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5-HT2A Receptor Agonist-Induced Hyperthermia Is Induced Via Vasoconstriction By Supplemental material to this article can be found at: http://jpet.aspetjournals.org/content/suppl/2018/09/11/jpet.118.250217.DC1 1521-0103/367/2/356–362$35.00 https://doi.org/10.1124/jpet.118.250217 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS J Pharmacol Exp Ther 367:356–362, November 2018 Copyright ª 2018 by The American Society for Pharmacology and Experimental Therapeutics 5-HT2A Receptor Agonist-Induced Hyperthermia Is Induced via Vasoconstriction by Peripheral 5-HT2A Receptors and Brown Adipose Tissue Thermogenesis by Peripheral Serotonin Loss at a High Ambient Temperature s Mami Nakamura, Kaori Shintani-Ishida, and Hiroshi Ikegaya Department of Forensic Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan Received April 26, 2018; accepted September 6, 2018 Downloaded from ABSTRACT Recreational drugs such as 3,4-methylenedioxymethamphet- destruction of central noradrenaline or serotonin neurons, amine and cocaine induce hyperthermia, which is affected by peripheral 5-HT2A receptors were considered contributors to ambient temperature. 2-(4-Bromo-2,5-dimethoxyphenyl)-N-(2- the development of hyperthermia at a high ambient temperature, methoxybenzyl)ethanamine (25B-NBOMe), a selective agonist of independently from central neurons. The temperature of brown jpet.aspetjournals.org 5-HT2A receptor used as a recreational drug, reportedly induces adipose tissue (BAT) increased 60–120 minutes postadministra- hyperthermia. This study aimed to verify whether 25B-NBOMe tion of 25B-NBOMe at 29°C, indicating thermogenesis. Previous induces ambient temperature-dependent hyperthermia and to studies have reported that peripheral serotonin contributes to clarify its mechanism. Eight-week-old male Sprague-Dawley rats the inhibition of BAT thermogenesis. Decreased plasma seroto- were administered intraperitoneal injection of 25B-NBOMe at an nin levels were observed at 29°C, and serotonin administration ambient temperature of 23°C or 29°C. 25B-NBOMe administra- partially suppressed 25B-NBOMe-induced hyperthermia at a tion at 23°C did not change the core body temperature of the high ambient temperature, suggesting that decreased levels of rats, whereas administration at 29°C induced significant hyper- peripheral serotonin induced BAT thermogenesis. Our findings at ASPET Journals on September 24, 2021 thermia 30–120 minutes postadministration. Tail surface tem- indicate that 25B-NBOMe induces hyperthermia at a high perature temporarily decreased 30 minutes postadministration, ambient temperature via vasoconstriction regulated by 5-HT2A indicating heat storage by peripheral vasoconstriction despite receptors and BAT thermogenesis mediated by decreased levels a high ambient temperature. Because 25B-NBOMe-induced- of plasma serotonin. Thus, peripheral serotonin plays a partial hyperthermia was suppressed by sarpogrelate, but not by but important role in thermoregulation. Introduction administered at 20°C induced hypothermia. Malberg and Seiden (1998) studied MDMA-induced changes in the body Recreational drugs such as 3,4-methylenedioxymetham- temperature of rats at every 2°C change in a strictly controlled phetamine (MDMA) or cocaine are known to induce hyper- ambient temperature and demonstrated that ambient tem- thermia, which is affected by ambient temperatures (Parrott, peratures of $24°C and #22°C induce hyperthermia and 2012; Auger et al., 2017). Freedman et al. (2005) verified that hypothermia, respectively, suggesting that MDMA attenuates ambient temperature-dependent hyperthermia is induced by thermoregulation. However, the precise mechanism underly- MDMA administration in 10 participants, and reported that ing ambient temperature-dependent hyperthermia remains body temperature among the participants following drug- unknown. administration at 30°C was significantly higher than that at Thermal information is perceived by the transient re- 18°C. Many studies have reported ambient temperature- ceptor potential family in the skin. At high ambient dependent drug-induced hyperthermia in animal models. temperatures, signals from the thermoregulatory central Gonzalez (1993) demonstrated that hyperthermia occurred neural pathways of the preoptic area, medial preoptic area, in rats administered cocaine at 27°C, whereas cocaine and dorsal hypothalamic area, as well as the rostral raphe pallidus nucleus, are transmitted to the peripheral ther- moregulatory organs, resulting in heat loss through vaso- This work was supported by the Japan Society for the Promotion of Science dilation and evaporative cooling by sweating or through KAKENHI [Grant Number 16K09215]. https://doi.org/10.1124/jpet.118.250217. reduced thermogenesis in skeletal muscles and brown s This article has supplemental material available at jpet.aspetjournals.org. adipose tissue (BAT) (Morrison and Nakamura, 2011). ABBREVIATIONS: 25B-NBOMe, 2-(4-bromo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine; 5-HT, 5-hydroxytryptamine; 5,7-DHT, 5,7- dihidroxytryptamine; 6-OHDA, 6-hydroxydopamine; ANOVA, analysis of variance; BAT, brown adipose tissue; BBB, blood brain barrier; iBAT, intrascapular brown adipose tissue; DOI, (6)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane; MDMA, 3,4-methylenedioxymethamphetamine; PBS, phosphate-buffered saline; TPH, tryptophan hydroxylase. 