of traumatic experiences on memory this has raised a number of ethical concerns – see Henry et al (2007)

Drugs that increase NA levels in the brain often have psychostimulant (alertness increasing) & anxiogenic (anxiety producing) effects – e.g. amphetamine, ephedrine, yohimbine some antidepressants also raise levels of NA monoamine oxidase inhibitors (MAOIs) inhibit enzymatic breakdown of NA, dopamine & serotonin tricyclic antidepressants inhibit reuptake of NA & serotonin increases in NA can improve energy levels, concentration, cognitive performance

Amphetamine increases release of both noradrenaline and dopamine also blocks reuptake of these neurotransmitters (so they remain longer in synaptic cleft and can bind to receptors again) acute effects – euphoria; increased subjective energy, alertness & confidence; racing thoughts; increased motor activity & speech

Amphetamine & cognitive performance LOW (5-30 mg) oral dose: faster reaction times in simple psychomotor tasks & improved vigilance performance reduces effects of sleep deprivation HIGH dose: impaired task performance increased distractibility anxiety

Inverted-U relationship (Yerkes-Dodson law) Increase in psychostimulant drug dose →

inverted-U relationship between arousal & task performance (Yerkes-Dodson law) being either under-aroused (fatigued, bored) or over-aroused (anxious, excited) can impair task performance so, increasing arousal with psychostimulant drugs can either improve performance (if arousal is low) or impair performance (if arousal is already high)

optimal level of arousal also depends on task complexity or difficulty - optimal level is lower for more complex tasks

so, effect of psychostimulant drugs also depends on task demands - more likely to improve performance on simple tasks (e.g. SRT, vigilance) more likely to impair performance on complex tasks (e.g. driving – see Silber et al, 2005)

Effect of 0.42mg/kg oral amphetamine on driving simulator performance – Silber et al (2005) compared to placebo, amphetamine – reduced signalling (e.g. at junctions & when changing lanes or over-taking) increased likelihood of driving through red lights decreased speed in simulated motorway driving – which may reflect a strategy to compensate for experienced difficulties

Silber et al (2005) suggest that high doses of amphetamine can lead to an experience of ‘sensory overload’ if subject is engaged in a complex task (e.g. driving), they may adopt a strategy of ‘attentional narrowing’ or ‘tunnel vision’ in an attempt to cope with overload i.e. they try to focus on ‘central’ aspects of task (e.g. controlling speed, staying in lane) but fail to attend to peripheral aspects (e.g. signalling) & cues (e.g. road signs)

Attention-Deficit / Hyperactivity Disorder (ADHD) estimated to affect ~ 5% of the population a ‘developmental disorder’ - usually presents during childhood inattention and/or hyperactivity plus forgetfulness, impulsivity, distractibility website: www.adders.org/info.htm

ADHD reduced levels of noradrenaline are implicated in ADHD often treated with psychostimulant drugs: – amphetamine (Dexedrine, Adderall) – methylphenidate (Ritalin) drug side-effects: disturbed sleep, loss of appetite, increased heart rate & blood pressure, palpitations, anxiety

From Zeiner et al (1999): 36 boys aged 7-11 years with ADHD in a double-blind, placebo-controlled, crossover design

ADHD improvements following treatment with psychostimulant drugs suggests chronic under-arousal in ADHD behavioural abnormalities (e.g. hyperactivity) may be attempts to increase arousal to optimal levels (see White, 1999)

ADHD drugs with selective noradrenergic actions are now being used to treat ADHD atomoxetine - noradrenaline reuptake inhibitor these drugs don’t also stimulate release of dopamine (unlike psychostimulants) no euphoric ‘high’, so less likely to be abused

NT re-uptake

Reuptake inhibitor blocks transporters - so NT concentration increases

Double-blind placebo-controlled study of atomoxetine in children & adolescents with ADHD - Michelson et al 2001, American Journal of Psychiatry 159, 1896-1901 p ≤ .001 at points marked ‘b’

Noradrenaline (NA) - summary important role in alertness, attention & anxiety drugs that reduce noradrenergic neurotransmission (alpha- & beta-blockers) have sedative & anxiolytic effects drugs that increase noradrenergic neurotransmission have psychostimulant & anxiogenic effects noradrenergic psychostimulants (e.g. amphetamine) may either enhance or impair cognitive performance, as predicted by the Yerkes-Dodson law drugs that increase noradrenergic neurotransmission are used to treat attention deficit / hyperactivity disorder (ADHD)

Learning outcomes Be able to describe how manipulating levels of noradrenaline in the brain affects mood and task performance. Understand the basis for using noradrenergic beta-blockers (e.g. propranolol) to reduce the incidence of post-traumatic stress disorder, and the ethical issues raised by this. Be able to describe the effects of amphetamine on task performance, with reference to the Yerkes-Dodson law. Understand why psychostimulant drugs are used to treat ADHD, why there may be concerns over long-term use of these, and what alternatives are available.

Recommended reading M Henry et al (2007) Propranolol and the prevention of post-traumatic stress disorder. The American Journal of Bioethics 7, 12-20 BY Silber et al (2005) The effects of dexamphetamine on simulated driving performance. Psychopharmacology 179, 536-543 AH van Stegeren et al (1998) Memory for emotional events. Psychopharmacology 138, 305-310 AH van Stegeren (2005) Beta-blockers in post-traumatic stress disorder. Expert Reviews in Neurotherapeutics 5, 699-702 JD White (1999) Personality, temperament and ADHD. Personality & Individual Differences 27, 589-598 P Zeiner et al (1999) Response to methylphenidate in boys with ADHD. Acta Paediatrica 88, 298-303