SPECIAL ISSUE This article is part of the Serotonin Research 2018 special issue.

The leading authorities on serotonin (5-hydroxytryptamine; 5-HT) science met on the “Wild Atlantic Way” at the 19th Meeting of the International Society for Serotonin Research (ISSR) in Cork, Ireland, from July 15 to 18, 2018. In Cork, the tourist byline is “leave the ordinary elsewhere and embrace the Wild Atlantic way of life,” as explained by Dr. John Cryan, Professor and Chair of the Department of Anatomy and Neuroscience at University College Cork (https://www.serotoninclub.org/pastmeetings). This special issue of ACS Chemical Neuroscience is an ode to that byline, as the creative hypotheses and methodologies published in this issue “leave the ordinary elsewhere”, presenting novel serotonin mechanisms to address 21st century public health challenges.

We reflect on another year of advances in the understanding of serotonin science within the context of the devastating opioid epidemic in the United States. One startling feature of this crisis is the rampant increase in overdose deaths attributable to prescription and illicit opioids, as well as the escalating upsurge in substance use disorders (SUDs) related not only to opioids but to cocaine and methamphetamine. To combat this medical crisis, the National Institute on Drug Abuse (NIDA) voiced a call to action to identify and to pursue targets for novel medications for the treatment of opioid overdose and opioid use disorder.(1) Notably, of the ten “most wanted” mechanisms noted for the rapid development of therapeutics, ligands targeting 5-HT 2A and 5-HT 2C receptors were highlighted. Of note, advances in the knowledge underlying the neuropharmacology and neurobiology of these and other serotonin receptors in the present volume provide guideposts for this quest. Thus, this special issue of ACS Chemical Neuroscience underscores how creative scientists engaged in serotonin research are meeting the challenge to delineate mechanisms underlying SUDs, epilepsy, and other neuropsychiatric disorders.

Neisewander and colleagues stress the need for an effective pharmacotherapy to treat methamphetamine use.(2) Exposure to the environment in which an individual previously used a drug increases relapse vulnerability.(3) Neisewander et al. found that systemic administration of a selective 5-HT 1B receptor agonist, CP94253, reduces the time mice spend in a methamphetamine-associated environment. These investigators proposed key brain regions involved in the neurocircuitry of SUDs that mediate this effect, for example, ventral tegmental area and nucleus accumbens. Nonselective 5-HT 1B receptor agonists are clinically available as antimigraine medications, and the Food and Drug Administration (FDA)-approved 5-HT 1B/1D receptor agonist zolmitriptan was recently shown to reduce methamphetamine intake in rats.(4) In a related paper, Neumaier and colleagues generated a neuron-like cell line that stably expresses 5-HT 1B receptors, enabling in-depth investigation of the nature of 5-HT 1B intracellular signaling.(5) These authors observed that agonist-induced 5-HT 1B receptor activation results in intracellular signaling via Gα i/o -dependent signaling but also interactions with β-arrestin 1 and β-arrestin 2 . The work of Neumaier et al. illustrates the complexity of downstream “biased signaling” of 5-HT 1B receptors, observations that potentially allow separation of therapeutic versus adverse effects of ligands for this receptor target.

The special issue of ACS Chemical Neuroscience on Serotonin Research features a Perspective by Simmler and Blakeley(6) who argue the need for better models to evaluate the contribution of serotonin transporters (SERT) to behavior. They highlight that psychostimulants, like cocaine, inhibit SERT but also dopamine and norepinephrine transporters, whereas serotonergic antidepressants target SERT but also serotonin receptors. Simmler and Blakeley discuss the design of a mouse model with a single point mutation in the SERT gene (SERT Met172). The SERT Met172 mutation does not affect SERT protein expression, serotonin uptake kinetics, or tissue serotonin levels in vivo, suggesting that native SERT function is unchanged. Systemic administration of the selective serotonin reuptake inhibitors fluoxetine or citalopram to wild-type mice lead to robust elevations in extracellular serotonin and elicit an antidepressant-like behavioral profile. However, these effects were absent in SERT Met172 mice, illustrating that these mice are insensitive to SERT-inhibitor mediated effects. Thus, the SERT Met172 mouse model is a valuable tool enabling evaluation of the contribution of SERT inhibition to the efficacy of novel therapeutics in vivo without altering the native function of SERT and providing a clear advantage over currently available constitutive gene knockout models.

