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Serotonin and Thermoregulation Physiologic and Pharmacologic Aspects of Control Revealed by Intravenous m-CPP in Normal Human Subjects Paul]. Schwartz, M.D., Thomas A. Wehr, M.D., Norman E. Rosenthal, M.D., John]. Bartko, Ph.D., Dan A. Oren, M.D., Christopher Luetke, B.S., and Dennis L. Murphy, M. D.

Mcta-c/1lorophenylpipera:i11c (111-CPP), 11 probe of crntml tlze effector mechanism primarily responsible for m-CPP­ function, elevaft's corr /e111perat11re 111 induced core hyperthermia is increased metabolic rodents, nonhuman primates, and humans uia serotoni11 t/1cnnogenesis. Individual differences in the magnitude of -mediated mechanisms. To further characterize t/1c hyperthermia were independent of m-CPP plasma the thermoregulaton1 aspects of this response, ,ue studied nmcentrations but were found to be linearly correlated 16 healthy uolunteers using multiple core and skin with the level of the previous night's core rectal temperature recording sites. Compared tu placebo, temperature minimum and mean. It appears that m-CPP intravenous 111-CPP (0. 08 mgikg) produced statisticaU11 adiuates a mode of metabolic thennogenesis governed by significant bipliasic changes in rectal lt'mperatu re, a noctu mally sensiti'ue proportional control mechanism. characterized by initial hypothermia ( - 0. ()4' Cat 1 The operation of such a proportional controller is minutes) followed by progrrssiz•e Jz11prrt/1em1ia I+ U. l-; (_ clza ractcrized by a set point and a gain, and has been at 90 minutes). 111-CPP also produced s1gnitica11t implicated in the general economy of mammalian energy increases in plasma 11urepimplz rinc I oncc11t ratio11s. /Jalancc. f Neuropsychopharmacology 13:105-115, Analysis ot tlzc skin te111pcra/11rc rccord111gs suggests t/111/ 1995]

KEY WORDS: Temperature; Meta-clzlorophenylpiperazinc; moregulatory action of (Bligh 1979), 5-HT Serotonin; Norepinph rine receptors are also located throughout the peripheral vasomotor and peripheral nervous systems (Fozard Serotonin (5-HT) is a major neurotransmitter involved 1984), indicating that the serotonergic regulation of in both central and peripheral aspects of thermoregu­ body temperature is complex. Elevated core body tem­ lation (Simon et al. 1986; Bruck and Hinckel 1990; Hori perature, especially at night, has been a reproducible 1991). While the anterior hypothalamus has been con­ finding in depressed patients, as has been the reduc­ clusively identified as a primary central site for the ther- tion of nocturnal core temperature following success­ ful treatment (Avery et al. 1982; Lund et al. 1983; Smallwood et al. 1983; von Zerssen et al. From the Clinical Psychobiology Branch (PJS, TAW, !\'ER, DAO, 1985; Souetre et al. 1988; Rosenthal et al. 1990). Given CL1, Division of Epidemiology and Services Research (JJB), and Lab­ this association between abnormal thermoregulation oratory of Clinical Science (DLM) of the National Institute of Mental Health, Bethesda, MD. and (Avery et al. 1982; Elsenga and van den Address correspondence to Paul I Schwart/, M.D., l\ational In­ Hoofdakker 1988; Wehr 1989), and given that seroto­ stitute of Mental Health, Clinical Psvchobiology Branch, Building W, nin is clearly an important neurotransmitter in both Room 45-239, 10 Center Dr. MSC 1390, Bethesda, MD 20892-1390 Rf'Ceived October 3, 1994; revised Februarv 1, 1995; accepted Febru­ mood (Meltzer and Lowy 1987; Coppen and Boogan ary 8, 1995. 1988; Murphy 1990) and temperature regulation, dis-

NF~ROPSYCHOPH.-\RM\< OllH.,\ Jliu, \(ll ·;_ "-..l) _' Published 1995 b\· Else\ ll'r c;l-tl'nu· Irie 0893-133X/95/$0. 00 65" Avenue "f the Amen,-a, '.\,·" '\ ,,rl,., ,-, ltlillll SSDI 0893-133X(95)00026-A 106 P.J. Schw,irtz l't al. NEUROl'SYCHOPHARMACOLOGY 1995-VOL. 13, NO. 2

