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Dihydrexidine produces hypothermia in rats via activation of dopamine D1 receptors
Neuroscience Letters 236 (1997) 57–59
Dihydrexidine produces hypothermia in rats via activation of dopamine D1 receptors Peter Salmi a , b ,*, Sven Ahlenius b a
Division of Biological Psychology, Department of Psychology, Stockholm University, Stockholm, Sweden b Department of Pharmacology, Astra Arcus AB, S-151 85 So¨derta¨lje, Sweden Received 28 July 1997; received in revised form 25 September 1997; accepted 26 September 1997
Abstract The selective dopamine D1 receptor agonist dihydrexidine (2.0–8.0 mg/kg, s.c.) caused a dose-dependent decrease in core temperature in rats. The hypothermia produced by dihydrexidine (4.0 mg/kg), was completely blocked by the dopamine D1 receptor antagonists SCH 23390 (0.1 mg/kg, s.c.) or NNC 687 (4.0 mg/kg, s.c.), but not by the dopamine D2/3 receptor antagonist raclopride (0.2 mg/kg, s.c.). Neither of the dopamine antagonists by themselves produced any effects on core temperature. The present results provide important evidence for the notion that activation of dopamine D1 receptors induces hypothermia in rats. 1997 Elsevier Science Ireland Ltd.
Keywords: Dopamine; Dopamine D1 receptor; Thermoregulation; Rats
The role of dopamine in body temperature regulation in rats is well documented. Studies with selective dopamine D2/3 receptor agonists, such as quinpirole, have shown that activation of this dopamine receptor subtype results in hypothermia that is blocked with selective dopamine D2/3 receptor antagonists [5,9,10]. Studies on the role of dopamine D1 receptors, however, have been hampered by lack of specific and selective pharmacological tools. Thus, activation of dopamine D1 receptors, by use of the classical dopamine D1 receptor agonist SKF 38393, have given conflicting results. This compound, which is a partial agonist at dopamine D1 receptors, has been shown to have no effects, to produce hyperthermia or to act synergistically with dopamine D2/3 receptor agonists in rats [5,8,10,12]. Recently, we reported that the administration of the selective and full dopamine D1 receptor agonist A 68930 [4], produces hypothermia in rats [10]. This hypothermia was completely blocked by the dopamine D1 receptor antagonist SCH 23390, but not by the dopamine D2/3 receptor antagonist raclopride. Thus, it appears that hypothermia can be produced via activation of either dopamine D1 or D2/3 receptors, * Corresponding author. Tel.: +46 8 55327759; e-mail: [email protected]
suggesting distinct roles of dopamine D1 and D2/3 receptors in temperature regulation. In order to exclude a possible contamination of these effects due to lack of selectivity, we have in the present study used the structurally different, full dopamine D1 receptor agonist dihydrexidine [7], as well as the two different dopamine D1 receptor antagonists SCH 23390 and NNC 687 to further examine the role of dopamine D1 receptors in rat thermoregulatory mechanisms. Adult male Sprague–Dawley rats (280–320 g) (B and K Universal AB, Sollentuna, Sweden) were used. The rats were housed five per cage (Makrolon IV), under controlled conditions of temperature (21.0 ± 0.4°C), relative humidity (55–65%) and light-dark cycle (12:12 h, lights off at 0600 h). Food (R36, Ewos, So¨derta¨lje, Sweden) and tap water were available ad libitum. The rats arrived in the laboratory at least 1 week before being used in the experiments. Drugs used in the experiments were: dihydrexidine HCl (Tocris, Bristol, UK), raclopride tartrate (Astra Arcus, So¨derta¨lje, Sweden), R(+)-7-chloro-8-hydroxy-1-phenyl2,3,4,5,-tetrahydro-1H-benzazepine HCl (SCH 23390) (RBI), (+)-5-(2,3-dihydrobenzofuran-7-yl)-3-methyl-8nitro-2,3,4,5-tetrahydro-1H-3-benzazepine-7-ol, maleate (NNC 687) (Novo Nordisk AS, Bagsvaerd, Denmark).
