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The Journal of Neuroscience, July 16, 2003, 23(15):6385-6391
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Clozapine Reverses Hyperthermia and Sympathetically Mediated Cutaneous Vasoconstriction Induced by 3,4-Methylenedioxymethamphetamine (Ecstasy) in Rabbits and Rats
W. W. Blessing, B. Seaman, N. P. Pedersen, andY. Ootsuka Centre for Neuroscience, Departments of Medicine and Physiology, Flinders University, Bedford Park, South Australia 5042, Australia
Abstract
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Abstract
Introduction
Life-threatening hyperthermia occurs in some individuals taking 3,4-methylenedioxymethamphetamine (MDMA, ecstasy). In rabbits, sympathetically mediated vasoconstriction in heat-exchanging cutaneous beds (ear pinnae) contributes to MDMA-elicited hyperthermia. We investigated whether MDMA-elicited cutaneous vasoconstriction and hyperthermia are reversed by clozapine and olanzapine, atypical antipsychotic agents. Ear pinna blood flow and body temperature were measured in conscious rabbits; MDMA (6 mg/kg, i.v.) was administered; and clozapine (0.1–5 mg/kg, i.v.) or olanzapine (0.5 mg/kg, i.v.) was administered 15 min later. One hour after MDMA, temperature was 38.7 ± 0.5°C in 5 mg/kg clozapine-treated rabbits and 39.0 ± 0.2°C in olanzapine-treated rabbits, less than untreated animals (41.5 ± 0.3°C) and unchanged from pre-MDMA values. Ear pinna blood flow increased from the MDMA-induced near zero level within 5 min of clozapine or olanzapine administration. Clozapine-induced temperature and flow responses were dose-dependent. In urethane-anesthetized rabbits, MDMA (6 mg/kg, i.v.) increased ear pinna postganglionic sympathetic nerve discharge to 217 ± 33% of the pre-MDMA baseline. Five minutes after clozapine (1 mg/kg, i.v.) discharge was reduced to 10 ± 4% of the MDMA-elicited level. In conscious rats made hyperthermic by MDMA (10 mg/kg, s.c.), body temperature 1 hr after clozapine (3 mg/kg, s.c.) was 36.9 ± 0.5°C, <38.6 ± 0.3°C (Ringer's solution-treated) and not different from the pre-MDMA level. One hour after clozapine, rat tail blood flow was 24 ± 3 cm/sec, greater than both flow in Ringer's solution-treated rats (8 ± 1 cm/sec) and the pre-MDMA level (17 ± 1 cm/sec). Clozapine and olanzapine, by interactions with 5-HT receptors or by other mechanisms, could reverse potentially fatal hyperthermia and cutaneous vasoconstriction occurring in some humans after ingestion of MDMA.
Key words: cutaneous blood flow; cutaneous sympathetic nerve activity; serotonin; 5-HT1A receptors; 5-HT2A receptors; hallucinations; hyperthermia; body temperature; olanzapine; atypical antipsychotic agents
Introduction
Life-threatening and sometimes fatal hyperthermia occurs in some individuals taking 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) or related drugs (Callaway and Clark, 1994; Milroy, 1999
Recently we demonstrated in rabbits that MDMA-elicited hyperthermia is preceded and accompanied by intense vasoconstriction in the ear pinnae, the principal heat-exchanging cutaneous bed in this species (Pedersen and Blessing, 2001
In pilot studies, we screened a number of pharmacological agents to determine whether they would reverse MDMA-elicited cutaneous vasoconstriction and hyperthermia in rabbits. We now present evidence that clozapine, the first atypical antipsychotic agent (Baldessarini and Frankenburg, 1991
Materials and Methods
Experimental procedures were approved by the Flinders University Animal Welfare Committee.Instrumentation for studies in conscious animals. New Zealand White rabbits (2.5–4.5 kg) and Sprague Dawley rats (300–450 gm) were prepared with chronically implanted Doppler ultrasonic flow probes around the ear pinna artery (rabbits) and around the tail and superior mesenteric arteries (rats) as described by Pedersen and Blessing (2001
Data acquisition and statistical analysis for studies in conscious animals. Temperature and Doppler signals were processed (Triton Technology, San Diego, CA) and digitized (40 Hz) using PowerLab and Chart software (AD Instruments, Sydney, New South Wales, Australia) and a Macintosh computer (Apple Computer, Cupertino, CA). After a 30 min control recording, MDMA was administered, and after 15 min in rabbits and 90 min in rats, clozapine or olanzapine was administered. Effects on blood flow and body temperature were recorded for an additional 45 min in rabbits and 60 min in rats.
