Editorial pubs.acs.org/chemneuro
Why Monitor Molecules in Neuroscience?
T
he 16th International Conference on Monitoring Molecules in Neuroscience (MMN) took place in Gothenburg, Sweden from May 29 to June 2, 2016 at Chalmers University (http://mmingothenburg.se/). The meeting was last held in Sweden in 2003 in Stockholm. Sweden is of particular historical significance for the monitoring molecules community and neuroscientists at large as many key central nervous system (CNS) explorers have been or are Swedish. Notable examples include Kjell Fuxe and Annica Dahlström who originally mapped brain monoamine neurons using a fluorescence method developed by Bengt Falck and Nils-Åke Hillarp. The most recent MMN meeting opened with a conversation between Arvid Carlsson (Nobel Prize 2000) and Elias Eriksson titled “Aberrations in brain neurotransmitter function as a possible root of neuropsychiatric illnesswhich conclusions may be drawn after 60 years of research?” Like most neuroscientists, Professor Carlsson no longer subscribes to the simple hypothesis of neurotransmitter deficits and their correction as a basis for the etiology and treatment of neuropsychiatric disorders. (This is contrary to widespread public misconception largely perpetuated by oversimplified education of medical professionals and drug company advertisements.) Nonetheless, if neuropsychiatric disorders
The fact remains that the preponderance of current treatments for psychiatric, neurologic, and neurodegenerative disorders, as well as those for the foreseeable future, depend on the modulation of chemical neurotransmission by small-molecule drugs. nian activities in animal studies. Carlsson is interested in the actions of OSU-6162 to mitigate chronic fatigue. As a competitive mixed agonist/antagonist, this drug increases dopamine transmission in parts of the circuit where it is (too) low, yet reduces transmission in other places where it is (too) high by competing with endogenous dopamine for receptor and transporter occupancy. The MMN Conference highlighted additional efforts in drug development that exemplify how complex and nuanced mechanisms of action underlie new and future therapeutics having improved efficacies and better side-effects profiles, and that target larger or specific patient populations. Connie Sanchez, in her plenary lecture on vortioxetine, discussed a “multimodal” drug being developed by Lundbeck. Vortioxetine is a “designer” 5-HT3, 5-HT7, and 5-HT1D receptor antagonist, a 5-HT1B partial agonist, and a 5-HT1A agonist. Similar to serotonin-selective reuptake inhibitors (SSRIs), vortioxetine also inhibits serotonin transporters.1 Vortioxetine has been shown to have both antidepressant and procognitive effects. It may be particularly useful for the treatment of depression in the elderly, but also for patients of all ages that respond poorly to typical SSRIs. Swedish neurochemist Jan Kerr pointed out that there were 45 new drugs approved by the United States Food and Drug Administration across indications in 2015.2 This is greater than the average number of new drugs approved per year in the previous decade. Four new approvals were for CNS drugs: cariprazine, aripiprazole lauroxil (a long-lasting injectable form of aripiprazole), and brexpiprazole all for the treatment of schizophrenia, and flibanserin for sexual dysfunction in premenopausal women. Cariprazine (Vraylar) acts as a partial agonist at dopamine D2 and D3 receptors with preferential actions at the D3 subtype. Approved for the management of psychosis in schizophrenia and mania in bipolar disorder, cariprazine may also be useful in patients with treatmentresistant depression. Ongoing and future research aimed at developing new medications for brain disorders depends on our ability to monitor neurotransmitters. This is exemplified by work carried out at the Swedish company Pronexus Analytical AB (http://
Nonetheless, if neuropsychiatric disorders such as major depressive disorder, anxiety disorders, bipolar disorder, schizophrenia, and others do not result from frank insufficiencies in serotonin, norepinephrine, and dopamine neurotransmission, then of what value are neurochemistry and neuropharmacology research? such as major depressive disorder, anxiety disorders, bipolar disorder, schizophrenia, and others do not result from frank insufficiencies in serotonin, norepinephrine, and dopamine neurotransmission, then of what value are neurochemistry and neuropharmacology research? In other words, why monitor molecules in neuroscience? The fact remains that the preponderance of current treatments for psychiatric, neurologic, and neurodegenerative disorders, as well as those for the foreseeable future, depend on the modulation of chemical neurotransmission by smallmolecule drugs. Carlsson’s research, which he continues to pursue actively at age 94, focuses on a novel dopamine “stabilizer”. Carlsson does not support the continued development of full agonists or antagonists for many treatment purposes since these types of drugs impact all parts of a neurochemical circuit equally. He is investigating OSU-6162, a partial agonist at dopamine D2 and 5-HT2A receptors. This compound has antipsychotic, antiaddictive, and anti-Parkinso© 2017 American Chemical Society
Special Issue: Monitoring Molecules in Neuroscience 2016 Published: February 15, 2017 211
DOI: 10.1021/acschemneuro.7b00052 ACS Chem. Neurosci. 2017, 8, 211−212
ACS Chemical Neuroscience
Editorial
and chronic FSCV recording by Wightman, Phillips, and coauthors (DOI: 10.1021/acschemneuro.6b00393). We are indebted to our Swedish colleagues who organized the 2016 MMN Meeting including Andrew G. Ewing (Chalmers University of Technology, University of Gothenburg), Ann-Sofie Cans (Chalmers University of Technology), Mia Ericson (University of Gothenburg), Jörg Hanrieder, (University of Gothenburg, University College London), and Jan Kehr (Uppsala University, Karolinska Institutet), as well as Ricardo Borges (University of La Laguna Medical School, Tenerife, Spain) and Martin Eysberg (Antec BV, Netherlands). I want to extend my personal gratitude to the authors, reviewers, and ACS staff who contributed to and made possible this special issue of ACS Chemical Neuroscience. The rich and exciting work showcased puts us closer to a chemical connectome,3 and provides resounding evidence for the motivations for and importance of monitoring molecules in neuroscience.
