ELSEVIER Antidepressant Drug-Induced Hypothalamic Cooling in Syrian Hamsters Wallace C. Duncan, Jr., Ph.D., Kimberly A. Johnson, B.A., and Thomas A. Wehr, M.D. Antidepressant drugs have been reported to alter the decreased more than peritoneal temperature (Tp), thus circadian pattern of body temperature, but specific effects reducing the temperature difference between the on the amplitude or on average body temperature are not hypothalamus and the peritoneal cavity. Less general consistent, and there have been no specific studies to effects of the antidepressants were also observed. examine chronic drug effects on brain temperature. To Clorgyline and fluoxetine, but not lithium, delayed the address these issues, hypothalamic temperature (Thy) was 24-hour rhythm of Thy, Clorgyline and lithium, but not monitored telemetrically in hamsters treated with three fluoxetine decreased the average 24-hour Thy, The antidepressant drugs: the monoamine oxidase inhibitor neuroleptics chlorpromazine and haloperidol decreased the (MAOI), clorgyline; the SHT reuptake inhibitor, amplitude of the 24-hour Thy rhythm. The fact that fluoxetine; and the alkali metal, lithium. For comparison, chronic antidepressant drugs, but not neuroleptic drugs, hamsters were also treated with two neuroleptic drugs, decrease Thy is consistent with their different chlorpromazine and haloperidol. Each of the three neurotransmitter effects and clinical applications, and antidepressant drugs, but neither of the neuroleptic raises the possibility that their antidepressant property drugs, produced a chronic decrease in diurnal (rest-phase) might be related to their capacity to decrease Thy during hypothalamic temperature. The Thy-decreasing effect of sleep. [Neuropsychopharmacology 12:17-37, 1995] clorgyline was not prevented by pinealectomy, and Thy KEY WORDS: Body temperature; Hypothalamus; 1986; Lund 1987; Souetre et al. 1988). These observa­ Circadian rhythm; Depression; Serotonin; tions suggest that impaired regulation of the circadian Antidepressant drugs variation in Tb is part of the pathophysiology of depression. Primary depression is often characterized by abnormal­ Pharmacological and nonpharmacological treat­ ities in the circadian phase, amplitude, and/or body ments of depression restore a more normal daily pat­ temperature level (Tb) (Tupin 1970; Mellerup et al. tern of Tb in patients with these abnormalities. For ex­ 1978; Pflug et al. 1981; Avery et al. 1982; Beersma et ample, tricyclic antidepressant drugs (Souetre et al. al. 1983; Lund et al. 1983; Schulz and Lund 1983; van 1988), lithium (Mellerup et al. 1978; Lund 1987), elec­ den Hoofdakker and Beersma 1985; Avery et al. 1986; troconvulsive therapy (Avery et al. 1986), and bright Goetze and Tolle 1987; Elsenga and Van den Hoofdak­ light (Rosenthal et al. 1990) are reported to either in­ ker 1988; Souetre et al. 1988), which are sometimes crease the circadian amplitude of Tb, and/or to de­ reversed in remission (Pflug et al. 1981; A very et al. crease average Tb during sleep. Chronic antidepres­ sant drug treatment (Fernstrom et al. 1985), bright light From the Oinical Psychobiology Branch, NIMH, NIH, Bethesda, treatment (Gaist et al. 1990), and sleep deprivation ther­ Maryland. apy (Wu et al. 1991) have also been reported to decrease Address correspondence to: Wallace C. Duncan, Jr., Ph.D., Room total or regional brain glucose utilization in humans. 4S-239, Building 10, NIMH, Bethesda, Maryland 20892. Received November 8, 1993; revised June 21, 1994; accepted July The fact that a variety of pharmacological and nonphar­ 2, 1994. macological treatments tend to restore a more normal NEUROPSYCHOPHARMACOLOGY 1995-VOL. 12, NO. 1 © 1995 American College of Neuropsychopharmacology Published by Elsevier Science Inc. 0893-133X/95/$9 .50 655 Avenue of the Americas, New York, NY 10010 SSDI 0893-133X(94)00055-5 18 W.C. Duncan, Jr., et al. NEUROPSYCHOPHARMACOLOGY 1995-VOL. 12, NO. 1 circadian pattern of Tb suggests that daily variation in Mitter, Inc.) were implanted in order to concurrently Tb is an important correlate of clinical antidepressant record peritoneal temperature (resolution = 0.02°C). response. These transmitters were located between the ileum and Relatively few animal studies have examined the abdominal wall. Surgical procedures for transmit­ chronic effects of antidepressant treatments on Tb. ter implants and pinealectomy were conducted under Most have focused on acute effects (Oark and Clark sodium pentobarbital anaesthesia (90 mg/kg, IP). Iden­ 1980; Oark and Lipton 1986). Brown and Seggie (1988) tity of extracted pineals was verifted histologically. observed a decrease in radiotelemetry-monitored peri­ After surgery, hamsters were individually housed toneal temperature (Tp) during