5 Catecholamines as neurotransmitters

From: <a href="http://fblt.cz/en/skripta/regulacni-mechanismy-2-nervova-regulace/5-neurotransmisni-systemy/">4. Neurotransmitter Systems • Functions of Cells and Human Body</a>
Catecholamines as neurotransmitters

Catecholamines (noradrenaline, adrenaline and dopamine) are important neurotransmitters in the CNS. In this chapter we will mostly cover the functions of the noradrenergic and dopaminergic systems.

Synthesis and inactivation of catecholamines

All catecholamines are derived from the aromatic amino acid L-tyrosine (or from phenylalanine via tyrosine). Their structure contains a catechol ring – benzene ring with two hydroxyl groups – with a side chain containing an amino group.

The conversion of tyrosine to adrenaline occurs in the following steps:

1) Ring hydroxylation

2) Decarboxylation – formation of dopamine

3) Side chain hydroxylation – formation of noradrenaline

4) N-methylation – formation of adrenaline

1) Tyrosine hydroxylation

In the first step L-tyrosine is converted to L-dihydroxyphenylalanine (L-DOPA). The reaction is catalysed by tyrosine hydroxylase, the rate limiting enzyme for catecholamine synthesis. The main regulatory mechanism is feedback inhibition by catecholamines.

2) DOPA decarboxylation

In the second step L-DOPA is decarboxylated to the biogenic amine 3,4-dihydroxyphenylethylamine – dopamine. This reaction is catalysed by DOPA decarboxylase a.k.a. aromatic L-amino acid decarboxylase (LAAD) as it can decarboxylate other aromatic amino acids (see also serotonin synthesis).

Clinical correlations:

Alpha-methyldopa, is a competitive inhibitor of DOPA decarboxylase and is used to treat hypertension.

Catecholamines are unable to cross the blood-brain barrier (BBB) and must be synthesised directly in the CNS. Parkinson’s disease is characterised by an insufficient formation of dopamine in the brain and L-DOPA as a dopamine precursor can be used for its treatment because it can cross the BBB.

3) Dopamine hydroxylation

The third step is the hydroxylation of the dopamine side chain and the formation of noradrenaline. This reaction is catalysed by dopamine beta-hydroxylase.

4) Noradrenaline N-methylation

The last step is the methylation of the noradrenaline amino group and the formation of adrenaline. This reaction is catalysed by phenylethanolamine-N-methyltransferase (PNMT) with S-adenosylmethionine as its co-substrate and methyl group donor. The activity of this enzyme is positively regulated by glucocorticoids (cortisol) formed in the adrenal cortex and transported into the medulla via the suprarenal portal system.

The catecholamine signal is terminated by the re-uptake of the neurotransmitter and subsequent intracellular inactivation. The two enzymes catalysing this inactivation are:

1) Catechol-O-methyltransferase (COMT)

catalyses the transfer of a methyl group from S-adenosylmethionine to a catechol hydroxyl group causing the following transformations:

Noradrenaline → normetanephrine

Adrenaline → metanephrine

Dopamine → 3-methoxytyramine

2) Monoamine oxidase (MAO)

catalyses the oxidative deamination of aromatic monoamines resulting in the formation of an aldehyde group, which is subsequently oxidised by an aldehyde dehydrogenase to a carboxyl group. This sequence is responsible for the following transformations:

Metanephrine or normetanefrin → vanillylmandelic acid (VMA)

3-methoxytyramine → homovanillic acid (HVA)

MAO is a mitochondrial enzyme bound to the outer mitochondrial membrane. It is a flavoprotein – contains a covalently bound FAD. There are two types of MAO in humans, MAO A and MAO B. Both types are found in the nervous tissue, MAO A also in the liver and GIT and MAO B also in platelets.

Clinical correlation:

MAO inhibitors (MAOI) are used to treat depression.

Vanillylmandelic acid is excreted mainly in the urine and its excretion can be used to estimate the production of catecholamines in the organism. It is mainly used when an adrenal medulla tumor (pheochromocytoma) is suspected.

