Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2012 Feb 18.
Published in final edited form as: Neurosci Lett. 2010 Dec 21;490(1):68–71. doi: 10.1016/j.neulet.2010.12.028

Enhanced responsivity of 5-HT2A receptors at warm ambient temperatures is responsible for the augmentation of the 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced hyperthermia

Gongliang Zhang a,b,*, Rui Tao a
PMCID: PMC3056355  NIHMSID: NIHMS265005  PMID: 21172407

Abstract

Warm ambient temperature facilitates hyperthermia and other neurotoxic responses elicited by psychogenic drugs such as MDMA and methamphetamine. However, little is known about the neural mechanism underlying such effects. In the present study, we tested the hypothesis that a warm ambient temperature may enhance the responsivity of 5-HT2A receptors in the central nervous system and thereafter cause an augmented response to 5-HT2A receptor agonists. This hypothesis was tested by measuring changes in body-core temperature in response to the 5-HT2A receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) administered at four different ambient temperature levels: 12 °C (cold), 22 °C (standard), 27 °C (thermoneutral zone) and 32 °C (warm). It was found that DOI only evoked a small increase in body-core temperature at the standard (22 °C) or thermoneutral ambient temperature (27 °C). In contrast, there was a large increase in body-core temperature when the experiments were conducted at the warmer ambient temperature (32 °C). Interestingly, the effect of DOI at the cold ambient temperature of 12 °C was significantly reduced. Moreover, the ambient temperature-dependent response to DOI was completely blocked by pretreatment with the 5-HT2A receptor antagonist ketanserin. Taken together, these findings support the hypothesis that 5-HT2A receptors may be responsible for some neurotoxic effects of psychogenic drugs in the central nervous system, the activity of which is functionally inhibited at cold but enhanced at warm ambient temperature in contrast to that at standard experimental conditions.

Keywords: ambient temperature, hyperthermia, MDMA, serotonin, 5-HT2A receptor

Previous studies have demonstrated that the neurotoxic effect of psychogenic drugs is strongly dependent on the ambient temperature (Tamb) at which drug administration takes place. For instance, although amphetamine and its derivates administered at the standard Tamb of 22 °C caused hyperthermia, this effect was alleviated when the tests were carried out at cold Tamb [1,17]. Conversely, warm Tamb facilitated the hyperthermic effect evoked by antidepressants, opiate, methamphetamine, and 3,4-methylenedioxy methamphetamine (MDMA, “ecstasy”) [3,11,12,14]. Recently, it has been revealed that the responsivity of 5-HT2A receptors in the central nervous system (CNS) may depend on Tamb, which could be the underlying mechanism responsible for variations in neurotoxic responses to excessive 5-HT [8].

Methodologically, functional activity of 5-HT2A receptors in the CNS can be estimated in vivo by measuring changes in body-core temperature in response to 5-HT2A receptor agonists [13]. Physiological investigations have indicated that 5-HT2A receptors are present in the thermoregulation-related regions of the brain [9]. Under the standard Tamb of 22 °C, it has been shown that increases in extracellular 5-HT or administration of 5-HT2A receptor agonists such as 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) [9,13] and MK212 [15] are able to elicit a hyperthermic response. This effect is blocked by selective 5-HT2A receptor blockers, e.g., ketanserin, ritanserin, and MDL 100,907 [4,10,16], suggesting the involvement of 5-HT2A receptors. However, the role of warm Tamb in 5-HT2A receptor-mediated hyperthermia remains to be determined. To address this question, we designed experiments in which animal tests were conducted in temperature-controlled chambers set at a warm Tamb of 32 °C. For comparison, animals were also examined in cold and thermoneutral temperatures. Thus, changes in functional activity of 5-HT2A receptors were thoroughly examined at four different ambient temperatures: 12 °C (cold), 22 °C (standard), 27 °C (thermoneutral zone), and 32 °C (warm). By measuring changes in body-core temperature following DOI administration, we tested the hypothesis that the functional response of 5-HT2A receptors can be enhanced at the warm Tamb.

