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.

Noradrenaline

As neurotransmitter, noradrenaline is used in relatively few neurons in the brain, but those receive input and send output to almost all parts of the brain and spinal cord. Most of noradrenaline in the brain is derived from the locus coeruleus in the brain stem. Outside of the CNS, noradrenaline is synthesized and released from postganglionic neurons of the sympathetic nervous system. Noradrenergic neurons are clustered in the synpathetic ganglia next to the spinal column. Noradrenaline is a major neurotransmitter in the peripheral nervous system. Noradrenaline is involved in regulation of cognition, arousal, attention, sleep-wake cycles, stress, memory formation, emotions, synaptic plasticity, sensory processing, cardiovascular function, and neuroendocrine signalling. Degeneration of the noradrenergic system is typical in neurodegenerative diseases such as PD, AD, and HD (Marien et al., 2004; Holland et al., 2021).

Synthesis of noradrenaline begins with hydroxylation of L-phenylalanine to L-tyrosine and then, in a rate-limited step catalysed by tyrosine hydroxylase (TH), into dihydroxyphenylalanine (L-DOPA). TH is considered as a marker of sympathetic neurons. DOPA decarboxylase (AADC) converts DOPA into dopamine, which is taken up into synaptic vesicles by vesicular monoamine transporter 2 (VMAT2). Dopamine is converted into noradrenaline by dopamine β-hydroxylase (DβH) in the synaptic vesicles of noradrenergic and adrenergic neurons. Synaptically released noradrenaline is taken back into presynaptic neurons by noradrenaline transporter (NAT/NET). Extraneuronal monoamine transporters (EMTs), mainly organic cation transporter 3, mediate low level sequestering of noradrenaline in most tissues. Noradrenaline is metabolized by MAO-A and MAO-B, and COMT.

The noradrenic neurons exhibit both tonic and phasic firing. The basal (tonic) activity makes up the most of synaptic noradrenaline. Presynaptic autoreceptors inhibit synaptic release. Noradrenergic neurons release noradrenaline also from non-synaptic sites; this "volume transmission" leads to broad spatial and temporal effects.

Metaraminol is a synthetic noradrenaline analogue that shares the same neuronal uptake, storage, and release pathways, but is not metabolized by COMT and MAO.

Adrenaline

Synthesis of adrenaline follows the same route as synthesis of noradrenaline. In the central adrenergic neurons and in adrenal chromaffin cells, the synaptic vesicles contain phenylethanolamine N-methyltransferase (PNMT), which methylates noradrenaline to adrenaline.

Adrenergic receptors

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 α_1A, α_1B, α_1D, α_2A, α_2B, α_2C, 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, α_2AAR is widely distributed, constituting about 90% of the α₂ARs, while α_2CAR (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 α_2AARs are under development (Krzyczmonik et al., 2019). Density of available α_2CARs 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). Laurencin et al (2023) have published [¹¹C]yohimbine brain BP_ND maps of healthy subjects.

In rodent brown adipose tissue (BAT) β₃ARs are highly expressed, while in human BAT β₂ARs are dominant. The β₂AR and β₃AR agonists increase [¹⁸F]FDG uptake (Cypess et al., 2015; Baskin et al., 2018; Straat et al., 2023) 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).

See also:

• Noradrenaline transporter
• Dopaminergic system
• Serotonergic system
• Cholinergic system
• Glutamatergic system
• Endocannabinoid system

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Literature

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Lehto J. The alpha_2C-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. doi: 10.1385/1592599311.

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. ISBN: 978-0-7923-0254-4.

Vuorenpää A: Cellular regulation of the norepinephrine transporter. Annales Universitatis Turkuensis, D1336. Sarja - ser. D osa - tom. 1336 ISBN: 978-951-29-7131-2.

Wang Q (ed.): Advances in Adrenergic Receptor Biology. Elsevier, 2011. ISBN: 978-0-12-384921-2. doi: 10.1016/B978-0-12-384921-2.00013-6.

Tags: Adrenoceptors, Adrenaline, Noradrenaline, Catecholamines, NAT, Autonomic nervous system

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Updated at: 2024-01-25
Created at: 2017-10-07
Written by: Vesa Oikonen