Data were analyzed with Chart, IgorPro (WaveMetrics, Lake Oswega, OR), and Statview (SAS Institute, Cary, NC) software. Individual 40 Hz traces were averaged over 1, 5, or 10 min. For each animal in a particular condition, we then obtained an overall mean of the pre-MDMA control period. Group data were analyzed by repeated measures ANOVA, with comparison of post-MDMA injection values with the corresponding control mean. We compared posttreatment temperature and flow values with the corresponding values recorded 15 min after MDMA in rabbits and 90 min after MDMA in rats and with the overall value of the pre-MDMA control period. Factorial ANOVA was used to compare corresponding time points in vehicle- and drug-treated animals and to assess the effect of drug dose. Data from anesthetized rabbits were analyzed by repeated measures ANOVA. Fisher's protected least significance difference (PLSD) comparison was used to determine significant differences, with the limit for statistical significance set at the p = 0.05 level. Regression analysis was used to determine whether temperature and ear pinna blood flow responses to clozapine in rabbits were dose-dependent.
Studies in anesthetized rabbits. Rabbits were anesthetized with urethane (1.5 gm/kg, i.v., infused over 30 min). An endotracheal tube was inserted via a tracheostomy. The trunk fur was shaved, and the trunk was enclosed by an aluminum foil water jacket through which it was possible to perfuse water of different temperatures. Arterial pressure was measured via a catheter placed in a femoral artery, and body temperature was measured via a rectal thermistor. Skin temperature was measured by a thermistor glued to the skin over the rib cage. The rabbit was placed in a Kopf stereotaxic apparatus. For the initial part of the experiment, the rabbit breathed oxygen spontaneously. The core temperature was maintained at 39–40°C by perfusing warm water through the water jacket.
A small (
0.1-mm-diameter) nerve trunk was dissected from the central ear branch of the posterior auricular artery
When stable nerve recordings were obtained, we perfused cold water (10°C) through the water jacket, causing skin and body temperature to fall. We verified that this procedure increased the amplitude of the integrated nerve activity, thereby confirming the activity as sympathetic in origin, as previously documented for the tail artery nerve in rats (Owens et al., 2002
Drugs and doses. Racemic MDMA (Australian Government Analytical Laboratories, Sydney, Australia) was dissolved in Ringer's solution. Clozapine (ampoules of 50 mg/2 ml) was kindly supplied by Novartis Pharmaceuticals (Sydney, Australia). Olanzapine (kindly supplied by Eli Lilly and Co., Indianapolis, IN) was dissolved in acidified Ringer's solution and dimethylsulfoxide. In rabbits, drugs were administered intravenously. In rats, drugs were administered subcutaneously. We previously showed that 6 mg/kg intravenous MDMA is a high dose for rabbits, causing hyperthermia-related death in some animals (Pedersen and Blessing, 2001
Results
Ear pinna blood flow and body temperature in conscious rabbits
MDMA gradually increased body temperature and rapidly reduced ear pinna blood flow in rabbits (Figs. 1A, 2). In rabbits given MDMA (6 mg/kg) but no subsequent active drug treatment, body temperature increased from 38.3 ± 0.1 to 41.3 ± 0.1°C measured 45 min after MDMA; ear pinna blood flow decreased from 28 ± 2 to 3 ± 2 cm/sec measured 15 min after MDMA (nine rabbits studied on 13 occasions; p < 0.01, repeated measures ANOVA; Fig. 2A,B; data from some of these rabbits were previously been published by Pedersen and Blessing, 2001
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Figure 1. Effect of MDMA and then clozapine on body temperature and cutaneous blood flow in one rabbit (A, B, intravenous injection of drugs) and in one rat (C, D, subcutaneous injection of drugs). The traces are continuously recorded Doppler ear pinna (rabbit) and tail (rat) signals and telemetrically measured continuously recorded intraperitoneal temperature signals. In both species, administration of MDMA causes intense cutaneous vasoconstriction and increase in body temperature. Both of these effects are reversed by subsequent administration of clozapine.