Male Sprague-Dawley rats (Charles River Laboratories at Raleigh, NC, USA) weighing 250 – 300 g were housed two animals per cage in a temperature-controlled facility (22 ± 1 °C) with a 12-h light/dark cycle (lights on at 7:00 a.m.). Animals had free access to food and water. All animal procedures used were in strict accordance with the NIH Guild for the Care and Use of Laboratory Animals and approved by the local animal study committees. (±) DOI-hydrochloride was purchased from Sigma-RBI (St. Louis, MO, USA) and ketanserin tartrate was obtained from Tocris Bioscience (Ellisville, MO, USA). Animals were randomly assigned into control or experimental groups. On the day of the experiment, rats were allowed to habituate in a temperature-controlled test chamber for at least 2 h before starting body-core temperature measurements. The thermostatic chamber built for this study was similar to that described previously [11].

Body-core temperature was measured in the rectum by inserting a 5 cm vinyl-jacketed thermoprobe (402 model; YSI Inc., Dayton, Ohio, USA) connected with a digital thermometer (Traceable®, Fisher Scientific, Pittsburgh, USA). All experiments were carried out between 12:00 noon and 2:30 pm. Temperature recordings at 15 min intervals consisted of two measurements before drug injection and six additional measurements after DOI administration. In the case of ketanserin or vehicle pretreatment, one more measurement was taken 15 min before DOI injection. The baseline was defined as the mean of two recordings before drug administration. Changes in body temperature relative to the baseline are expressed as mean ± SEM and analyzed by ANOVA followed by post-hoc Scheffe’s test. The significant level was set at p < 0.05.

The objective of the first experiment was to estimate the dose-response relationship between body-core temperature and DOI doses at the standard Tamb of 22 °C. Animals were assigned to one of four groups: vehicle control, 0.05 mg/kg, 0.1 mg/kg, and 0.5 mg/kg DOI groups. The baseline measurement was 38.00 ± 0.04 °C (n = 22). As shown in Fig. 1a, DOI administration produced a dose-dependent increase in body-core temperature. The effect became significant 15 min after administration, and the peak increase was at 30 min. This mild hyperthermia lasted for at least 90 min. Specifically, injection of 0.05 mg/kg DOI resulted in a 0.29 °C increase (± 0.09; n = 6), while 0.1 mg/kg evoked a 0.64 °C increase (± 0.06; n = 5), and 0.5 mg/kg DOI elevated the body-core temperature by 0.79 °C (± 0.06; n = 5) above the baseline. Two-way repeated measures ANOVA revealed significant main effects of treatment (F3, 18 = 32.9, p < 0.001), time (F7, 126 = 11.0, p < 0.001), and treatment × time (F21, 126 = 4.6, p < 0.001). Post-hoc Scheffe’s test showed that the effect of 0.05 mg/kg DOI was not significant by comparison to the vehicle-control group (p = 0.697). In contrast, the body temperature was significantly elevated in response to 0.1 and 0.5 mg/kg DOI (p < 0.01). To further understand the time course of DOI, a one-way ANOVA followed by post-hoc Scheffe’s test was used to analyze each time point of action between 15 – 90 min. The analyses indicated that 0.1 mg/kg DOI increased the body-core temperature at the time points of 30, 45, and 60 min, while the significant effect of 0.5 mg/kg DOI was found at 15, 30, 45, 60, and 90 min. It was observed that DOI at 0.1 mg/kg had already produced a maximal effect, and body-core temperature was not further elevated even when the dose was increased by five times up to 0.5 mg/kg under the standard Tamb of 22 °C. For the above reasons, the DOI dose at 0.1 mg/kg was used in the majority of the subsequent experiments to test the activity of 5-HT2A receptors as described below.

Fig. 1. Effect of DOI on body-core temperature at the standard ambient temperature (Tamb) (22 °C).

Fig. 1

Open in a new tab

The y-axis indicates changes in body-core temperature (ΔTcor) plotted against the time of measurement expressed in the x-axis (min). a, DOI at the doses of 0.05, 0.1 and 0.5 mg/kg, s.c., was administered at time of zero as indicated by an arrow. Injection of DOI at the standard Tamb produced a dose-dependent increase in body-core temperature. *p < 0.05, 0.1 mg/kg vs. vehicle; # p < 0.05, 0.5 mg/kg vs. vehicle (one-way ANOVA followed by post-hoc Scheffe’s test). b, Ketanserin (Ket, 5 mg/kg, i.p.) was administered 15 min before 0.1 mg/kg DOI injection. Pretreatment with ketanserin blocked the DOI-induced increase in Tcor. * p < 0.05 vs. vehicle + DOI (one-way ANOVA followed by post-hoc Scheffe’s test). Each value is the mean ± SEM of 5–8 animals.

