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Catecholamines: Knowledge and Understanding in the 1960S, Now, and in the Future

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Catecholamines: Knowledge and Understanding in the 1960S, Now, and in the Future BNA0010.1177/2398212818810682Brain and Neuroscience AdvancesStanford and Heal 810682review-article2019 Review Article Brain and Neuroscience Advances Volume 3: 1 –11 Catecholamines: Knowledge and © The Author(s) 2019 Article reuse guidelines: sagepub.com/journals-permissions understanding in the 1960s, now, DOI:https://doi.org/10.1177/2398212818810682 10.1177/2398212818810682 and in the future journals.sagepub.com/home/bna S. Clare Stanford1 and David J. Heal2 Abstract The late 1960s was a heyday for catecholamine research. Technological developments made it feasible to study the regulation of sympathetic neuronal transmission and to map the distribution of noradrenaline and dopamine in the brain. At last, it was possible to explain the mechanism of action of some important drugs that had been used in the clinic for more than a decade (e.g. the first generation of antidepressants) and to contemplate the rational development of new treatments (e.g. l-dihydroxyphenylalanine therapy, to compensate for the dopaminergic neuropathy in Parkinson’s disease, and β1-adrenoceptor antagonists as antihypertensives). The fact that drug targeting noradrenergic and/or dopaminergic transmission are still the first-line treatments for many psychiatric disorders (e.g. depression, schizophrenia, and attention deficit hyperactivity disorder) is a testament to the importance of these neurotransmitters and the research that has helped us to understand the regulation of their function. This article celebrates some of the highlights of research at that time, pays tribute to some of the subsequent landmark studies, and appraises the options for where it could go next. Keywords catecholamine; dopamine; drug development; noradrenaline Received: 12 February 2018 Introduction In the 1980s, the development of in vivo microdialysis, high- performance liquid chromatography (HPLC) coupled with electro- Until the late 1960s, most research of catecholamines focused on chemical detection, and fast cyclic voltammetry (see Anderzhanova measuring responses to noradrenaline in peripheral tissues in vitro and Wotjak, 2013; Young, 1993) made it possible to monitor in order to gain a better understanding of the function and regula- changes in the concentration of extracellular catecholamines of tion of the sympathoadrenal system. The low sensitivity of freely moving animals, following an experimental challenge. These noradrenaline assays meant that quantitative neurochemical stud- approaches are now complemented by a raft of brain imaging tech- ies were restricted to studying sympathetically innervated tissues niques, for example: positron emission tomography (PET; see of large species or (noradrenaline-storing) chromaffin cells from Finnema et al., 2015; Volkow et al., 2007), single-photon emission the adrenal medulla. Like sympathetic neurons, chromaffin cells computed tomography (SPECT), and functional magnetic reso- are activated by preganglionic cholinergic neurons and derive from nance imaging (fMRI; see Borsook et al., 2006; DeCharms, 2008). the same embryonic tissue, and so it was thought that they could However, unlike microdialysis and voltammetry, neuroimaging serve as a large-scale model for postganglionic sympathetic neu- techniques suffer the limitation that they provide only ‘snapshots’ rons: a prediction that turned out to be broadly correct. of the functional status of the brain of immobilised subjects. Three technical developments in the 1960s enabled rapid pro- A detailed and contemporary account of the state-of-the-sci- gress in catecholamine research: refinement of fluorescence his- ence of catecholamine research, 50 years ago, is to be found in tochemistry; development of a sensitive fluorometric assay for catecholamines; and production of radiolabels for biological molecules. Collectively, these technologies made detailed ana- 1 Department of Neuroscience, Physiology and Pharmacology, University tomical and neurochemical research on catecholamines in the College London, London, UK 2 periphery and, later, the brain, realistic objectives. However, RenaSci Ltd, Nottingham, UK research of dopamine lagged behind that of noradrenaline mainly Corresponding author: because it was hard to confirm that this catecholamine was pre- S. Clare Stanford, Department of Neuroscience, Physiology and sent in neurons that were phenotypically different from those that Pharmacology, University College London, London, WC1E 6BT, UK. contained noradrenaline. Email: [email protected] Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). 