0304-3940/97/$17.00 1997 Elsevier Science Ireland Ltd. All rights reserved PII S0304- 3940(97) 00740- 4
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P. Salmi, S. Ahlenius / Neuroscience Letters 236 (1997) 57–59
way analysis of variance, followed by Dunnett’s t-test for comparison with controls, or Student’s t-test for comparisons between two groups only [13]. Dihydrexidine (2.0–8.0 mg/kg) caused a dose-dependent decrease in core temperature (Fig. 1). Time for maximal effects was 20 min after administration, and the duration of effect was ,2 h, although inspection of data in the figure suggests a somewhat longer duration at the highest dose (8.0 mg/kg). The hypothermia produced by dihydrexidine (4.0 mg/kg), was completely blocked by SCH 23390 (0.1 mg/kg) or by NNC 687 (4.0 mg/kg), but not by raclopride (0.2 mg/
Fig. 1. Effects of dihydrexidine on core temperature in rats. Dihydrexidine was administered s.c. in the dose-range 2.0–8.0 mg/kg, and core temperature was recorded 20–120 min. thereafter. The predrug temperature is shown at 0 min in the figure. The results are presented as the mean ± SD based on five animals per group. Statistical analysis was performed by means of a one-way ANOVA, followed by the Dunnett’s t-test for comparisons with saline-treated controls, at the respective time interval. (X) Saline, (B) 2.0 mg/kg, (P) 4.0 mg/kg (♦) 8.0 mg/kg. nsP . 0.05, **P , 0.01.
The doses of drugs refer to the form indicated above. NNC 687 was dissolved in a minimal amount of glacial acetic acid and made up to volume in isotonic glucose, while the other compounds were dissolved in physiological saline. All injections were made subcutaneously in a volume of 2 ml/ kg. Core temperature was measured in a temperature-controlled room (ambient temperature 21.0 ± 0.4°C). The rats were habituated to the experimental procedure, including core temperature measurement readings, the day before experiments. On the day of experiments, the animals were transferred to the room 1 h before the experiments started and were housed in a ventilated cabinet between temperature measurements. The rats were individually identified, and for each experiment every nth rat was assigned to one of the n different treatment or dose groups (including controls). The core temperature was recorded by means of a commercially available telethermometer (YSI-2100, Yellow Springs Instruments, Yellow Springs, OH, USA) and an accompanying probe (YSI-402). The probe, lubricated with mucilago etalosi AF-68 (ACO La¨kemedel AB, Stockholm, Sweden), was inserted rectally (about 90 mm) in gently hand-restrained rats. The telethermometer was connected to an automatic printer device (Metod and Produkt Svenska AB, Va¨stra Fro¨lunda, Sweden) that was activated when the temperature reading had stabilized (±0.1°C) for 10 s, for further details see [11]. All experiments were carried out between 0900 and 1400 h. Statistical evaluation was performed by means of one-
Fig. 2. Antagonism of dihydrexidine-induced hypothermia in rats by SCH 23390 or NNC 687, but not by raclopride. Dihydrexidine (4.0 mg/kg, s.c.) was administered 25 min before temperature readings. SCH 23390 (0.1 mg/kg, s.c.), NNC 687 (4.0 mg/kg, s.c.) or raclopride (0.2 mg/kg, s.c.) were given 5 min before dihydrexidine. The results are presented as the mean ± SD based on 4–8 animals per group. Statistical analysis was performed by means of a one-way ANOVA, followed by the Dunnett’s t-test for comparisons with saline-treated controls, or the Student’s t-test for comparisons as indicated by brackets in the figure. Open bar, saline; fine grid, dihydrexidine; coarse grid, dihydrexidine + SCH 23390, NNC 687 or raclopride. ns P>0.05, **P , 0.01.