Next, ketanserin was used to test whether the effect of 0.1 mg/kg DOI on body-core temperature was mediated by 5-HT2A receptors (Fig. 1b). In this set of experiments, a total of 26 animals was divided into 4 groups: veh + veh, veh + DOI, ket + DOI, and ket + veh. It was found that vehicle injection had no effect on body-core temperature in the veh + veh group, indicating that handling distress did not significantly contribute to the increased body-core temperature in this study. Additionally, injection of the 5-HT2A receptor antagonist ketanserin (5 mg/kg, i.p.) alone did not significantly alter body-core temperature. This suggests that there is relatively little tonic activity of 5-HT2A receptors in the regulation of body-core temperature at the standard Tamb of 22 °C. As shown in Fig. 1b, ketanserin blocked the DOI-evoked increase in body-core temperature under the standard Tamb of 22 °C. Two-way ANOVA test revealed significant effects of ketanserin on treatment (F3, 18 = 15.9, p < 0.001) and on treatment × time (F24, 144 = 4.9, p < 0.001). One-way ANOVA followed by post-hoc Scheffe’s test at each time point after DOI treatment indicated that ketanserin could block the effect of DOI at the time points of 45, 60, 75, and 90 min (p < 0.05).

In the second set of experiments, the effects of DOI were reevaluated at the warm Tamb of 32 °C (Fig. 2). The basal level of body-core temperature was 37.87 ± 0.30 °C (n = 22). The statistical analysis showed that the basal level at warm Tamb had no significant difference from that at standard Tamb of 22 °C (Student t = 1.5, p = 0.154). This is not surprising since body-core temperature of homeothermic animals is constantly regulated by the autonomic nervous system in response to environmental changes. Additionally, the data suggest that the body-core temperature regulation is unimpaired at the warmer ambient temperature under our experimental condition. As expected, DOI evoked a dose-dependent increase in body-core temperature, showing that the peak increase was 0.50 ± 0.09, 1.70 ± 0.25, and 2.71 ± 0.17 °C in response to 0.05, 0.1, and 0.5 mg/kg DOI, respectively. Two-way ANOVA test demonstrated significant effects of treatment (F3, 18 = 64.9, p < 0.001), time (F7, 126 = 106.6, p < 0.001), and treatment × time (F21, 126 = 30.6, p < 0.001). By comparison with the vehicle group, the post-hoc Scheffe’s test showed that, except for 0.05 mg/kg (p > 0.05), both 0.1 and 0.5 mg/kg DOI produced a significant increase in body-core temperature (p < 0.001).

Fig. 2. Effect of DOI on body-core temperature at the warm ambient temperature (32 °C).

Fig. 2

Open in a new tab

The y-axis indicates changes in body-core temperature (ΔTcor) plotted against the time of measurement expressed in the x-axis (min). a, DOI at the doses of 0.05, 0.1 and 0.5 mg/kg (s.c.) were administered at time zero. Similar to that at the standard Tamb, DOI at the warm Tamb evoked a dose-dependent increase in Tcor. * p < 0.05, 0.1 mg/kg vs. vehicle; # p < 0.05, 0.5 mg/kg vs. vehicle (one-way ANOVA followed by post-hoc Scheffe’s test). The increased body-core temperature at the warm Tamb was significantly greater than that under the standard condition (see text). b, Ketanserin pretreatment (Ket, 5 mg/kg, i.p.) blocked the increase in body-core temperature induced by DOI (0.1 mg/kg, s. c.) at the Tamb of 32 °C. * p < 0.05 vs. vehicle + DOI (one-way ANOVA followed by post-hoc Scheffe’s test). Data are expressed as mean ± SEM relative to baseline (n= 5–8 animals).