entangling the interactions between the various com­ To investigate further the integration of the com­ ponents of the serotonergic and thermoregulatory sys­ ponent parts of the thermoregulatory response to tems remains an important challenge for depression m-CPP and the potential relevance of this response research. to mood disorders, we measured m-CPP-induced [n clinical studies, serotonergic pharmacological changes in core and skin temperature in healthy volun­ probes have been used to perturb mood, plasma hor­ teers and in patients with winter-seasonal affective dis­ mones, and temperature to provide possible indices of order (SAD). A condition of recurrent fall/winter the status of brain serotonergic neurotransmission. One depressions, SAD (Rosenthal et al. 1984) may involve such probe, meta-chlorophenylpiperazine (m-CPP), has pathology of central serotonin function (Rosenthal and been consistently found to induce hyperthermia in ro­ Wehr 1992), which may vary seasonally even in nor­ dents (Maj and Lewandowska 1980; Mazzola-Pomietto mals (Carlsson et al. 1980). Herein we describe a detailed et al. 1995), nonhuman primates (Aloi et al. 1984), and investigation of the temperature responses to m-CPP humans (Mueller et al. 1985, 1986; Zahar et al. 1987; in healthy volunteers. La½ lor et al. 1989; Murphy et al. 1989; Kahn et al. 1992). In addition, the hyperthermic response to m-CPP is modified by antidepressant in animals METHODS (Wozniak et al. 1989; Volterra et al. 1991) and humans Subjects (Zohar et al. 1988), making m-CPP's thermoregulatory mechanism of action of potential clinical interest. Sixteen subjects (13 women, 3 men; mean age 37.1 ± In binding studies, m-CPP has affinity for 5-HT2c > 10.2 years) were recruited as age- and sex-matched 5-HT3 > 5-HT2,\ > 5-HT!K > 5-HTtA receptors (lnver­ healthy volunteers for the SAD patients. Subjects were nizzi et al. 1981; Martin and Sanders-Bush 1982; Kil­ screened using the Structured Clinical Interview from patrick et al. 1987; Hoyer 1988) as well as for a2-adren­ the DSM Ill-R (SCIO; Spitzer et al. 1989) and were ergic receptors (Smith and Suckow 1985). In rats, the judged free of any current or past Axis I psychiatric dis­ hyperthermic response to m-CPP seems selectively orders. In addition, none had any first-degree family mediated by the 5-HT receptor, as it is attenuated by members with a history of psychiatric illness. All sub­ (5-HT 1/5-HT 2 antagonist), , jects had a complete physical exam and laboratory and (5-HT2cS-HT2,; antagonists), but not by evaluation, including thyroid function studies. Individ­ or (5-HT t-'., 5-HT rn, and 0-adren­ uals with any history of significant medical illness (in­ ergic receptor antagonists), (a1- an­ cluding migraine [Brewerton et al. 1988]) tagonist), or MDL 72222, , or were excluded. Subjects were free of all (5-HT3 antagonists) (Wozniak et al. 1989a; Klodzinska throughout the study and were specifically instructed and Chojnacka-Wojcik 1992; Mazzola-Pomietto et al. to avoid all temperature-altering medications, such as 1995). In humans, the hyperthermia is attenuated by and acetaminophen. No was permitted metergoline (Mueller et al. 1986) but not by ondanse­ during the study. All subjects had normal sleep-wake tron (a 5-HT:1 antagonist) (Broocks et al. 1992), leaving schedules, with sleep onset routinely occurring be­ several receptor subtypes as potential mediators of the tween 10:00 P.M. and midnight. All subjects gave writ­ hyperthermic response in humans. ten consent prior to their participation in the study. There are several physiological mechanisms through which m-CPP might induce hyperthermia. Procedures Thus, m-CPP-induced hyperthermia could result from (1) a change in the characteristics of the central temper­ Subjects were outpatients for the six-week protocol, ex­ ature controller, (2) a change in thermoeffector outputs cept when they were admitted to the NIH Clinical Cen­ (e.g., metabolic heat production or vasomotor heat dis­ ter the night before the infusions. The study was con­ sipation), (3) a change in the processing of afferent ther­ ducted between December 15, 1991, and March 21, mal information, or (4) some combination of these, tu 1992. All subjects underwent a pair of infusions (one name but a few possibilities. Conceivably, m-CPP acts m-CPP and one placebo, separated by at least 2 days, via several different mechanisms, including direct or order randomized) after completing 2 weeks in each of indirect effects at central or peripheral serotonergic or two respective lighting conditions (off lights vs. on adrenergic receptors (Cohen and Fuller 1983; Bagdy et lights, order also randomized). Subjects went directly al. 1989a; Murphy et al. 1991). Indeed, direct serotoner­ from the first to the second lighting condition, with no gic activation of peripheral effectors alone (e.g., periph­ intervening days in between. In the off-light condition, eral vasomotor heat exchange) can be sufficient to in­ subjects wore dark, wraparound goggles (3% transmit­ duce changes in core temperature in animals at room tance) when outdoors in bright sunlight, in order to temperature (Sugimoto et al. 1991; Key and Wigfield maximize the contrast between the off- and on-light con­ 1992). ditions. In the on-light condition, subjects sat in front NEUROPSYCHOl'HARMAl OLOC\ l'l'IS- Hll .. 11, r-..o. 2 Serotonin, Thermoregulation, and m-CPP 107