P. Salmi, S. Ahlenius / Neuroscience Letters 236 (1997) 57–59 Table 1 Effects of SCH 23390, NNC 687 and raclopride on core temperature in rats. SCH 23390 (0.1 mg/kg), NNC 687 (4.0 mg/kg) or raclopride (0.2 mg/kg) was administered 30 min before temperature readings Control
38.7 ± 0.3
NNC 687 SCH 23390 Raclopride
39.1 ± 0.3 38.8 ± 0.2 38.8 ± 0.1
Data are the mean ± SD based on 4–12 animals per group. Statistical analysis was performed by means of a one-way ANOVA. F3,22 = 2.76, P>0.05.
kg) (Fig. 2). By themselves, neither of the antagonists, in doses used in the present study, produced any effects on core temperature (Table 1). In agreement with an earlier study, activation of dopamine D1 receptors resulted in hypothermia in rats [10]. This hypothermia, produced by the selective full dopamine D1 receptor agonist dihydrexidine, was antagonised by either of the two dopamine D1 receptor antagonists, SCH 23390 or NNC 687, but not by the dopamine D2/3 receptor antagonist raclopride. Although SCH 23390 displays considerable affinity also for 5-HT2 receptors [6], this seems not to be of importance in the present context, since NNC 687 has a very low affinity for this 5-HT receptor sub-type [1]. Furthermore, both SCH 23390 and NNC 687 display low affinity for other receptors, as for example a1, a2 and b-adrenoceptors, as well as 5-HT1A and dopamine D2 receptors [1]. All together, this provides strong support for the notion that activation of dopamine D1 receptors by dihydrexidine induces hypothermia in rats. Previous studies on the role of dopamine D1 receptors in temperature regulation in rats have given contradictory results. These results are mainly based on the use of SKF 38393 as a dopamine D1 receptor agonist, and SKF 38393 has been shown to have no effects, to produce hyperthermia or to act synergistically with dopamine D2 receptor agonists [5,8,10,12]. One explanation for these conflicting results may be the partial dopamine D1 receptor properties of this compound. In fact, hypothermia produced by the selective full dopamine D1 receptor agonist A 68930 can be completely antagonised by SKF 38393, providing support for the partial agonistic properties of SKF 38393 [10]. In support for independent roles of dopamine D1 and D2/3 receptors in body temperature regulation in rats, we recently found that the selective dopamine D1 and D2/3 receptor agonists, A 68930 and 7-OH-DPAT, respectively, interact in an additive, rather than a synergistic, manner (Salmi, 1997, submitted). Thus, hypothermia produced by A 68930 was augmented in an additive manner by a sub-threshold dose of 7-OH-DPAT, and vice versa. Based on work with dopamine, and the non-selective dopamine receptor agonist apomorphine, the preoptic area of the anterior hypothalamus has been suggested as a likely
59
target for hypothermic effects produced by systemically administered dopamine receptor agonists [2,3]. However, the involvement of this brain area for effects produced by dihydrexidine remains to be demonstrated. In conclusion, the dopamine D1 receptor agonist dihydrexidine produced hypothermia that was antagonised by either of the dopamine D1 receptor antagonists SCH 23390 or NNC 687, but not by the dopamine D2/3 receptor antagonist raclopride. This supports the notion that activation of dopamine D1 receptors induces hypothermia in rats. The animal experiments were approved by the Stockholm South Local Committee on Ethics of Animal Experimentation. This study was generously supported