Most importantly, compared to that at the standard Tamb of 22 °C, the response of body-core temperature seemed to be markedly enhanced at the warm Tamb of 32 °C. This observation was supported by a statistical analysis, showing that the same dose caused a greater effect at warm Tamb of 32 °C: 0.05 mg/kg, F1, 10 = 5.4, p < 0.05; 0.1 mg/kg, F1, 8 = 12.6, p < 0.01; 0.5 mg/kg, F1, 9 = 75.5, p < 0.001. Thus, the new data from the present study demonstrated that warm Tamb facilitated the DOI-evoked hyperthermia. However, this raises the question of whether the increased hyperthermia is attributed to a direct effect of the warm Tamb since warm environment may compromise heat dissipation. We observed that the baseline of body temperature was somewhat altered. However, this change was not statistically significant. In addition, injection of vehicle failed to have an effect in the control group, likely arguing against the possibility that warm Tamb directly contributes to the increased body-core temperature.

Strikingly, we observed that the time-response curve as shown in Fig. 2a, which can be used to estimate the rate of changes in body temperature, was altered at the warm Tamb of 32 °C. Unlike that at the standard Tamb of 22 °C, the body-core temperature increase was sustained throughout the 90 min observation time, showing the upward slope of a near-perfect linear relationship between time and dose response. This change strongly suggests that the high level of hyperthermia may in turn further enhance the responsivity of 5-HT2A receptors under our experimental condition (see discussion below). However, the alternative possibility that a reduced rate of heat loss in the warm Tamb might be the cause of the continued linear increase in body-core temperature should be taken into account in future studies. Overall, the results strongly suggest that the functional response to DOI was significantly enhanced at warm Tamb.

Next, ketanserin was employed to further explore the underlying mechanism for the enhanced functional response. Animals were divided into 4 groups: veh + veh, veh + DOI, ket + DOI, and ket + veh. As shown in Fig. 2b, vehicle injection had no effect in the veh + veh group, suggesting that changes in body-core temperature could not be simply ascribed to physical distress in the handing of body temperature measurement at the warm Tamb of 32 °C. Results from the veh + DOI group confirmed the previous observation demonstrating that DOI at 0.1 mg/kg evoked a near-perfect linear increase in body-core temperature at the warm Tamb of 32 °C. Interestingly, injection of ketanserin alone slightly reduced the body temperature. However, this effect was not statistically different from that of the veh + veh group (p > 0.05). It was found that the enhanced functional effect of DOI was blocked by ketanserin injected 15 min before DOI. A two-way ANOVA test demonstrated significant main effects of treatment (F3, 17 = 28.1, p < 0.001), time (F8, 136 = 7.4, p < 0.001), and treatment × time (F24, 136 = 19.3, p < 0.001). Compared to the veh + DOI group, post-hoc Scheffe’s test showed that ketanserin pretreatment blocked the DOI-induced increase in body temperature (p < 0.001). Further one-way ANOVA analyses of body temperature to DOI treatment indicated that ketanserin effectively blocked the enhanced effect at each of the time points (p < 0.01). Thus, the results of the ketanserin data agree with the hypothesis that 5-HT2A receptors are involved in the molecular mechanisms responsible for the enhanced effect of DOI at warm Tamb.

The purpose of the final set of experiments was to test whether cold Tamb in contrast to warm Tamb exerts an opposite effect on the functional response of 5-HT2A receptors to DOI administration. Experiments were conducted at cold Tamb of 12 °C, standard Tamb of 22 °C and warm Tamb of 32 °C. For comparison, one group of animals was exposed to the thermoneutral zone of 27 °C in which the metabolic rate is near minimum [6]. The basal levels of body temperature were 38.08 ± 0.13 °C (n = 6), 37.71 ± 0.12 °C (n = 5), 37.33 ± 0.15 °C (n = 6) and 37.72 ± 0.10 °C (n = 5) at the Tamb of 12, 22, 27, and 32 °C, respectively. After two baseline samples, animals were injected at time zero with 0.1 mg/kg DOI. As shown in Fig. 3, DOI produced a Tamb-dependent increase in body-core temperature. The maximal increase was 0.20 ± 0.07, 0.69 ± 0.06, 0.99 ± 0.13, and 1.45 ± 0.23 °C at the Tamb of 12, 22, 27, and 32 °C, respectively. Two-way repeated measures ANOVA test revealed significant effects of treatment (F3, 18 = 25.2, p < 0.001), time (F7, 126 = 29.6, p < 0.001), and treatment × time (F21, 126 = 8.3, p < 0.001). Post-hoc Scheffe’s test showed that, compared to that at 22 °C, the DOI-evoked increase in body temperature was reduced at the Tamb of 12 °C (p < 0.05) but enhanced at 32 °C (p < 0.01), indicating that functional activity of 5-HT2A receptors appears to be reduced in a cold environment but enhanced in a warm environment. However, changes at the Tamb of 27 °C were not significantly different from that at 22 °C.