of a 10,000-lux bright white light for 45 minutes twice trifugation were stored at - 70°C until analysis. High­ a day between 6:00 and 9:00 A.M. and 6:00 and 9:00 l'.M., performance liquid chromatography (HPLC) with elec­ in a manner previously described (Terman et al. 1990), trochemical detection procedures was used to assay and did not wear goggles while outdoors. We did not plasma m-CPP levels (Murphy et al. 1989) and plasma control for or systematically track menstrual phase. NE concentrations (Mefford et al. 1987). For the NE as­ The evening prior to their infusions, subjects were says, the internal standard, dihydroxybenzylamine admitted to the research ward. Subjects were allowed (l µm), was added to0.8 ml plasma, and the free amines to sleep from 11:00 P.M. to 7:00A.M. in hospital pajamas were extracted in a two-stage procedure using alumi­ (light cotton, short sleeves, and long pants). Overnight num oxide/Tris (pH 8.5) and 1 % acetic acid elution. The rectal temperatures were recorded by a rectal ther­ HPLC system consisted of an LKB (Pharmacia, Piscata­ mocouple (Malinckrodt Anesthesia, St. Louis, MO), way, NJ) 2150-010 pump, a Gilson (Thomson Instru­ connected to a high-resolution electronic thermometer ment Co., Springfield, VA) 231 autosampler/401 diluter (Isothermex, Columbus Instruments, Columbus, OH; htted with a 50 µl sample loop, a BAS (Bioanalytical Sys­ accuracy = 0.1 °C, resolution = 0.015"C). Upon tems, Inc., W. Lafayette, IN) LK-4B amperometric de­ awakening at 7:00 A.M., subjects arose only to void, tector at an applied potential of 0.6V vs. Ag/ AgCl ref­ returning immediately to bed, where they remained erence electrode, and a 3 µm C-18 Axxion (Thomson without covers and with their torsos inclined at 45 Instrument Co., Springfield, VA) ODS column (4.6 x throughout the morning study. Subjects wore standard 150 mm length). The mobile phase was sodium phos­ styrofoam slippers which left their insteps exposed. Be­ phate monobasic with sodium dodecyl sulfate as the tween 7:00 and 7:30 A. M., two intravenous catheters ion pairing agent and methanol, 10% to 12%. were inserted, and skin temperature probes wen· (Malinckrodt Anesthesia) attached. Skin sites used werl' forehead (1 cm superior to the midpoint of one eye­ Statistical Analysis brow), hand (just distal to the hrst metacarpal-carpal joint on the dorsum of the hand), trunk (mid-axillarv Core rectal temperature data were smoothed using a line at level of xiphoid process), and foot (instep). low-pass filter (fast Fourier transform filtering, Passage At 9:30 A.M., over the course of 90 seconds, 20 ml Software) to eliminate occasional spike noise distor­ of m-CPP (0.08 mg1kg) or saline placebo was admin­ tions. Overnight (11:00 P.M. to 7:00 A.M.) rectal tem­ istered intravenously. Temperatures were recorded e,·­ perature minimum (T min) and mean (T mean) were ex­ ery minute for the next 90 minutes. Subjects were ob­ tracted for the preinfusion nights. Morning temperatures served for, and were asked to note, any shivering. Pulsl' were analyzed by repeated measures ANOVA, with and blood pressure were monitored every 10 minutes. three within-factors, namely, light condition (off vs. on Blood samples for (NE) concentrations lights), drug (m-CPP vs. placebo), and time. Green­ and m-CPP levels were obtained immediately before house-Geisser corrections were used for all repeated the infusion, and at 10, 30, and 60 minutes after the in­ measures analyses. Data were also baseline corrected fusion for NE, and at 10, 30, and 90 minutes for m-CPP. at t = 0 (time of infusion) for additional analyses. When Plasma for m-CPP assays was obtained through the in­ significant drug x time interactions occurred, post hoc travenous line not previously used for the infusion, in Bonferroni t tests, comparing average (off lights and on order to avoid contamination of blood samples with anv lights) responses to m-CPP and placebo at each time m-CPP that might have adhered to the tubing. point, were used to determine the specific time points at which the m-CPP-induced temperature response differed from that of placebo, Plasma NE concentrations Inpatient Environmental Conditions were similarly analyzed by repeated measures Room temperature was maintained at 22.75 ± 0.75 C ANOVA. Temperature and NE responses were also Ambient lighting conditions were maintained at <1 lux analyzed by calculating the total area under the curve overnight and at 30 lux after awakening. Humidity was (AUC after baseline corrections, trapezoidal rule) over not controlled. In the on-lights condition only, subjects the 90-rninute postinfusion sampling period (negative received their usual 10,000-lux light treatment from 8:00 deflections resulted in negative contributions to the to 9:00 P.M. the nights before, and from 8:00to 9:00A.M. AUC). Maximum temperature rise from baseline (Max the mornings of their infusions. t). = T maximum - T base) following the infusion (before and after bright-light exposure) was also analyzed by Assay Procedures repeated measures ANOV A. Data are presented as mean ± SD unless otherwise specified. Data were Venous blood samples were collected with EDT A as the analyzed with SuperAnova (Abacus Concepts, Berke­ anticoagulant, and plasma samples obtained by cen- ley, CA). 108 P.J. Schwartz et al. NEUROPSYCHOPHARMACOLOGY 1995-VOL. 13, NO. 2