by Astra Arcus AB, So¨derta¨lje, Sweden. [1] Andersen, P.H., Grønvald, F.C., Hohlweg, R., Hansen, L.B., Guddal, E., Braestrup, C. and Nielsen, E.B., NNC-112, NNC687 and NNC-756, new selective and highly potent dopamine D1 receptor antagonists, Eur. J. Pharmacol., 219 (1992) 45–52. [2] Colboc, O. and Costentin, J., Evidence for thermoregulatory dopaminergic receptors located in the preopticus medialis nucleus of the rat hypothalamus, J. Pharm. Pharmacol., 32 (1980) 624–629. [3] Cox, B., Kerwin, R. and Lee, T.F., Dopamine receptors in the central thermoregulatory pathways of the rat, J. Physiol., 282 (1978) 471–483. [4] DeNinno, M.P., Schoenleber, R., Mackenzie, R., Britton, D.R., Asin, K.E., Briggs, C., Trugman, J.M., Ackerman, M., Artman, L., Bednarz, R., Bhatt, R., Curzon, P., Gomez, E., Kang, C.H., Stittsworth, J. and Kebabian, J.W., A 68930: a potent agonist selective for the dopamine D1 receptor, Eur. J. Pharmacol., 199 (1991) 209–219. [5] Faunt, J.E. and Crocker, A.D., The effects of selective dopamine receptor agonists on body temperature in rats, Eur. J. Pharmacol., 133 (1987) 243–247. [6] Hyttel, J., SCH 23390 – the first selective dopamine D-1 receptor antagonist, Eur. J. Pharmacol., 91 (1983) 153–154. [7] Mottola, D.M., Brewster, W.K., Cook, L.L., Nichols, D.E. and Mailman, R.B., Dihydrexidine, a novel full efficacy D1 dopamine receptor agonist, J. Pharmacol. Exp. Ther., 262 (1992) 383– 393. [8] Nagashima, M., Yamada, K., Kimura, H., Matsumoto, S.-I. and Furukawa, T., Hyperthermia induced by the dopamine D1 receptor agonist SKF 38393 in combination with the dopamine D2 receptor agonist talipexole in the rat, Pharmacol. Biochem. Behav., 43 (1992) 993–997. ¨ gren, S.-O. and Fuxe, K., Apomorphine and pergolide induce [9] O hypothermia by stimulation of dopamine D2 receptors, Acta Physiol. Scand., 133 (1988) 91–95. [10] Salmi, P., Jimenez, P. and Ahlenius, S., Evidence for specific involvement of dopamine D1 and D2 receptors in the regulation of body temperature in the rat, Eur. J. Pharmacol., 236 (1993) 395–400. [11] Salmi, P., Karlsson, T. and Ahlenius, S., Antagonism by SCH 23390 of clozapine-induced hypothermia in the rat, Eur. J. Pharmacol., 253 (1994) 67–73. [12] Verma, A. and Kulkarni, S.K., Dopamine receptor mediated hypothermic action of B-HT 920 in rats, J. Pharm. Pharmacol., 43 (1991) 421–424. [13] Winer, B.J., Statistical Principles in Experimental Design, McGraw-Hill, New York, 1971.
Dihydrexidine produces hypothermia in rats via activation of dopamine D1 receptors Peter Salmi a , b ,*, Sven Ahlenius b a
Division of Biological Psychology, Department of Psychology, Stockholm University, Stockholm, Sweden b Department of Pharmacology, Astra Arcus AB, S-151 85 So¨derta¨lje, Sweden Received 28 July 1997; received in revised form 25 September 1997; accepted 26 September 1997
Abstract The selective dopamine D1 receptor agonist dihydrexidine (2.0–8.0 mg/kg, s.c.) caused a dose-dependent decrease in core temperature in rats. The hypothermia produced by dihydrexidine (4.0 mg/kg), was completely blocked by the dopamine D1 receptor antagonists SCH 23390 (0.1 mg/kg, s.c.) or NNC 687 (4.0 mg/kg, s.c.), but not by the dopamine D2/3 receptor antagonist raclopride (0.2 mg/kg, s.c.). Neither of the dopamine antagonists by themselves produced any effects on core temperature. The present results provide important evidence for the notion that activation of dopamine D1 receptors induces hypothermia in rats. 1997 Elsevier Science Ireland Ltd.