Let’s now have a look at individual catecholaminergic systems.

Noradrenergic system

Noradrenaline in the CNS mainly regulates the activity of other neurotransmitter systems. Noradrenergic pathways increase or decrease the excitability of target areas depending on the receptors expressed and other poorly understood mechanisms. Noradrenergic pathways can thus regulate both the excitatory function of glutamate and the inhibitory function of GABA.

Noradrenaline binds to specific receptors in the target cell’s membrane. There are four subtypes of adrenergic receptors in the CNS:

1) α1 receptor

Present in postsynaptic neurons, mediates excitatory effects of noradrenaline.

2) α2 receptor

Present mainly in presynaptic terminals and mediates inhibitory effects. Its main role is in feedback inhibition of noradrenaline release in the synapse.

3) β1 receptor

Neuronal receptor with excitatory effects.

4) β2 receptor

In the CNS mainly expressed in glial cells. Latest research shows that beta-2 receptors mediates the integration of the nervous and immune systems. The exact physiological role is being studied.

Noradrenergic neurons are found in the brainstem, particularly in the locus coeruleus (group A6), tegmentum and the reticular formation of the medulla and pons (groups A1, A2, A5, A7).

1) Locus coeruleus

Axons of neuron in the locus coeruleus project virtually to all CNS regions. This system modulates the excitability of other projection systems and regulates attention, arousal, sleep cycle and response to stress. Projections into association cortical areas influence emotional behaviour.

2) Neuronal groups of the tegmentum and reticular formation

Neurons of these groups project into the spinal cord, brainstem, hypothalamus and the limbic system, particularly into regions responsible for the regulation of visceral functions.

In the spinal cord they regulate the excitability of anterior horn motoneurons.

The reticular formation contains a smaller group of neurons releasing adrenaline with projections similar to those of locus coeruleus. It is thought that they cooperate with noradrenergic neurons in the regulation of alarm reaction and adaptation to stress.

Clinical correlation:

The catecholaminergic hypothesis aims to explain the pathogenesis of affective disorders such as depression primarily as an hypoactivity of noradrenergic projections from locus coeruleus into certain cortical areas (with a concomitant disorder of the serotonergic system).

Dopaminergic system

Dopamine in the CNS plays an important role in the regulation of motor functions, initiation of behavioural patterns and modulation of visceral functions.

Five dopamine receptors have been identified to date, which are all coupled to a G-protein regulating adenylate cyclase activity. They can be divided into two groups depending on whether they activate AC via a Gs protein (D1, D5) or inhibit it via a Gi protein (D2, D3, D4). The density of various receptor subtypes differs in different areas of the CNS, e.g. cortical motor areas are rich in D2 receptors while the limbic system mainly expresses D3 and D4 receptors. Adrenaline and noradrenaline act as partial agonists on most dopamine receptors.

Dopaminergic neurons can be found in the mesencephalon and hypothalamus. From a functional point of view several distinct dopaminergic projections are described.

1) Nigrostriatal projection

Neurons form the pars compacta of substantia nigra project mainly into the striatum, globus pallidus and putamen and as such influence the functioning of basal ganglia. They play a role in the planning and execution of cortical activities with their main effect on motor cortex.

Decreased function of this projection manifests as tremor at rest, bradykinesis, muscle stiffness and impaired posture. Damage to these neurons may be caused by idiopathic degenerative processes (Parkinson’s disease) or atherosclerotic narrowing of the blood vessels (parkinsonism).

2) Mesolimbic projections

Dopaminergic neurons from the ventral tegmentum and mesencephalic reticular formation project into nucleus accumbens, amygdala and hippocampus. They play a role in motivation, reward and punishment, instinctive behaviour and addiction. Their increased activity leads to stereotypical behavioural patterns, repeated movements, etc.