0.5 0.6

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0 u Ol 00 Q) Q) f- 0.3 - en 0.3 "O 0 Q) 0 Q) 0) < 0 cu 0.2 CD 0 0 ::, 0.2 iii - ai 0.1 C. - 0 E r 2 0.1 0 35 35.5 36 36.5 37 37.5 38

T m,n (degrees C)

Figure 2. The maximal core hyperthermic response (Max~) 0 following m-CPP is proportional to the previous night's core temperature minimum (Tmin). The graph represents pooled data, with two m-CPP infusions for each subject. See the text for statistics and discussion. -0.1 0 20 40 60 80 .05; pooled data are depicted in Figure 2) and Tmean (off minutes after m-CPP infusion lights, r = -0.55, p < .05; on lights, r = -0.61, p < .05). Max~ was also equally well correlated with Tmin from Figure 1. m-CPP (0.08 mg:kg) induces a biphasic response the night prior to the placebo infusion (i.e., 2 to 4 nights in core rectal temperature. Data are smoothed and corrected either before or after the night preceding the m-CPP to baseline; mean ± SD are shown. Post hoc Bonferroni I test~ comparing m-CPP to placebo change from baseline:* p< .05. infusion: off lights, r = -0.79, p < .001; on lights, r = ** p < .01, *** p < .001. o. m CPP: ... placebo. -0.66, p < .01). Max~ was not correlated with (1) m­ CPP plasma concentrations (at any time or total m-CPP Al:C), (2) the baseline rectal temperature immediately RESULTS preceding the m-CPP infusion, or (3) body weight, ei­ ther alone as simple regressors or as second regressors Compared to placebo, m-CPP significantly altered rec• when combined with T min in a multiple regression tal temperature in a biphasic manner (Figure 1 shows model. Bright-light exposure had no significant effect drug x time interaction: F( 11 i ,2) = 33.12, p < .0001, un the slope of the Max ~IT min relationship (slopes: off analyzed each 8 minutes, three subjects with missing lights, -· 0.17; on lights, -0.20; repeated measures mul­ data from one of the infusions). Post hoc Bonferroni tivariate test of slopes [Press 1972]: t = 1.36, df = 11, t tests revealed that, compared to placebo, the maxi­ p = .20). mal hypothermic effect uf m-CPP (-0.04)C at 12 We investigated whether the Max ~/Tmin correla­ minutes) was statistically significant, as was the latt>r tions might represent trivial correlates of the intrinsic hyperthermic effect of m-CPP ( + 0.17 Cat 90 minutes) circadian waveform. That is, subjects with the deepest at all time points from 56 tu 90 minutes (analyzed each overnight core temperature descent might have the 8 minutes). There were no significant main or interac­ steepest morning ascent, and hence a greater Max ~, tion effects of the bright-light exposure on the core rec­ simply by having an m-CPP-induced response su­ tal temperature response to m-CPP. Furthermore, there perimposed on a more steeply rising intrinsic temper­ were no significant effects of bright-light exposure on ature waveform. This was examined in two ways. First, any of the measures studied, and no significant differ­ slopes were derived for the morning rise in core tem­ ences first and second responses to m-CPP. perature that occurred from 8:00 to 9:30 A.M. and from Across the individual subjects, m-CPP-induced 9:00 and 9:30 A.M. There were no significant correla­