2 Brain and Neuroscience Advances Iversen (1967). A particularly striking point about that book is that of noradrenaline in peripheral neurons and the factors that influ- only the last chapter, which is relatively short, is devoted to cat- ence its release. It was even possible to expose a diurnal rhythm echolamines in the brain and it offers the tentative conclusion: ‘In for the noradrenaline content of the pineal gland. recent years, the evidence that noradrenaline and dopamine may By combining evidence from noradrenaline assays with elec- act as neurotransmitters in the central nervous system has become tron microscopy, it was confirmed that noradrenaline was con- progressively more convincing’. This comment speaks for itself. fined within membrane-bound (dense-core) vesicles that are This article highlights some of the ‘hot topics’ of the late 1960s, located in the terminal varicosities of sympathetic neurons (Bisby some key developments since then and how, in many cases, they and Fillenz, 1971). Such findings ratified the predicted analogy directly underpinned therapeutic developments. A testament to the between postganglionic sympathetic neurons and chromaffin pioneering work by Axelrod’s group at the National Institute of cells of the adrenal medulla. However, a leading question in the Mental Health (NIMH) and Arvid Carlsson (Lund) is that both were 1960s was how does noradrenaline gain access to the vesicles awarded Nobel prizes for their different contributions to the field. and, given the immense concentration gradient, how it could remain confined there? The latter question was explained by the discovery of an Neurobiology adenosine triphosphate (ATP)-Mg2+-dependent uptake process by neuronal vesicles (Potter and Axelrod, 1963). We now know Distribution that this is carried out by one of a family of transporters (VMAT2) Noradrenaline (‘sympathin’) had long been known to effect sym- whose structure and regulation is well understood (see Blakely pathetic neurotransmission and had been found in the brain in the and Edwards, 2012). Early on, it was clear that this vesicular mid-1940s, but the possibility that it served any specific purpose, uptake was a relatively non-specific process, which became an other than regulating the cerebral vasculature, was controversial integral feature of the explanation for the actions of the so-called (see Vogt, 1954). Refinement of the formaldehyde condensation ‘false transmitters’ (e.g. α-methylnoradrenaline and tyramine) histochemical reaction enabled catecholamines to be visualised and psychostimulants (see below). in freeze-dried tissues and, by the late 1960s, there was a swathe of publications, mapping their distribution in a range of species and organs. This effort revealed that noradrenaline within the Synthesis brain was confined to an anastomosing network of neurons, with The pathway for the synthesis of noradrenaline was predicted by clusters of cell bodies (nuclei) located in the brainstem. This Blaschko in the 1930s (see Blaschko, 1959). By the mid-1960s, it complex network strengthened the view that noradrenaline might was confirmed that all the enzymes needed for noradrenaline bio- have a direct influence on brain function, as Vogt had suggested synthesis are expressed by catecholamine-releasing neurons in many years before. The nucleus that has attracted the most inter- both the periphery and the brain and are delivered to their termi- est is the locus coeruleus because, despite containing remarkably nals by axoplasmic transport. However, by 1967, the details of few cell bodies (about 1500, bilaterally, in the rat), its neurons where in the neurons each step took place were still uncertain. An project to nearly all regions of the neuraxis and provide nearly important finding was that the enzyme, dopamine-β-hydroxylase half of all noradrenergic nerve terminals in the brain. (DβH), which converts dopamine to noradrenaline, is bound Dopamine was known to exist in specialised cells in periph- within the noradrenaline storage vesicles (see De Potter, 1971), eral tissues and its presence in the brain was reported in the late confirming that they are the location of the final step in the path- 1950s, together with its high concentration in the striatum way. This finding also helped resolve a long-term dispute over (Bertler and Rosengren, 1959) and nigrostriatal neurons (Anden the process of transmitter release (see below). et al., 1962). However, there was a lingering doubt that neuronal In the light of evidence that the tissue content of noradrena- stores of dopamine served merely as a store
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