Cameron and coauthors(7) remind us that serotonergic psychedelics have a rich history as experimental therapeutics to treat depression, anxiety, and SUDs. These authors found that chronic, intermittent, low doses of the psychedelic N,N-dimethyltryptamine elicit an antidepressant-like phenotype in rodents concomitant with enhanced fear-extinction learning independent of effects on working memory or social interaction. Together, their findings suggest that uncoupling the perceptual effects of psychedelics from their therapeutic properties provides a novel avenue for medication development for neuropsychiatric disorders.

We hope the ACS Chemical Neuroscience readership is energized by the new knowledge of serotonin science presented in this special issue. We hope the volume encourages the research community to address key 21st century public health challenges, including the opioid crisis, depression, and suicide. We are grateful to the authors, reviewers, and other contributors to this special issue for their dedication to ACS Chemical Neuroscience and to the readership at-large. We encourage you to join us at the 20th international meeting of the International Society for Serotonin Research, “Serotonin on the Mexican Caribbean” to be held July 26–29, 2020, at the Marriot Cancún Resort in Cancún, Mexico (https://www.serotoninclub.org/).

Views expressed in this editorial are those of the authors and not necessarily the views of the ACS. References ARTICLE SECTIONS Jump To This article references 7 other publications. 1 Rasmussen, K. , White, D. A. , and Acri, J. B. ( 2019 ) NIDA’s medication development priorities in response to the Opioid Crisis: Ten most wanted . Neuropsychopharmacology 44 , 657 – 659 , DOI: 10.1038/s41386-018-0292-5 2 Der-Ghazarian, T. S. , Charmchi, D. , Noudali, S. N. , Scott, S. N. , Holter, M. C. , Newbern, J. M. , and Neisewander, J. L. ( 2019 ) Neural circuits associated with 5-HT 1B receptor agonist inhibition of methamphetamine seeking in the conditioned place preference model . ACS Chem. Neurosci. DOI: 10.1021/acschemneuro.8b00709 3 Cunningham, K. A. and Anastasio, N. C. ( 2014 ) Serotonin at the nexus of impulsivity and cue reactivity in cocaine addiction . Neuropharmacology 76 , 460 – 478 , DOI: 10.1016/j.neuropharm.2013.06.030 4 Garcia, R. , Cotter, A. R. , Leslie, K. , Olive, M. F. , and Neisewander, J. L. ( 2017 ) Preclinical evidence that 5-HT 1B receptor agonists show promise as medications for psychostimulant use disorders . Int. J. Neuropsychopharmacol. 20 , 644 – 653 , DOI: 10.1093/ijnp/pyx025 5 Liu, Y. , Gibson, A. W. , Levinstein, M. R. , Lesiak, A. J. , Ong, S. E. , and Neumaier, J. F. ( 2019 ) 5-HT 1B receptor-mediated activation of ERK1/2 requires both Galphai/o and beta-Arrestin proteins . ACS Chem. Neurosci. DOI: 10.1021/acschemneuro.8b00596 6 Simmler, L. D. and Blakely, R. D. ( 2019 ) The SERT Met172 mouse: An engineered model to elucidate the contributions of serotonin signaling to cocaine action . ACS Chem. Neurosci. DOI: 10.1021/acschemneuro.9b00005 7 Cameron, L. P. , Benson, C. J. , DeFelice, B. C. , Fiehn, O. , and Olson, D. E. ( 2019 ) Chronic, intermittent microdoses of the psychedelic N,N-dimethyltryptamine (DMT) produce positive effects on mood and anxiety in rodents . ACS Chem. Neurosci. DOI: 10.1021/acschemneuro.8b00692

Cited By