Max was correlated with the previous night's 1 111111 tions between these slopes and Max ~, indicating that (off lights, r = -0.66, p< .O=i; on lights, r = -0.56, p < the hyperthermic response to m-CPP was independent NEL'ROPSYCHOPHARMACOLOGY lYY'i- VOL 11, NO. 2 Serotonin, Thermoregulation, and m-CPP 109

of the rate of rise of morning rectal temperature prior Nonetheless, we investigated whether some of the to the infusion. Second, there was no correlation be­ interindividual variability in core hyperthermic re­ tween the Max ~'s for the placebo days and the previ­ sponses might have been attributable to individual ous night's T min or T mean, indicating that the rate of rise differences in the degree of heat exchange at the periph­ in the intrinsic waveform from 9:30 to 11:00 A.M. was eral skin sites (taking the component lead baseline­ independent of the previous night's nocturnal temper­ corrected AU Cs to represent an approximation of the ature. Thus, the m-CPP-induced Max ~/Tmin relation­ cumulative heat exchange at each site). We found no ships were not trivially implicit in the intrinsic circa­ significant correlations between peripheral (AUChand) dian waveform. and core (AUCectal) responses to m-CPP (off lights: Examination of the average skin temperature re­ r = 0.41, p = .13; on lights: r = 0.39, p = .15), even sponses at the different body locations (Figure 3) re­ after T min was included as a regressor for AUCectal in vealed that they were essentially independent of the a multiple regression model. Similar analyses were per­ core temperature response. The progressive increase formed for the temperature responses at the remain­ in average core temperature from 20 to 90 minutes was ing skin sites (including an unweighted mean skin tem­ not accompanied by a progressive decrease in skin tem­ perature), and no significant correlations were found. perature (i.e., heat conservation) at any of the sites over Thus, the magnitude of the hyperthermia was only the same period of time, and, except for the forehead significantly correlated with T min and T mean from the temperature, there were no statistically significant previous night. changes in skin temperature after infusion of m-CPP. m-CPP administration elevated circulating NE In three cases, progressive core hyperthermia was ob­ plasma concentrations (Figure 4: baseline corrected served despite a progressive increase in temperature ANOVA, main effect of drug, F(1.10) = 10.44, p < .01; (increased heat loss) at all skin sites. Comparison of the five subjects with missing data). We found no correla­ Max ~'s following m-CPP in these three experiments tion between rectal temperature Max~ and AUCNE, with the Max ~'s following placebo revealed a either alone or with Tmin included in a multiple regres­ significantly greater Max~ response for the m-CPP in­ sion model. fusions compared with the placebo infusions (0.21 vs. Mean plasma concentrations of m-CPP were maxi­ 0.10, p < .01). mal at 10 minutes (43.0 ± 33. 9 ng/ml), declining fairly

0.5 0.6 HAND FOREHEAD 0 - 0.4 l) Q) :s, 1 Q) .£ -1 0 ai coC p = .59; foot, F(n,143) = 0.51, p = ,C .60; forehead, F(11,110) = 3.46, p = 0 0.1 0 l!! .02. -e-. m-CPP; -H-. placebo. :::J iii ai Q. 0 -0.5 E Q) r- -0.1 -1 TRUNK FOOT -0.2 -1.5 0 20 40 60 80 0 20 40 60 80

Minutes following infusion 110 P.J. Schwartz. et al. I\ECROPSYCHOPHARMACOLOGY 1995-VOL. 13, NO. 2

7 - et al. 1985, 1986; Zahar et al. 1987; Lawlor et al. 1989; Murphy et al. 1989; Kahn et al. 1992). This is the first human study in which (1) continuous temperature mea­ surements were obtained, (2) core rectal temperature was documented, (3) skin temperatures were mea­ :§ 6 sured, and (4) overnight, pre-m-CPP/placebo baseline 0 T core temperatures were measured. These features E per­ -9, mitted a more careful dissection of the factors that con­ C .Q tributed to the hyperthermic response. The biphasic, "signoidal" shape (Figure 1) of the T c 5 - average hyperthermic response was characteristic of the

