Noradrenaline · Grey Matter

Noradrenaline (norepinephrine) is the neuromodulator of arousal and alertness: released across almost the whole brain from the locus coeruleus, it raises the gain of cortical circuits so that salient inputs stand out, and it rises with novelty, effort and stress.

Noradrenaline. Noradrenaline (norepinephrine) is the neuromodulator of arousal and alertness: released across almost the whole brain from the locus coeruleus, it raises the gain of cortical circuits so that salient inputs stand out, and it rises with novelty, effort and stress.

It is a catecholamine, made from dopamine by one extra enzymatic step inside the vesicles of noradrenergic terminals. In the brain it comes overwhelmingly from the locus coeruleus, with smaller groups elsewhere in the brainstem; in the body it is the transmitter of the sympathetic nerves. It acts only through metabotropic adrenergic receptors: alpha-1 (generally exciting), alpha-2 (inhibiting, including the autoreceptors on its own terminals) and beta (raising cyclic AMP, favouring plasticity). Its action is ended by reuptake through NET and by MAO and COMT.

It changes how cells respond more than whether they fire. Noradrenaline enhances strong inputs relative to weak ones and sharpens responses, which is the sense of gain.

It rises and falls with state. Release is low in sleep (almost absent in REM sleep), moderate in calm waking and high in stress, and too much impairs the prefrontal cortex while helping fast, habitual responses.

It shifts excitability. By closing some potassium conductances it makes cortical networks easier to drive, one of the ways arousal moves the excitation-inhibition balance.

Noradrenaline turns the volume of the cortex up for what matters now.

It carries no content of its own; it changes how loudly everything else is heard.

Questions: What is the difference between adrenaline and noradrenaline? Chemically they differ by one methyl group: adrenaline is made from noradrenaline by one more enzymatic step, and both act on the same family of adrenergic receptors. The difference is where they are released. Noradrenaline is a neurotransmitter, released by sympathetic nerves onto organs and, inside the brain, by the locus coeruleus onto almost every region. Adrenaline is mainly a hormone, released into the blood by the adrenal medulla, and it barely crosses the blood-brain barrier, so the brain's arousal runs on its own noradrenaline while adrenaline acts on the body. Does emotional arousal, through noradrenaline, push the cortex closer to a seizure? The evidence does not support the simple version of this hypothesis. Arousal releases noradrenaline from the locus coeruleus across the cortex, which raises responsiveness and could plausibly lower thresholds, yet in animal models noradrenaline mostly protects against seizures and damage to the locus coeruleus makes seizures worse. At the same time, people with epilepsy report stress as one of their most common triggers, and diary studies find more seizures after stressful days. The link between arousal and seizures is real at the level of reports and statistics, and the route, through noradrenaline, cortisol, lost sleep or something else, remains open. How can a nucleus of a few tens of thousands of neurons supply noradrenaline to the whole cortex? Stereological counts find about 16,000 neurons on each side of the human locus coeruleus (roughly 12,000 to 25,000 per side), and counts of the pigmented cells give totals of about 22,000 to 51,000. Each of these neurons has an axon that branches enormously, running through the forebrain and cerebellum and releasing noradrenaline from swellings (varicosities) all along its length, often away from classical synapses. Noradrenaline then diffuses and acts on receptors over a wide volume. The design suits a state signal: a small, internally coupled population can switch the whole brain toward alertness at once, at the cost of saying little about any specific place.