356 5-HT2AR Agonist-Induced Hyperthermia at High Temperature 357 Certain serotonin neurons have been reported to play Materials and Methods specific roles in the central neural thermoregulation system Eight-week-old male Sprague-Dawley rats (n 5 131) correspond- (Hodges and Richerson, 2010), and central serotonin neu- ing to young adults in human (Sengupta, 2013) were purchased from rons in the thermoregulatorysystemhavebeenthekey Shimizu Laboratory Supplies Company (Kyoto, Japan). Postopera- focus of drug-induced hyperthermia studies, because many tively, the rats were individually housed in cages with wood-chip drugs affecting serotonergic neurons induce hyperthermia bedding at 23 6 1°C ambient temperature, 12-hour light/dark cycle, (Musselman and Saely, 2013). Lin et al. (1998) have reported with free access to water and food. The experiments were performed that the 5-HT2 receptor agonist (6)-1-(2,5-dimethoxy-4- with the rats freely moving in the same cage. iodophenyl)-2-aminopropane (DOI) injected into the rat hypo- All experiments were started at 2:30 PM in consideration of the thalamus increased intracellular serotonin levels, leading to influence of the circadian rhythm. The ambient temperature was controlled by a room air conditioner and was maintained (23°C or hyperthermia, whereas 5-HT1A receptor agonist 8-hydroxy-2- (di-n-propylamino)tetralin (8-OH-DPAT) injections exerted an 29°C) from 1 hour before the start of the experiment. The core body temperature was measured by implanting a logger, adverse hypothermic effect. Some studies have reported that DST milli-T (Star-Oddi, Gardabaer, Iceland), which was set up to DOI induced peripheral vasoconstriction and nonshivering gather samples at 5-minute intervals during the experiment, into thermogenesis in the intrascapular BAT (iBAT) in rabbits the abdominal cavity. Implantation was performed under general and rats via sympathetic neural stimulation (Blessing anesthesia (isoflurane inhalation, 2.0% to 2.5%) at least 4 days and Seaman, 2003; Ootsuka and Blessing, 2006). before the start of the experiment for recovery. Data were retrieved Serotonin is a neurotransmitter, but at the same time it also after the experiment and analyzed using Mercury software (Star- Downloaded from acts as a peripheral hormone in various organs (Gamoh et al., Oddi). The same method was used to measure BAT temperature with 2013; Herr et al., 2017). Separated by the blood-brain barrier the logger implanted into the intrascapular area (Cannon and (BBB), central serotonin is synthesized by tryptophan hydrox- Nedergaard, 2004). Tail surface temperature was measured using ylase (TPH) 2 in the brain stem, whereas peripheral serotonin an infrared thermometer FHT-P2 Avantek (Claybox Ltd., Hong Kong) at 10-minute intervals during the experiment. Before the experiment, is synthesized by TPH1 in the gut (Walther and Bader, 2003); the accuracy of the infrared thermometer was confirmed to be less jpet.aspetjournals.org hence, central and peripheral serotonins are considered to be than 1.76% at 23°C to 29°C ambient temperatures by measuring water independent from each other. Currently, the roles of periph- at 34°C to 50°C. eral serotonin and its receptors in the thermoregulatory 25B-NBOMe hydrochloride (PubChem CID: 76965389; Kim system are receiving increased attention. et al., 2016) was obtained from Lipomed AG (Arlesheim, Switzer- m 5-HT2A receptors are distributed in cardiovascular smooth land), and 1 mg of the compound was dissolved in 10 lofdimethyl muscle cells and platelets and contribute to vasoconstriction sulfoxide and 90 ml of methanol and subsequently diluted to and aggregation, respectively (Kaumann and Levy, 2006). Rat 0.25 mg/ml with phosphate-buffered saline (PBS) for intraperito- neal administration. Serotonin hydrochloride (CID: 160436) was at ASPET Journals on September 24, 2021 adipose tissue has also been reported to bear 5-HT2A recep- tors, which suppress lipolysis by b-adrenergic stimulation purchased from Nakalai Tesque (Kyoto, Japan) and was dissolved (Hansson et al., 2016). Recently, Crane et al. (2015) formu- in PBS to achieve a concentration of 0.05 or 0.1 mg/ml. Sarpogrelate hydrochloride (CID: 444005) was
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