C individual responses as well, with interindividual vari­ 0 0 ations in response mainly a function of the fmal tem­ CJ) C perature attained. Therefore, the lack of a relationship i between m-CPP plasma concentrations and the mag­ 0. CJ) 4 nitude of these hyperthermic responses suggests that ·c..C CJ) (1) the former is not a significant source of this interin­ 0 dividual variability in the latter, and (2) the latter is prob­ C «I ably regulated by a graded response mechanism. Al­ E en though a dose-response relationship for temperature «I 0. 3 has yet to be demonstrated in humans (Kahn et al. 1990), m-CPP-induced hyperthermia has been found dose dependent in rats (Wozniak et al. 1989). Further dose-response studies in humans using lower dosages of m-CPP may reveal whether m-CPP' s activation of this 2 graded response is dose dependent. 0 10 30 60 - The physiological basis of the hyperthermic re­ minutes post-infusion sponse to m-CPP can be inferred from the results of this study. As hyperthermia was observed in three cases Figure 4. m-Cl'P ( 11111) induce, a ,ignihcant increase 111 ,1\ l'r­ despite instances of widespread peripheral vasomotor age plasma NE concentration Cllmparcd 11 ith placebo ( I. dilatation (increased heat loss) at all skin sites, heat Mean ± SD are sholl'n. production must have (1) exceeded the increased heat luss, and (2) contributed significantly to the increase in rapidly by 30 minutes Ill.! (29.Y ± ng. ml), and reach­ core temperature. In the absence of overt shivering, the ing a relative plateau subsequently (22.4 ± 6.2 ng•ml necessary conclusion is that hyperthermia primarily at 90 minutes). The mean plateau-phase (30 to 90 resulted from increased metabolic heat production. This minutes) m-CPP level was 26.3 ± 6.3 ngiml. These conclusion is further supported by the fact that the skin m-CPP concentrations at the 10-, 30-, and 90-minutl' temperature (vasomotor) responses were inconsistent time points were slightly lower than those in our prior in direction and magnitude, and quantitatively in­ study (48, 33, and 25 ngiml, respectively), which used significant in the overall determination of the much a do;e of 0.1 mg/kg intravenous m-CPP (Murphy et al more statistically robust core hyperthermia. Although, 1989). without EMG recordings, we cannot rule out the pos­ No subjects reported or were observed shivering sibility of a small increase in asynchronous muscle fiber in any of the experiments. re• Although the subjective activity as a cause for some of the heat production, it sponses to m-CPP were varied, most subjects reported is improbable that this degree of hyperthermia could a marked and distinctive "hot flushing" sensation that be caused by such a mechanism (Kleinebeckel and started minutes after the infusion and spread gradu­ Klussmann 1990). We also had no quantitative measure allv over the face and torso. This flushing was some­ of the skin surface/boundary characteristics of heat ex­ ti~es accompanied bv a burning sensation down thP change in response to m-CPP (e.g., sweating). How­ neck and upper back and bv trunca\ sweating. ever, our observation that sweating generally increased following m-CPP infusions reinforces the inference that DISCUSSION a significant increase in heat production occurred, since hyperthermia was observed despite an apparent in­ The results of the present experiment are consistent crease in evaporative heat loss from sweating. with earlier observations that m-CPP induces oral The inference that m-CPP caused increased meta­ hyperthermia (0.3 to 0.6°C) in human subjects (Mueller bolic thermogenesis is consistent with a number of NELROPSYCHOPHARMACOL()(;) 144C,-- \l)l. I\ NO. 2 Serotonin, Thermoregulation, and m-CPP 111

