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. Noradrenaline is metabolized by MAO-A and MAO-B, and COMT.
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 denervation can be detected using PET tracers that are taken up by noradrenaline transporter; the status of sympathetic innervation in the heart has been studied using [11C]HED. [11C]HED is not stored in presynaptic vesicles or released from them 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). [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). [18F]LMI1195 is a new promising PET tracer myocardial sympathetic activity; similarly to noradrenaline and a widely used SPECT tracer [131I]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).Catecholamine synthesis rate can be estimated using [18F]FDOPA.
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). Density of available α2CARs in the brain can be quantified using [11C]ORM-13070, and the tracer can also be used to detect changes in synaptic noradrenaline levels (Finnema et al., 2015; Lehto et al., 2016). For the α2AARs, specific tracers are under development (Krzyczmonik et al., 2019).
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).
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).
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. 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 tracers for NET. NET tracers have also been used to detect Brown adipose tissue depots.
Several NET tracers have been developed; including [11C]HED, [4-18F]FMR (Eskola et al., 2004), [11C]MRB (Gallezot et al., 2011), (S,S)-[18F]FMeNER-D2 (Arakawa et al., 2008; Sekine et al., 2010; Moriguchi et al., 2017), and [18F]LMI1195 (Higuchi et al., 2013; Sinusas et al., 2014; Werner et al., 2015). In a preclinical study [18F]NS12137 was shown to be a promising radiotracer for NET imaging in the brain (Kirjavainen et al., 2018). [11C]MRB has been used in human brain studies, for instance in patients with Parkinson’s disease (Brumberg et al., 2019). [11C]HED and [18F]LMI1195 have been used to assess the status of cardiac sympathetic innervation.
Kirjavainen AK, Forsback S, López-Picón FR, Marjamäki P, Takkinen J, Haaparanta-Solin M, Peters D, Solin O. 18F-labeled norepinephrine transporter tracer [18F]NS12137: radiosynthesis and preclinical evaluation. Nucl Med Biol. 2018; 56: 39-46. doi: 10.1016/j.nucmedbio.2017.10.005.
Lehto J. The alpha2C-adrenoceptor as a neuropsychiatric drug target - PET studies in human subjects. Annales Universitatis Turkuensis, D1209, 2015.
Liu H, Leak RK, Hu X. Neurotransmitter receptors on microglia. Stroke Vasc Neurol. 2016; 1(2): 52-58. doi: 10.1136/svn-2016-000012.
Lymperopoulos A (ed.): The Cardiovascular Adrenergic System. Springer, 2015. doi: 10.1007/978-3-319-13680-6.
MacDonald E, Scheinin M. Distribution and pharmacology of α2-adrenoceptors in the central nervous system. J Physiol Pharmacol. 1995; 46(3): 241-258. PMID: 8527807.
Perez DM (ed.): The adrenergic Receptors - in the 21st Century. Humana Press, 2006. ISBN 1-58829-423-4.
Scheinin M, Hietala J. Alpha-2-adrenoceptors in the central nervous system: perspectives for PET studies. In: Beckers C, Goffinet A, Bol A (eds.): Positron Emission Tomography in Clinical Research and Clinical Diagnosis: Tracer Modelling and Radioreceptors. Kluver Academic Publishers, 1989, pp 118-126.
Wang Q (ed.): Advances in Adrenergic Receptor Biology. Elsevier, 2011. ISBN: 978-0-12-384921-2.
Updated at: 2019-02-17
Created at: 2017-10-07
Written by: Vesa Oikonen