Which group of neurons releases the neurotransmitters epinephrine and norepinephrine?

Introduction

Norepinephrine (also called noradrenaline) is a neurotransmitter in both the peripheral and central nervous systems. Norepinephrine produces many effects in the body, the most notable being those associated with the ‘fight or flight’ response to perceived danger. The effects of norepinephrine and a related catecholamine, epinephrine (also called adrenaline), are mediated by the family of adrenergic receptors. The chemical structure of norepinephrine, as shown in Figure 1, indicates that it is a catecholamine because it has both the catechol moiety (two hydroxyl groups on a benzene ring) and an amine (NH2) group.

Structure and Biosynthesis of Noradrenaline

Noradrenaline, a catecholamine, is derived from l-tyrosine, an aromatic amino acid present in the body fluids and taken up by noradrenaline-producing cells. Through various intermediate steps (Figure 1), l-tyrosine is converted to noradrenaline and, finally, to its methylated form, adrenaline, in phenylethanolamine N-methyltransferase-containing cells. The first cytosolic enzyme, tyrosine hydroxylase, is inhibited by excess production of noradrenaline and is the rate-limiting step in the regulation of noradrenaline synthesis. Tyrosine hydroxylase is found only in the cytosol in catecholamine-containing cells and is used as a marker for detection of adrenergic neurons. Dopamine β-hydroxylase is also used as a selective marker for catecholamine-containing cells, but it is located in the secretory vesicles, usually membrane bound; however, a small amount is soluble and released with the vesicle contents upon exocytosis.

Neurochemistry of norepinephrine

Biosynthesis of Catecholamines

Norepinephrine is synthesized in neurons starting with the amino acid tyrosine, which is obtained from the diet and can also be synthesized from phenylalanine. Tyrosine is converted to dihydroxyphenylalanine (DOPA) by the enzyme tyrosine hydroxylase; DOPA in turn is converted to dopamine in the cytoplasm. Dopamine, also a neurotransmitter, is taken up into vesicles and converted to norepinephrine by the enzyme dopamine β-hydroxylase. In the adrenal medulla and in a few brain regions, norepinephrine is converted to epinephrine by the enzyme phenylethanolamine N-methyltransferase. The biosynthesis of the catecholamines is summarized in Fig. 2.

Figure 2. Biosynthesis of catecholamines.

General information

Noradrenaline is a catecholamine with agonist effects mainly at alpha-adrenoceptors. It is still occasionally used to maintain blood pressure in acute emergencies.

Norepinephrine

Norepinephrine plays a role in vigilance and conditioned fear, and therefore should also modulate unconditioned fear. Norepinephrine was shown to increase in the hippocampus in mice exposed to a cat and in the bed nucleus of the stria terminalis of rats exposed to synthetic fox odor. Complementary to increases in norepinephrine, blockade of norepinephrine neurotransmission in the bed nucleus of the stria terminalis with local infusion of clonidine, decreased unconditioned fear-related freezing responses to synthetic fox odor. Furthermore, in a drug schedule of intermittent methylphenidate treatment for 3 weeks that sensitizes dopamine and norepinephrine systems, rats given yohimbine, which facilitates norepinephrine neurotransmission, displayed increased avoidance of a predator odor. Together, the studies confirm that norepinephrine neurotransmission is important for unconditioned fear to predators and predator odors.

Action of Noradrenaline (Norepinephrine)

Noradrenaline (norepinephrine) is found in cell bodies in the pons and medulla. These bodies project neurons to the hypothalamus, thalamus, limbic system and cerebral cortex. It comes as no great surprise, therefore, to discover that noradrenaline contributes to control of mood and arousal and can affect sleep patterns.

Depletion of noradrenaline (norepinephrine) in the brain has been shown to cause a decrease in drive and motivation and might be linked to depression. It is part of the ‘fight or flight’ response, which increases heart rate, etc.

NA Phenotype

NA is a major neurotransmitter of the ANS, especially in sympathetic neurons, and fundamentally mediates the function of the ANS. Consistent with this, a rare human disease called the dopamine β-hydroxylase deficient disease, in which NA is undetectable, was identified to be associated with severe autonomic function failure [28]. NA is one of the catecholamine neurotransmitters that are synthesized from tyrosine by three consecutive enzymatic steps. While tyrosine hydroxylase is responsible for the first step of catecholamine biosynthesis, converting tyrosine to L-dopa, and is expressed in all catecholamine neurons, dopamine β-hydroxylase (DBH) is responsible for conversion of dopamine to NA and is specifically expressed in NA neurons. Thus, DBH is a hallmark protein of NA neurons and the control mechanism of its expression is an essential feature of the development of NA neurons.

Impaired Neuronal Noradrenaline Reuptake

Neuronal NA reuptake may be impaired in essential hypertension, perhaps due to dysfunction of the NA transporter, and might contribute to the development of essential hypertension (Fig. 2). We have further tested this proposition by applying specific radiotracer methods and using pharmacological blockade of NA transport. The fractional extraction of plasma-tritiated NA in passage through the heart, determined mainly by neuronal NA uptake, was found to be reduced in essential hypertensive patients, as was the cardiac release of the tritiated NA metabolite, tritiated DHGP, produced intraneuronally by monoamine oxidase after uptake of tritiated NA by the transporter. The reduction in NA transport in response to its blockade with the tricyclic antidepressant desipramine was found to be less pronounced in hypertensive patients. These findings strongly suggest that neuronal reuptake of NA is impaired in essential hypertension. By amplifying the neural signal, such a defect could constitute a neurogenic variant of essential hypertension. No mutation in the NA transporter gene that might explain this phenotype has been found.

DA and NE

NE is formed from DA and shares many of its basic characteristics. Acute exposure to stress causes an activation of NE neurons in the locus coeruleus and an increase in both the synthesis and release of NE. The exact relationship between these events and stress-induced changes in DA are unclear. NE terminals in the prefrontal cortex modulate the dopaminergic responses to stress and interactions between NE and DA in the prefrontal cortex modulate synaptic function interactively.31 In fact, the NE transporter, rather than the DA transporter, is responsible for the reuptake of DA within the prefrontal cortex.32,33 The NAC and striatum, on the other hand, exhibit increases in dopaminergic activity with stress but are NE-poor regions; presumably, NE–DA interactions have little significance in these regions. However, novel roles for the NE-rich bed nucleus of the stria terminalis in mediating polysynaptic responses to stress and drugs of abuse have recently been implicated and are a current area of intense scrutiny.34