www.pronexus.se/services/analytical-services) founded by Karolinska Institutet collaborators Kjell Fuxe, Jan Kehr, and Urban Ungerstedt, one of the originators of microdialysis methods.
The actions of drugs and drug candidates on chemical neurotransmission need to be identified to understand how new drug molecules work. Research on basic neurotransmitter mechanisms will further uncover normal and disease-related neurophysiologies to identify novel targets for future pharmaceutical development. The actions of drugs and drug candidates on chemical neurotransmission need to be identified to understand how new drug molecules work. Research on basic neurotransmitter mechanisms will further uncover normal and disease-related neurophysiologies to identify novel targets for future pharmaceutical development. Methodological advances for monitoring neurotransmitters and other molecules in vivo and ex vivo having better spatial, temporal, and chemical resolution will enable mapping of neurochemical circuits at finer scales and with better biological precision. For example, Weber and co-workers illustrate how improved temporal resolution in dopamine microdialysis was used to elucidate the effects of sustained depolarization on dopamine oscillations and spreading depolarization (DOI: 10.1021/acschemneuro.6b00383). As with the previous two special issues of ACS Chemical Neuroscience devoted to Monitoring Molecules in Neuroscience, a majority of technological and biological advances are being made in the area of dopamine neurotransmission. Investigation of the actions of cocaine on dopamine neurotransmission continue to reveal new insights, high-fat diets were shown to impact dopamine signaling in an insulin-dependent manner, and evidence for glutamate, GABA, and glucosedependent effects on dopamine signaling were revealed. Beyond dopamine, authors in this special issue report on neurochemical monitoring of glucose, adenosine, amyloid plaques, and chloride ions. A number of different methods, in addition to microdialysis, are employed for monitoring and manipulating molecules of importance in neuroscience including mass spectrometry, amperometry, diamond multiarrays, deep-brain calcium imaging, and optogenetics. Far and away, fast-scan cyclic voltammetry (FSCV) continues to be used by many due to its high temporal and spatial resolution and the ability to monitor endogenous neurotransmitter transients. These high-resolution and highly biologically relevant measurements require sophisticated methods for analyzing data and ensuring reproducibility and robustness. Efforts to improve data analysis and interpretation are evidenced by work from Sombers and co-workers using background signals to interpret dopamine measurements by FSCV (DOI: 10.1021/acschemneuro.6b00325), algorithms from Venton and colleagues for detecting adenosine transients by FSCV (DOI: 10.1021/acschemneuro.6b00262), and a comprehensive practical guide to the art and practice of acute
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Anne Milasincic Andrews, Associate Editor AUTHOR INFORMATION
ORCID
Anne Milasincic Andrews: 0000-0002-1961-4833 Notes
Views expressed in this editorial are those of the author and not necessarily the views of the ACS.
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REFERENCES
(1) Leiser, S. C., Li, Y., Pehrson, A. L., Dale, E., Smagin, G., and Sanchez, C. (2015) Serotonergic regulation of prefrontal cortical circuitries involved in cognitive processing: A review of individual 5-HT receptor mechanisms and concerted effects of 5-HT receptors exemplified by the multimodal antidepressant vortioxetine. ACS Chem. Neurosci. 6, 970. (2) Lindsley, C. W. (2016) Novel Drug Approvals in 2015 and Thus Far in 2016. ACS Chem. Neurosci. 7, 1175−1176. (3) Andrews, A. M. (2013) The BRAIN initiative: Toward a chemical connectome. ACS Chem. Neurosci. 4, 645.
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DOI: 10.1021/acschemneuro.7b00052 ACS Chem. Neurosci. 2017, 8, 211−212