chronic treatment of in ventilated and sound-attenuated chambers (Napco rats with desipramine (DMI). Our group (Gao et al. Model 3810) with free access to food and water. Animals 1991) observed a decrease in radiotelemetry-monitored were maintained under LD 14:10 (L: 0100-1500 hours, Tp in Syrian hamsters chronically treated with the D: 1500-0100 hours) or in constant darkness (DD) in monoamine oxidase inhibitor (MAOI) and clorgyline, an ambient temperature of 22 ± 1 °C. Light intensity 2 and a decrease in Thy was observed during treatment within the chamber was 10 µ W to 20 µ W cm- • Ham­ with the selective 5HT reuptake inhibitor fluoxetine sters were allowed at least 7 days to recover from sur­ (Gao et al. 1992). Others have reported that chronic DMI gery, and recovery was judged to have occurred when treatment decreased glucose utilization in the rat brain the rhythm stabilized. (Gerber et al. 1983), and chronic electroconvulsive stim­ Hamsters received clorgyline (2 mg/kg/d; ad­ ulation decreased rectal temperature in mice (Gleiter ministered SC via mini osmotic pumps (Alzet Model et al. 1989). The results of these studies suggest that 2002), fluoxetine (Eli Lilly and Company; 2, 10, or 20 chronic antidepressant treatments may chronically al­ mg/kg/d; administered in a liquid diet, lithium (0.075% ter Tb. to 0.45%, administered in chow), chlorpromazine (In­ In the current experiments, effects of chronic treat­ novative Research of America; implanted SC as a ment with antidepressant and neuroleptic drugs on 3-week, 25 mg pellet), or haloperidol (Haldol Decono­ brain temperature are examined within the hypothala­ ate 100, McNeil Pharmaceutical; administered IM; or mus, the location of a central thermostat that controls implanted SC as a 3-week, 25 mg haloperidol pellet; a variety of themoregulatory functions. To reduce the Innovative Research of America). In these experiments, effects of stress on thermoregulatory physiology (Ber­ different routes of drug delivery were used in order to key et al. 1990), we used radiotelemetry techniques to achieve appropriate clinical doses whereby minimiz­ measure temperature in freely moving animals. We ing stress to the animals. During fluoxetine treatment, speciftcally investigated whether antidepressant and the caloric intake of fluoxetine-treated hamsters was neuroleptic drug treatments alter the amplitude, phase, yoked to that of a control group. Consumption was or level of hypothalamic temperature (Thy), as would monitored daily and little evidence of spillage was ob­ be predicted on the basis of results of previous studies served. In the course of the experiment, orbital blood (Mellerup et al. 1978; Avery et al. 1986; Lund 1987; samples were taken from anesthetized hamsters to ob­ Souetre et al. 1988; Rosenthal et al. 1990). tain measurements of plasma lithium or fluoxetine lev­ els. At the end of the experiment, blood samples were collected by cardiac puncture to obtain measurements METHODS of plasma chlorpromazine or haloperidol levels. At the Animals and Procedures end of the experiment, the animals were sacriftced and their brains rapidly frozen on dry ice, cut into 30 µm Male golden hamsters (Mesocricetus auratus, LGV: lak, sections, and examined for placements of transmitter Charles River), 12 weeks to 16 weeks old weighing ap­ probes. All probe tips were verifted to have been in the proximately 140 grams, were used in all studies. Prior hypothalamus. Following the experiment, transmitters to surgery, animals were group-housed in LD 14:10 were recalibrated and found to be consistent with with access to food and water ad libitum. Transmitters presurgery calibration levels. (Model XM-FH, Mini-Mitter, Inc.) for recording hypo­ thalamic temperature (resolution = 0.02°C) were im­ Data planted using dental cement. Temperature-sensitive Collection and Analysis probes were positioned with their tips (:::::460µ diameter) Thy (0 C) was recorded telemetrically every 5 minutes, in the hypothalamus using the following stereotaxic and data were stored on a laboratory computer. Twen­ coordinates (with bregma and lambda in the same ty-four hour waveforms were analyzed after reducing horizontal plane): 0.25 mm posterior to bregma, 1.8 mm data to 15 minute averages. Chronic drug effects were lateral to midline, and 7.3 mm below the skull. In visually examined and plotted for each animal after cal­ selected hamsters, immediately following hypothalamic culating 2-hour averages. Between 5 days and 7 days probe surgery, transmitters (Model TM-Disc, Mini- of continuously monitoring, temperatures were se- NEUROPSYCHOPHARMACOLOGY 1995-VOL. 12, NO. 1 Antidepressant Drug-Induced Hypothalamic Cooling 19 lected to represent baseline (BL), subchronic (WEEK 1), RESULTS OF CHRONIC ANTIDEPRESSANT