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Figure 2. Group data (means and SE) in rabbits showing the effect of intravenous MDMA and then clozapine (1 and 5 mg/kg) or olanzapine on body temperature (A) and ear pinna blood flow (B). Data points at time 0 are means and SE of the preinjection control period. Two rabbits in the MDMA-no treatment group were killed 45 min after MDMA. Numbers of rabbits: see Results for number of rabbits in MDMA-no treatment group; n = 7 for clozapine 1 mg/kg; n = 5 for clozapine 5 mg/kg; n = 6 for olanzapine 0.5 mg/kg. Symbols for analysis by repeated measures ANOVA and Fisher's PLSD comparison in A: ##significantly greater than pre-MDMA control temperature value (no treatment group, F(12,144) = 77.44; p < 0.0001; clozapine 1 mg/kg group, F(12,60) = 17.61; p < 0.001; clozapine 5 mg/kg group F(12,48) = 3.68; p < 0.01; olanzapine group, F(12,60) = 33.48; p < 0.001); **significantly greater than pre-MDMA control value (F values as above; p < 0.0001 for no treatment group; p < 0.001 for clozapine 1 mg/kg group); significantly <30 min post-MDMA value (F values as above; p < 0.001 for clozapine 5 mg/kg group; p < 0.0001 for olanzapine group); ns, not significantly different from pre-MDMA control value (F values as above; p > 0.05 for clozapine 5 mg/kg group; p > 0.05 for olanzapine group). Symbols for analysis by factorial ANOVA and Fisher's PLSD comparison in A:
significantly <60 min post-MDMA temperature in MDMA-no treatment rabbits (F(3,26) = 17.503; clozapine 1 mg/kg group, p < 0.001; clozapine 5 mg/kg group, p < 0.0001; olanzapine group p < 0.0001). Symbols for analysis by repeated measures ANOVA and Fisher's PLSD comparison in B: ##significantly less than pre-MDMA ear pinna blood flow control value (no treatment group, F(12,144) = 28.26; p < 0.0001; clozapine 1 mg/kg group, F(12,72) = 13.28; p < 0.0001; clozapine 5 mg/kg group, F(12,48) = 18.29; p < 0.0001; olanzapine group, F(12,60) = 14.57; p < 0.0001); **significantly less than pre-MDMA control value (F values as above; p < 0.0001 for no treatment group; p < 0.0001 for olanzapine group);
significantly greater than pre-MDMA control value (F values as above; p < 0.01);
Low-dose clozapine (0.1 or 0.5 mg/kg) did not substantially reduce the hyperthermia elicited by MDMA, and some of these rabbits died or were killed before the experiment could be completed. The maximum increase in body temperature in MDMA-injected animals treated with 0.5 mg/kg clozapine (n = 4) was 3.8 ± 0.7°C, not significantly different from the maximum increase in untreated MDMA-injected animals [F(1,12) = 4.26; p > 0.05, factorial ANOVA]. In some MDMA-treated rabbits, ear pinna blood flow did increase after clozapine at 0.5 mg/kg, but the effect was quite variable and inconsistent, so statistical analysis was not appropriate.
After clozapine (1 mg/kg administered 15 min after MDMA), all rabbits remained well. Body temperature 1 hr after MDMA (45 min after clozapine) was less than the corresponding temperature in untreated animals but still greater than the pre-MDMA control value (Fig. 2A). In these rabbits, ear pinna blood flow rapidly increased after administration of 1 mg/kg clozapine (Fig. 2B), with values 5–45 min after clozapine (20–60 min after MDMA) being greater than the preclozapine value recorded 15 min after administration and also reduced the MDMA-provoked rise of body temperature, so that 60 min after MDMA, body temperature was 38.7 ± 0.5°C in clozapine-treated animals and 39.0 ± 0.2°C in olanzapine-treated animals. These temperatures were significantly <41.5 ± 0.3°C, the corresponding temperature 60 min after MDMA in untreated animals, and not significantly different from the pre-MDMA control temperature levels in the same rabbits (Fig. 2A). As determined by repeated measures ANOVA and Fisher's PLSD comparison, ear pinna blood flow increased significantly within 5 min of administration of 5 mg/kg clozapine [F(12,48) = 18.29; p < 0.001] and olanzapine [F(12,60) = 14.57; p < 0.05] and remained at a higher level for the duration of the observation period (Fig. 2B). At the 60 min post-MDMA time point, ear pinna blood flow in rabbits treated with 5 mg/kg clozapine was significantly higher than the pre-MDMA control blood flow level (Fig, 2B).