studies in animals which have demonstrated increased BAT as an effector of facultative thermogenesis in hu­ oxygen consumption after the administration of seroto­ mans remains uncertain (Himms-Hagen 1985), BAT has nergically active compounds ( Allen and Marley 1967; been estimated to account for as much as 4% to 7% of Bligh et al. 1974; Even and Nicolaidis 1986; Gordon et resting metabolic rate in humans ( et al. 1987), rais­ al. 1991). Direct intraventricular administration of ser­ ing the possibility of a significant role for BAT in selected otonin or D- (both of which enhance modes of human thermogenesis. Notwithstanding the 5-HT 2c receptor-mediated activity) has been shown tu uncertain role of BAT in m-CPP-induced thermogene­ increase central sympathetic nervous system (SNS) sis, systemically administered NE can increase oxygen outflow and peripheral NE release, resulting in in­ consumption in humans by as much as 10% to 20% creased brown adipose tissue (BAT) thermogenesis and (Karlberg et al. 1962; Joy 1963; Hensel et al. 1973). How­ oxygen consumption (Steiner and Evans 1976; Roth­ ever, as the NE response to m-CPP was statistically less well and Stock 1987). Corticotropin releasing hormone robust than the core hyperthermic response, and as (CRH), when released from the paraventricular nucleus there was no correlation between the amount of NE re­ of the hypothalamus, also triggers this response (Le lease and the core hyperthermia, the findings suggest Feuvre et al. 1991). Thus, a central serotonergic sym­ that the NE release following m-CPP administration pathetic drive mechanism exists in animals, which, may not be a very reliable indicator of thermogenic ac­ when stimulated, induces metabolic heat production. tivity in humans. It is conceivable that epinephrine re­ m-CPP's known action at suprahypophyseal sites lease following m-CPP administration may be more resulting in increases in CRH and ACTH (Calogero et directly related to m-CPP-induced thermogenesis in hu­ al. 1990) its consistent with the central serotonergic ac­ mans, although epinephrine increases following m-CPP tivation of such a drive mechanism, although the role have not yet been reported in humans. In rats, m-CPP of BAT thermogenesis in adult humans is controver­ stimulates epinephrine release to an even greater de­ sial (see below). There are also animal (Levitsky et al. gree than NE (Bagdy et al. 1989b), and human thermo­ 1986)andhuman(Breumetal.1990; Stinsonetal.1992) genesis appears more sensitive to epinephrine than to studies in which administration of some serotonergi­ NE (Sjostrom et al. 1983). cally active compounds (fenfluramine and fluoxetint:'1 We have not ruled out the possibility that m-CPP failed to increase resting metabolic rate. Thus, the in­ acts directly on peripheral structures (in addition to CNS ference that m-CPP-induced hyperthermia was second­ sites) to effect some of the postulated increase in meta­ ary to a centrally mediated increase in metabolic heat bolic heat production. In rats, however, blockade of pe­ production should be confirmed with studies directlv ripheral 5-HT2 receptors by (which does measuring oxygen consumption in humans. not cross the blood-brain barrier) does not alter the ca­ The m-CPP-induced elevation of plasma NE nrn­ pacity of MK-212 (a 5-HT2A c ) to raise core tem­ centrations in this study is also consistent with (1) the perature (Gudelsky et al. 1986). Thus, if there are 5-HT central activation of SNS outflow, and (2) the m-CPP - receptors on peripheral sympathetic nerves that stimu­ induced plasma NE elevation found in rat studies (Bagdy late thermogenesis (Steiner and Evans 1976), they ap­ et al. 1988, 1989a, 1989b). Both pithing and splanchnic pear not to participate substantially in the acute hyper­ denervation markedly reduce the NE response to sys­ thermic response to 5-HT 2 in rats. Since it has temically administered m-CPP (Bagdy et al. 1988), and been shown that m-CPP-induced hyperthermia in rats this response was unaffected by pretreatment with the is primarily mediated by 5-HT2c receptors (Klodzinska peripheral 5-HT2 antagonist, xylamidine (Bagdy et al. and Chojnacka-Wojcik 1992; Mazzola-Pomietto et al. 1989b). These fmdings point to a site of action of m-CPP 1995), it appears that stimulation of central 5-HT2c at the brainstem or higher in the neuraxis and also in­ receptors alone accounts for the hyperthermic response dicate that the bulk of NE release following m-CPP is in rats. Further, as m-CPP does not have important ac­ mainly of peripheral SNS origin. Since the increase in tivity at 13- or a,-adrenergic receptors, the types of oxygen consumption following exogenously adminis­ receptors on brown adipocytes that mediate BAT ther­ tered NE has been used to quantify BAT thermogenic mogenesis in most animals (Himms-Hagen 1985), di­ potential in rodents (Heldmaier et al. 1981; Ellison and rect stimulation (serotonergic or adrenergic) of BAT Skinner 1990), it is conceivable that the magnitude of does not appear to account for the rat hyperthermic re­ m-CPP-induced hyperthermia reflects, in part, the pe­ sponse to m-CPP. While m-CPP displays moderate ripheral thermogenic capacity of BAT as well as m-CPP's affinity for a 2-adrenergic receptors, it has recently been capacity to increase central SNS outflow. shown that these receptors are not involved in sym­ As BAT is primarily located in the nape of the neck, pathetically mediated thermogenesis in humans (Blaak interscapular area, trunk, pericardiaL and perirenal et al. 1993). Nevertheless, further experiments are areas, it is of some interest that subjects reported dis­ needed to rule out a role of peripheral 5-HT or adrener­ tinct burning sensations on their necks, upper backs, gic receptors in m-CPP-induced thermogenesis in and trunks after the m-CPP infusion. While the role ot humans. 112 P.J. Schwartz et al. NEUROPSYCHOPHARMACOLOGY 1995-VOL. 13, NO. 2

