Adrenergic nervous system
Adrenergic system is an evolutionarily ancient defence system, which consists of the organs and nerves in which catecholamines adrenaline (epinephrine) or noradrenaline (norepinephrine) act as neurotransmitter or neurohormone. Adrenaline and noradrenaline are released as neurotransmitters from sympathetic nerve endings and as neurohormones from adrenal medulla.
As neurotransmitter, noradrenaline is used in relatively few neurons in the brain, but those send projections to around the brain and exert powerful effects related to anxiety and arousal; noradrenaline is a major neurotransmitter in the peripheral nervous system. Synthesis of noradrenaline begins with hydroxylation of phenylalanine to tyrosine and then, in a rate-limited step catalyzed by tyrosine hydroxylase, into dihydroxyphenylalanine (DOPA). DOPA decarboxylase converts DOPA into dopamine, which is converted into noradrenaline by dopamine β-hydroxylase in the synaptic vesicles. Tyrosine hydroxylase is considered as a marker of sympathetic neurons. Noradrenaline is metabolized by MAO-A and MAO-B, and COMT. Metaraminol is a synthetic noradrenaline analogue that shares the same neuronal uptake, storage, and release pathways, but is not metabolized by COMT and MAO.
Sympathetic nervous system and parasympathetic nervous system are the two main parts of the autonomic nervous system. Noradrenaline is the main neurotransmitter of the sympathetic nervous system, while parasympathetic nervous system is cholinergic.
Sympathetic system has a central role in the development of many cardiovascular diseases, such as essential hypertension and cardiac arrhythmias. Many drugs aim to reduce the activity of sympathetic nervous system, and PET has been used to study the effectiveness of these treatments.
Sympathetic nervous systems consists of two neuron types: pregangliotic, which originate from the thoracolumbar region of spinal cord, travel to ganglions next to the spine, connecting to postgangliotic neurons, which extend to the rest of the body. Pregangliotic neurons are cholinergic, and postgangliotic neurons are adrenergic, releasing noradrenaline in the peripheral nerve terminals. The adrenal medulla works as a distant ganglion, and the cromaffin cells in the medulla as postgangliotic neurons, except that, when activated, they release more adrenaline than noradrenaline. Postgangliotic neurons that have their nerve endings in the kidney release dopamine with noradrenaline.
The synaptic noradrenaline is metabolized by catechol-O-methyl-transferase (COMT) or monoamine oxidase (MAO), or deactivated by reuptake into the presynaptic neuron. After reuptake, noradrenaline is either moved into vesicles by vesicular monoamine transporter (VMAT) or metabolized by MAO in mitochondria.
Sympathetic activity and denervation
Sympathetic denervation can be detected using PET radiopharmaceuticals that are taken up by noradrenaline transporter (NET). Sympathetic activity can be assessed using NET radioligands that are stored in presynaptic vesicles and released from them like noradrenaline.
Catecholamine synthesis rate can be estimated using [18F]FDOPA.
Cold pressor test (CPT)
In the cold pressor test, heart rate and blood pressure is measured before and after hand is immersed into ice water for one minute. Cutaneous application of cold water increases sympathetic neural outflow, increasing arterial pressure and heart rate. Baroreflex returns the heart rate quickly to the normal level. Blood pressure change in CPT provides an approximate index of muscle sympathetic activity. CPT responses are exaggerated in hypertension prone individuals and increased in patients with ischemic heart disease, but impaired in patients with orthostatic hypotension caused by efferent sympathetic failure (Victor et al., 1987). Face cooling and handgrip exercise can also be used as sympathoexcitatory stimuli. CPT with myocardial perfusion imaging (MPI) can be used to assess coronary endothelial function (Schindler et al., 2004; Tuffier et al., 2016).
Adrenergic receptors (adrenoceptors, ARs) belong to the superfamily of transmembrane G protein-coupled receptors. The two main types, α- and β-adrenoceptors are classified into subtypes α1A, α1B, α1D, α2A, α2B, α2C, and β1, β2 and β3. Adrenaline and noradrenaline act as an agonist of all adrenoceptor subtypes, with different affinity: α1AR and β3AR favour noradrenaline over adrenaline; β2AR favours adrenaline over noradrenaline; and α2AR and β1AR usually favour both equally. Adrenoceptors located on the catecholaminergic neurons are referred to as autoreceptors, and those located on non-adrenergic cells as heteroreceptors.
ARs can go through homo- and heterodimerization, even with other receptor types. Agonist binding to ARs will lead to internalization of the receptor, which does not only desensitize ARs, but can also increase AR signalling.