Linear regression analysis yielded a significant inverse relationship between logarithmic doses of clozapine (1 and 5 mg/kg) and body temperature at the 60 min post-MDMA time point [F(1,9) = 5.26; p < 0.05]. Similarly, linear regression analysis yielded a significant relationship between logarithmic doses of clozapine (1 and 5 mg/kg) and the level of blood flow at the 60 min post-MDMA time point [F(1,10) = 10.75; p < 0.01]. The effects of clozapine in reversing MDMA-elicited changes in temperature and ear pinna blood flow were thus dose-dependent.
Ear pinna sympathetic nerve activity and body temperature in anesthetized rabbits
When the trunk skin was cooled, the recorded ear pinna sympathetic nerve activity gradually increased in all five rabbits, so that 5 min after onset of cooling, the integrated nerve activity signal was 154 ± 14% of the precooling baseline [F(1,4) = 72.19; p < 0.01]. MDMA (6 mg/kg, i.v., over
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Figure 3. Effect in one anesthetized rabbit of MDMA and then clozapine on ear pinna sympathetic nerve activity (A), integrated (30 sec bins) ear pinna sympathetic nerve activity (B), body temperature (C), and arterial pressure (D). The circled numbers (1–4) in A correspond to the circled numbers on the x-axis in D, indicating the experimental period during which the nerve recording was made. The 10 min time base bar in D also applies for B and C.
MDMA increased core body temperature (Fig. 3C) from 38.8 ± 0.2 to 39.7 ± 0.4°C within 15 min of administration [F(1,4) = 8.87; p < 0.05]. MDMA caused a transient rise in arterial pressure (Fig. 3D), but 15 min after MDMA, there was no overall significant change in arterial pressure [102 ± 7 and 101 ± 5 mmHg before and after MDMA, respectively; F(2,8) = 22.66; p > 0.05]. Clozapine (1 mg/kg, i.v.) caused a moderate fall in arterial pressure, so that 5 min after clozapine, arterial pressure had fallen from 102 ± 7 (pre-MDMA level) to 72 ± 6 mmHg [F(2,8) = 22.66; p < 0.01].
Body temperature and tail artery blood flow in conscious rats
MDMA (10 mg/kg) increased body temperature in rats (Figs. 1C, 4A). Ninety minutes after subcutaneous injection of MDMA, body temperature had increased from 37.2 ± 0.1 to 38.1 ± 0.2°C in the group to be treated with vehicle and from 36.7 ± 0.1 to 38.4 ± 0.2°C in the group to be treated with clozapine (Fig. 4A). At this time, we administered either Ringer's solution (0.5 ml) or clozapine (3 mg/kg) subcutaneously. Clozapine rapidly and substantially decreased body temperature (Figs. 1C, 4A), so that 60 min after clozapine, temperature had fallen to 36.9 ± 0.5°C, substantially <38.6 ± 0.3°C, the corresponding value in Ringer's solution-treated animals and not significantly different from the pre-MDMA temperature value (Fig. 4A).