The small, but statistically significant drop in core (M - Mo = ~M = a(Thy - Tset) temperature that occurred shortly after m-CPP adminis­ where Mis , Mo is basal metabolism, and tration is a new finding. It could have resulted from (1) a is the gain (proportionality constant) (Hammel 1968). an immediate onset of sweating and increased evapora­ In the present context, our formulation becomes tive heat loss, (2) a decrease in metabolic heat produc­ tion, or (3) an increase in vasomotor (skin) heat loss. Max~ = a(Tmin - Tset). The patterns of skin temperature responses sho:-ved_ no where the parameters represent population statistics initial change that could have accounted for this bnef, rather than individual characteristics. It follows that initial hypothermia, and its mechanism remains un­ when Tmin = Tset, Max~ will be zero (not different known. While m-CPP has moderate affinity for 5-HTJA from placebo). Therefore, in Figure 2, the intersection receptors, and several 5-HT1A agonists have been of the regression line with the horizontal line repre~e_nt­ shown to lower temperature in humans (Lesch et al. ing the mean placebo Max~ approximates the p~sihon 1989; Anderson et al. 1990) and in other species (Good­ on the T min axis which corresponds to the location of win and Green 1985; Gudelsky et al. 1986; Murphy et Tset, while the slope corresponds to a. The unique role al. 1991), m-CPP is an antagonist at 5-HT1A sites (Raffa of the previous night's "masked" (i.e., measured dur­ et al. 1992), and hence a 5-HT1A-mediated effect seems ing sleep) T min in predicting Max ~, as opposed to the unlikely. . apparent independence of Max Li and diurnal co_re teu:i­ Our finding that the magnitude of the metabolic perature, suggests that the mechanisms regulating t~is thermogenesis (Max~) induced by m-CPP was propor­ thermogenic response may be intrinsically linked with tional to the previous nocturnal (i.e., rest phase) tem­ the rest phase of the circadian cycle and possibly sleep perature (T min and Tmean) can now be placed in context. dependent. Considerable evidence shows that sleep or rest-phase As noted earlier, since both clinical depression and temperature is uniquely sensitive to and reflective of antidepressant treatment are associated with changes the organism's metabolic state. First, Aschoff (1981; in the level of nocturnal temperature, it would be Aschoff and Pohl 1970) defined several fundamental of interest to know whether such thermoregulatory cross-species allometric laws by relating basal metabo­ changes result from deviations in a, Tset, or both. At lism to rest-phase temperature. Second, many types the level of the individual neuron, the firing character­ of animals maintain metabolic balance by selectively istics of thermosensitive neurons in the rodent hypo­ readjusting the level of rest phase core temperature dm­ thalamus are modified by both temperature (Parmeg­ ing energetically stressful conditions such as fastmg giani et al. 1987; Hori 1991) and serotonin (Hor~ 1:91). (Ketterson and King 1977; Shapiro and Weathers 1981; A recent report indicates that neuronal respons1v1ty to Berger and Phillips 1988; Daan et al. 1989), heat and serotonin is modified by temperature in hamsters (Hor­ cold stress (Fuller 1984), and circadian (Walker et al. rigan and Horowitz 1990). In light of studies demon­ 1983) and seasonal (Heller et al. 1977) torpor. strating that , which are thought to Several observations suggest that similar ther­ enhance serotonin function, lower nocturnal hypo­ moregulatory strategies exist in humans. Nocturnal thalamic temperature in hamsters (Brown and Seggie temperature normally undergoes selective readjust­ 1988; Duncan et al. 1995), it is possible that one mecha­ ment during the different phases of the menstrual cy­ nism of antidepressant action is to alter the ther­ cle (Lee 1988) as well as during certain psychopatho­ moregulatory characteristics of hypothala~ic neuro~s. logical states that may involve perturbations in energy Further clinical research is needed to elucidate the cir­ balance, such as mood disorders (Avery et al. 1982; cuitry regulating human mood and thermoregulation. Lund et al. 1983; Von Zerssen et al. 1985; Souetre et al. 1988; Severino et al. 1991) and anorexia nervosa (Okamoto et al. 1991). Our finding that the hyperther­ ACKNOWLEDGMENT mic response to m-CPP in humans was proportional to the level of nocturnal temperature seems consistent The authors express their appreciation to Teresa Tolliver for with these established relationships between rest-phase her assistance with the NE and m-CPP assays. temperature and metabolism. Of particular relevance to the present study are an­ imal studies (Hammel 1968; Heller et al. 1974) that show REFERENCES that the change in metabolic heat production that oc­ curs in response to manipulations of hypothalamic tem­ Allen DJ, Marley E (1967): Effect of sympathomimetic a:1d ~!­ perature is proportional to the difference between lied amines on temperature and oxygen consumption m hypothalamic temperature (T hv) and a set-point tem­ chickens. Br J Pharmacol Chemother 31:290-312 perature (Tset). 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