3) Mesocortical projections

Some neurons of the ventral tegmentum and mesencephalic reticular formation also project into prefrontal cortical areas. They influence planning and execution of frontal cortex activities (e.g. attention) and affect initiation of behaviour.

Mesolimbic and mesocortical projections are closely related and are the target of some antipsychotic drugs in the treatment of schizophrenia, obsessive-compulsive disorder, attention deficit/hyperactivity disorder and Tourette’s syndrome.

4) Tuberoinfundibular projections

Inhibit prolactin secretion.

5) Intrahypothalamic projection

Plays a role in modulating various visceral functions.

Clinical correlation:

It is currently thought that schizophrenia is at least partly caused by an excessive activity of the mesolimbic system and a deficient activity of the mesocortical system.

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Serotonergic system

The serotonergic system plays a similar role in the CNS as the noradrenergic system. It regulates a range of functions and modulates the activity of other projection systems. It often innervates the same structures and functionally complements noradrenergic afferents.

Seven types of serotonin receptors have been identified to date, 5-HT1-7R, some of which are inhibitory and some excitatory. The effect of serotonin depends on their localisation and the types of receptors expressed.

Serotonergic neurons can be found in raphe nuclei of the reticular formation, which can be divided into a rostral past with ascendent projections and a caudal part with descendent projections.

1) Ascendent serotonergic system (nc. raphe dorsalis, nc. raphe pontis centralis superior)

This system projects into the cortex, some limbic structures (hippocampus, amygdala), basal ganglia, many hypothalamic nuclei and areas and some thalamic nuclei.

It is important for the regulation of emotional behaviour, hypothalamic functions and the sleep cycle. It also modulates information processing in sensory areas (e.g. visual cortex).

2) Descendent serotonergic system (nc. raphe pontis, nc. raphe magnus, nc. raphe obscurus)

Projections from these structures project mainly to more caudal parts of the CNS: brainstem, cerebellum and spinal cord.

Caudal neurons influence pain perception via projection into posterior horns of the spinal cord. An increased activity of the serotonergic system potentiates the effect of analgesics and is essential for the effect of opiates. Their projections also modulate the excitability of preganglionic neurons of the autonomous nervous system and stimulate motor neurons in the anterior horns of the spinal cord.

Clinical correlation:

Drugs in the group of specific serotonin re-uptake inhibitors (SSRI) increase the activity of the serotonergic system and are used to treat patients with unipolar depression. Unfortunately they also decrease libido and cause food intake disorders, usually hyperphagia.

Synthesis and inactivation of serotonin

Serotonin is derived from L-tryptophan, chemically it is 5-hydroxytryptamine. Its synthesis occurs in two steps:

1) Tryptophan hydroxylation

Tryptophan is hydroxylated to 5-hydroxytryptamine, the reaction is catalysed by tryptophan hydroxylase, which is the rate limiting enzyme of serotonin synthesis.

2) Decarboxylation

Decarboxylation of 5-hydroxytryptophan gives rise to 5-hydroxytryptamine, i.e. serotonin, which is thus a biogenic amine (together with all catecholamines). This reaction is catalysed by aromatic L-amino acid decarboxylase (LAAD, see catecholamine synthesis), in this case also called 5-hydroxytryptophan decarboxylase.

Serotonergic neurotransmission is terminated by the reuptake of serotonin and its subsequent intracellular metabolism. The inactivation of serotonin is catalysed by two enzymes – monoamine oxidase (MAO) and aldehyde dehydrogenase (see catecholamine inactivation).

The product of serotonin inactivation is 5-hydroxyindoleacetic acid, which is mostly excreted in urine conjugated with glucuronic acid. It is used as a diagnostic marker for neuroendocrine tumours secreting serotonin (formerly carcinoid).

Serotonin also starts another metabolic pathway leading to the hormone melatonin. The amino group of serotonin is first acetylated and the resulting N-acetylserotonin is the methylated on the indole hydroxyl group to form melatonin.

Historical note:

The name serotonin points to its discovery as the substance in the serum, which affects smooth muscle tone.