Fig. 3. Effect of ambient temperatures (12, 22, 27, and 32 °C) on the increased body-core temperature induced by DOI.

Fig. 3

Open in a new tab

The y-axis indicates changes in body-core temperature (ΔTcor) while the x-axis shows the time of measurement (min). DOI at the dose of 0.1 mg/kg, s.c., was administered at time zero as indicated by the arrow. DOI produced a Tamb -dependent increase in body-core temperature (p < 0.001, main effect). Values are expressed as changes in body-core temperature relative to baseline. The baseline was the mean of two measurements before drug administration. Each value is the mean ± SEM of 5–8 animals.

In conclusion, the main finding of this study is that the responsivity of 5-HT2A receptors in the CNS is strongly dependent on the ambient temperature. It has been demonstrated that neurotoxicity induced by amphetamine derivatives is ambient temperature-dependent [1,3,11,14]. Thus, the results of the present study may have a significant impact on understanding the neurotoxic effects of these psychogenic drugs. Neurochemical studies have shown that a recreational dose of MDMA elicits an 8 fold increase in extracellular 5-HT in the CNS under normal laboratory conditions [2,7]. This level of 5-HT is unlikely able to over-activate the low affinity 5-HT2A receptors for inducing severe neurotoxicity [8,10], which is contrary to the clinical observation that MDMA can cause severe toxicity at club. We suggest that the hot environment at clubs may be responsible since the affinity of 5-HT to 5-HT2A receptors can be increased in a temperature-dependent manner [5]. Taken together, the present study provides the functional evidence that the 5-HT2A receptor may be the key molecule responsible, at least in part, for ambient temperature-dependent neurotoxic effects of psychogenic drugs.

Acknowledgments

The authors thank Dr. Howard Prentice and Zhiyuan Ma for comments on the manuscript. This work was supported by USPHS DA029863.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Reference List