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Figure 4. Group data (means and SE) in rats showing effect of subcutaneous MDMA and then Ringer's solution or clozapine on body temperature (A), tail blood flow (B), and superior mesenteric blood flow (C). Data points at time 0 are means and SE of the preinjection control period. Numbers of rats: n = 6 for MDMA and Ringer's solution; n = 5 for MDMA and clozapine for temperature and tail flow studies; n = 4 for mesenteric flow study. Symbols for analysis by repeated measures ANOVA and Fisher's PLSD comparison in A: ##significantly greater than pre-MDMA control temperature (Ringer's solution group, F(15,75) = 15.52; p < 0.0001; clozapine group, F(15,60) = 19.82; p < 0.001); **significantly greater than pre-MDMA control value (F values as above; p < 0.0001);
MDMA substantially decreased rat tail artery blood flow (Figs. 1D,4B). Ninety minutes after injection of MDMA, mean tail artery flow had decreased from 14 ± 1 to 8 ± 2 cm/sec in the group to be treated with Ringer's solution and from 17 ± 1 to 5 ± 2 cm/sec in the group to be treated with clozapine (Fig. 4B). Clozapine (3 mg/kg) administered 90 min after MDMA rapidly increased tail blood flow (Fig. 4B), with the increase being sustained so that by the end of the observation period (150 min after MDMA and 60 min after clozapine), tail flow was 24 ± 3 cm/sec, >8 ± 1 cm/sec, the corresponding flow level in Ringer's solution-treated rats, and >17 ± 1 cm/sec, the control level recorded before injection of MDMA (Fig. 4B). MDMA did not change blood flow in the rat superior mesenteric bed (Fig. 4C). Subsequent administration of clozapine slightly increased superior mesenteric flow (Fig. 4C).
Discussion
Clozapine and olanzapine, atypical antipsychotic agents in clinical use in psychiatry, reverse severe and potentially fatal hyperthermia elicited by MDMA. Reversal of hyperthermia occurs in association with reversal of cutaneous vasoconstriction. Effects of clozapine are dose-dependent. Pedersen and Blessing (2001Mechanisms whereby clozapine reverses MDMA changes
Our electrophysiological multifiber recordings of nerve discharge confirm that MDMA causes cutaneous vasoconstriction by activating sympathetic nerves innervating the cutaneous bed, and that clozapine reverses this vasoconstriction by inhibiting neural activity. In a study by Pedersen and Blessing (2001Pharmacological mechanisms underlying the dose-dependent reversal of MDMA-elicited hyperthermia and cutaneous vasoconstriction by clozapine remain to be elucidated. Body temperature depends on both heat production and heat loss and is therefore a particularly complex variable to study. Presumably, effects on both heat production and heat loss contributed to the reversal of MDMA-induced hyperthermia observed in our study. MDMA increases motor activity (Gordon et al., 1991
MDMA is thought to act by releasing a neurotransmitter from 5-HT, other monoamine neurons, or both or possibly by acting as a direct agonist at 5-HT receptors, dopamine receptors, other monoamine receptors, or a combination thereof (Rattray, 1991
-adrenoreceptors (Arnt and Skarsfeldt, 1998
Body temperature can be altered by both 5-HT1A and 5-HT2A receptor mechanisms. Activation of 5-HT1A receptors with specific agonists such as 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) lowers body temperature (Gudelsky et al., 1986
Activation of 5-HT2A receptors by direct agonists raises body temperature (Gudelsky et al., 1986
Clozapine and olanzapine, both potent antihallucinogenic agents in humans, have an antagonist action at 5-HT2A receptors (Kehne et al., 1996
MDMA and clozapine might alter cutaneous vasomotor tone via bulbospinal sympathetic premotor neurons in the medullary raphe nuclei, via effects at the spinal level, or both
Recent evidence suggests that neurons in the rostral medullary raphe region mediate nociceptive- and temperature-related changes in vasomotor tone in cutaneous vascular beds (Smith et al., 1998Psychotropic and cutaneous vasomotor effects of clozapine
We have documented a close link between the perception of potentially stressful environmental events and sudden falls in cutaneous blood flow (Yu and Blessing, 1997Conclusions
Clozapine and olanzapine reverse MDMA-elicited cutaneous vasoconstriction and hyperthermia in rabbits. Clozapine reverses MDMA-elicited increases in the discharge of sympathetic nerves supplying the cutaneous vessels, so that cutaneous vasodilatation occurs. Bodenham and Mallick (1996
Footnotes
Received Jan. 2, 2003; revised May. 6, 2003; accepted May. 7, 2003.This work was supported by the National Health and Medical Research Council. We thank Kate Barber, Melissa Blair, and Robyn Flook for technical assistance and Dr. Eugene Nalivaiko and Dr. Sue O'Brien for constructive criticism of this manuscript.
Correspondence should be addressed to Dr. W. Blessing, Department of Medicine, Flinders Medical Centre, Bedford Park, South Australia 5042, Australia. E-mail; w.w.blessing{at}flinders.edu.au.
Copyright © 2003 Society for Neuroscience 0270-6474/03/236385-07$15.00/0
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