In CNS, α2AAR is widely distributed, constituting about 90% of the α2ARs, while α2CAR (10% of total) is expressed mainly in the ventral and dorsal striatum and hippocampus (Fagerholm et al., 2008; Uys et al., 2017). Specific radiopharmaceuticals for the α2AARs are under development (Krzyczmonik et al., 2019). Density of available α2CARs in the brain can be quantified using [11C]ORM-13070, and the radiopharmaceutical can also be used to detect increase in synaptic noradrenaline levels (Finnema et al., 2015; Lehto et al., 2016).
In peripheral tissues α-adrenoceptors located on vascular smooth muscle cells mediate vasoconstriction. α2-adrenoceptors are also found in renal, pancreatic, hepatic, and adipose tissues (Scheinin & Hietala, 1989). Atipamezole is a specific antagonist for α2-ARs. [11C]yohimbine is an antagonist radioligand which binds with high specificity to all α2-AR subtypes (Jacobsen et al., 2006), and can be used in brain PET for occupancy studies (Laurencin et al., 2021).
In brown adipose tissue (BAT) β3ARs are highly expressed, and β3AR agonists increase [18F]FDG uptake (Cypess et al., 2015; Baskin et al., 2018) by inducing UCP1 expression, and can increase resting metabolic rate (Marlatt & Ravussin, 2017).
Cardiac and pulmonary β-AR density has been measured using [11C]CGP12177 (Delforge et al., 1991; Ueki et al., 1993; Hayes et al., 1996; Qing et al., 1996 and 1997; Ohte et al., 2012; Bernacki et al., 2016; Goto et al., 2021).
Synaptic noradrenaline is sequestered into presynaptic neuron via noradrenaline transporter (NAT, or norepinephrine transporter, NET), that belongs to the family of Na+/Cl- dependent transporters. NET and serotonin transporter can take up extracellular dopamine, too, especially in the Parkinsonian striatum when dopamine transporters are reduced. NET is involved in the pathophysiology and treatment of attention-deficit hyperactivity disorder, substance abuse, and neurodegenerative diseases, including AD and PD (Kirjavainen et al., 2018).
NET can be used as a marker of presynaptic sympathetic nervous system activity and cardiac sympathetic innervation. Also the cromaffin cells of the adrenal medulla use NET for noradrenaline uptake. Tumours that have neuroendocrine origin express NET, and can be detected using PET radiopharmaceuticals for NET. NET radiopharmaceuticals have also been used to detect Brown adipose tissue depots.
Several NET radiopharmaceuticals have been developed. [18F]fluorodopamine is taken up into sympathetic nerves, converted by β-hydroxylase into [18F]fluoronoradrenaline, stored in the transmitter vesicles and released like noradrenaline; therefore the washout rate of activity from tissue is quantitatively related to the sympathetic activity (Grassi & Esler, 1999). [11C]HED is a widely used NET radioligand; it is not stored or released like noradrenaline, and therefore the release of [11C]HED cannot directly be used as a measure of sympathetic activity, although it seems to be somewhat indicative of noradrenaline release (Grassi & Esler, 1999).
[131/123I]MIGB is a benzylguanidine-based ligand which has been used for imaging of neuroendocrine tumours and sympathetic function in cardiac studies. Substituting 18F for iodine provides [18F]MFBG (Zhang et al., 2014a and 2014b). [18F]3F-PHPG and [18F]4F-MHPG (Kobayashi et al., 2017) are close analogues, too. Metaraminol has been labelled with 18F, giving [4-18F]FMR (Eskola et al., 2004). [11C]MRB (Gallezot et al., 2011) has been used in human brain studies, for instance in patients with Parkinson's disease (Brumberg et al., 2019).
Other NET radiopharmaceuticals include (S,S)-[18F]FMeNER-D2 (Arakawa et al., 2008; Sekine et al., 2010; Moriguchi et al., 2017), [18F]LMI1195 (Higuchi et al., 2013; Sinusas et al., 2014; Werner et al., 2015). [18F]LMI1195 is promising for assessing myocardial sympathetic activity; similarly to noradrenaline and a widely used SPECT radiopharmaceutical [131/123I]MIBG, [18F]LMI1195 is stored in vesicles and released after cell membrane depolarization, and is not metabolized by MAO (Werner et al., 2015; Chen et al., 2018).
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Updated at: 2021-12-08
Created at: 2017-10-07
Written by: Vesa Oikonen