  • 1.Ali SF, Newport GD, Holson RR, Slikker W, Jr, Bowyer JF. Low environmental temperatures or pharmacologic agents that produce hypothermia decrease methamphetamine neurotoxicity in mice. Brain Res. 1994;658:33–38. doi: 10.1016/s0006-8993(09)90007-5. [DOI] [PubMed] [Google Scholar]
  • 2.Baumann MH, Clark RD, Franken FH, Rutter JJ, Rothman RB. Tolerance to 3,4-methylenedioxymethamphetamine in rats exposed to single high-dose binges. Neuroscience. 2008;152:773–784. doi: 10.1016/j.neuroscience.2008.01.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Bowyer JF, Davies DL, Schmued L, Broening HW, Newport GD, Slikker W, Jr, Holson RR. Further studies of the role of hyperthermia in methamphetamine neurotoxicity. J Pharmacol Exp Ther. 1994;268:1571–1580. [PubMed] [Google Scholar]
  • 4.Chio CC, Tsai SM, Wang JJ, Lin MT. 5-HT2A-µ opioid receptor mechanisms in the hypothalamus mediate interleukin-1β fever in rats. Neurosci Lett. 2005;381:6–11. doi: 10.1016/j.neulet.2005.01.074. [DOI] [PubMed] [Google Scholar]
  • 5.Dalpiaz A, Gessi S, Borea PA, Gilli G. Binding thermodynamics of serotonin to rat-brain 5-HT1A, 5-HT2A and 5-HT3 receptors. Life Sci. 1995;57:PL141–PL146. doi: 10.1016/0024-3205(95)02072-q. [DOI] [PubMed] [Google Scholar]
  • 6.Gordon CJ. Relationship between preferred ambient temperature and autonomic thermoregulatory function in rat. Am J Physiol. 1987;252:R1130–R1137. doi: 10.1152/ajpregu.1987.252.6.R1130. [DOI] [PubMed] [Google Scholar]
  • 7.Kankaanpaa A, Meririnne E, Lillsunde P, Seppala T. The acute effects of amphetamine derivatives on extracellular serotonin and dopamine levels in rat nucleus accumbens. Pharmacol Biochem Behav. 1998;59:1003–1009. doi: 10.1016/s0091-3057(97)00527-3. [DOI] [PubMed] [Google Scholar]
  • 8.Krishnamoorthy S, Ma Z, Zhang G, Wei J, Auerbach SB, Tao R. Involvement of 5-HT2A receptors in the serotonin (5-HT) syndrome caused by excessive 5-HT efflux in rat brain. Basic Clin Pharmacol Toxicol. 2010;107:830–841. doi: 10.1111/j.1742-7843.2010.00586.x. [DOI] [PubMed] [Google Scholar]
  • 9.Lin MT, Tsay HJ, Su WH, Chueh FY. Changes in extracellular serotonin in rat hypothalamus affect thermoregulatory function. Am J Physiol. 1998;274:R1260–R1267. doi: 10.1152/ajpregu.1998.274.5.R1260. [DOI] [PubMed] [Google Scholar]
  • 10.Ma Z, Zhang G, Jenney C, Krishnamoorthy S, Tao R. Characterization of serotonin-toxicity syndrome (toxidrome) elicited by 5-hydroxy-l-tryptophan in clorgyline-pretreated rats. Eur J Pharmacol. 2008;588:198–206. doi: 10.1016/j.ejphar.2008.04.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Malberg JE, Seiden LS. Small changes in ambient temperature cause large changes in 3,4-methylenedioxymethamphetamine (MDMA)-induced serotonin neurotoxicity and core body temperature in the rat. J Neurosci. 1998;18:5086–5094. doi: 10.1523/JNEUROSCI.18-13-05086.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Marzuk PM, Tardiff K, Leon AC, Hirsch CS, Portera L, Iqbal MI, Nock MK, Hartwell N. Ambient temperature and mortality from unintentional cocaine overdose. JAMA. 1998;279:1795–1800. doi: 10.1001/jama.279.22.1795. [DOI] [PubMed] [Google Scholar]
  • 13.Mazzola-Pomietto P, Aulakh CS, Tolliver T, Murphy DL. Functional subsensitivity of 5-HT2A and 5-HT2C receptors mediating hyperthermia following acute and chronic treatment with 5-HT2A/2C receptor antagonists. Psychopharmacology (Berl) 1997;130:144–151. doi: 10.1007/s002130050222. [DOI] [PubMed] [Google Scholar]
  • 14.Miller DB, O'Callaghan JP. Elevated environmental temperature and methamphetamine neurotoxicity. Environ Res. 2003;92:48–53. doi: 10.1016/s0013-9351(02)00051-8. [DOI] [PubMed] [Google Scholar]
  • 15.Nash JF, Meltzer HY, Gudelsky GA. Antagonism of serotonin receptor mediated neuroendocrine and temperature responses by atypical neuroleptics in the rat. Eur J Pharmacol. 1988;151:463–469. doi: 10.1016/0014-2999(88)90544-4. [DOI] [PubMed] [Google Scholar]
  • 16.Nisijima K, Yoshino T, Yui K, Katoh S. Potent serotonin (5-HT2A) receptor antagonists completely prevent the development of hyperthermia in an animal model of the 5-HT syndrome. Brain Res. 2001;890:23–31. doi: 10.1016/s0006-8993(00)03020-1. [DOI] [PubMed] [Google Scholar]
  • 17.Rusyniak DE, Ootsuka Y, Blessing WW. When administered to rats in a cold environment, 3,4-methylenedioxymethamphetamine reduces brown adipose tissue thermogenesis and increases tail blood flow: effects of pretreatment with 5-HT1A and dopamine D2 antagonists. Neuroscience. 2008;154:1619–1626. doi: 10.1016/j.neuroscience.2008.04.041. [DOI] [PMC free article] [PubMed] [Google Scholar]

RESOURCES