Keywords: Dopamine; Dopamine D1 receptor; Thermoregulation; Rats
The role of dopamine in body temperature regulation in rats is well documented. Studies with selective dopamine D2/3 receptor agonists, such as quinpirole, have shown that activation of this dopamine receptor subtype results in hypothermia that is blocked with selective dopamine D2/3 receptor antagonists [5,9,10]. Studies on the role of dopamine D1 receptors, however, have been hampered by lack of specific and selective pharmacological tools. Thus, activation of dopamine D1 receptors, by use of the classical dopamine D1 receptor agonist SKF 38393, have given conflicting results. This compound, which is a partial agonist at dopamine D1 receptors, has been shown to have no effects, to produce hyperthermia or to act synergistically with dopamine D2/3 receptor agonists in rats [5,8,10,12]. Recently, we reported that the administration of the selective and full dopamine D1 receptor agonist A 68930 [4], produces hypothermia in rats [10]. This hypothermia was completely blocked by the dopamine D1 receptor antagonist SCH 23390, but not by the dopamine D2/3 receptor antagonist raclopride. Thus, it appears that hypothermia can be produced via activation of either dopamine D1 or D2/3 receptors, * Corresponding author. Tel.: +46 8 55327759; e-mail: [email protected]
suggesting distinct roles of dopamine D1 and D2/3 receptors in temperature regulation. In order to exclude a possible contamination of these effects due to lack of selectivity, we have in the present study used the structurally different, full dopamine D1 receptor agonist dihydrexidine [7], as well as the two different dopamine D1 receptor antagonists SCH 23390 and NNC 687 to further examine the role of dopamine D1 receptors in rat thermoregulatory mechanisms. Adult male Sprague–Dawley rats (280–320 g) (B and K Universal AB, Sollentuna, Sweden) were used. The rats were housed five per cage (Makrolon IV), under controlled conditions of temperature (21.0 ± 0.4°C), relative humidity (55–65%) and light-dark cycle (12:12 h, lights off at 0600 h). Food (R36, Ewos, So¨derta¨lje, Sweden) and tap water were available ad libitum. The rats arrived in the laboratory at least 1 week before being used in the experiments. Drugs used in the experiments were: dihydrexidine HCl (Tocris, Bristol, UK), raclopride tartrate (Astra Arcus, So¨derta¨lje, Sweden), R(+)-7-chloro-8-hydroxy-1-phenyl2,3,4,5,-tetrahydro-1H-benzazepine HCl (SCH 23390) (RBI), (+)-5-(2,3-dihydrobenzofuran-7-yl)-3-methyl-8nitro-2,3,4,5-tetrahydro-1H-3-benzazepine-7-ol, maleate (NNC 687) (Novo Nordisk AS, Bagsvaerd, Denmark).
0304-3940/97/$17.00 1997 Elsevier Science Ireland Ltd. All rights reserved PII S0304- 3940(97) 00740- 4
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P. Salmi, S. Ahlenius / Neuroscience Letters 236 (1997) 57–59
way analysis of variance, followed by Dunnett’s t-test for comparison with controls, or Student’s t-test for comparisons between two groups only [13]. Dihydrexidine (2.0–8.0 mg/kg) caused a dose-dependent decrease in core temperature (Fig. 1). Time for maximal effects was 20 min after administration, and the duration of effect was ,2 h, although inspection of data in the figure suggests a somewhat longer duration at the highest dose (8.0 mg/kg). The hypothermia produced by dihydrexidine (4.0 mg/kg), was completely blocked by SCH 23390 (0.1 mg/kg) or by NNC 687 (4.0 mg/kg), but not by raclopride (0.2 mg/
Fig. 1. Effects of dihydrexidine on core temperature in rats. Dihydrexidine was administered s.c. in the dose-range 2.0–8.0 mg/kg, and core temperature was recorded 20–120 min. thereafter. The predrug temperature is shown at 0 min in the figure. The results are presented as the mean ± SD based on five animals per group. Statistical analysis was performed by means of a one-way ANOVA, followed by the Dunnett’s t-test for comparisons with saline-treated controls, at the respective time interval. (X) Saline, (B) 2.0 mg/kg, (P) 4.0 mg/kg (♦) 8.0 mg/kg. nsP . 0.05, **P , 0.01.
The doses of drugs refer to the form indicated above. NNC 687 was dissolved in a minimal amount of glacial acetic acid and made up to volume in isotonic glucose, while the other compounds were dissolved in physiological saline. All injections were made subcutaneously in a volume of 2 ml/ kg. Core temperature was measured in a temperature-controlled room (ambient temperature 21.0 ± 0.4°C). The rats were habituated to the experimental procedure, including core temperature measurement readings, the day before experiments. On the day of experiments, the animals were transferred to the room 1 h before the experiments started and were housed in a ventilated cabinet between temperature measurements. The rats were individually identified, and for each experiment every nth rat was assigned to one of the n different treatment or dose groups (including controls). The core temperature was recorded by means of a commercially available telethermometer (YSI-2100, Yellow Springs Instruments, Yellow Springs, OH, USA) and an accompanying probe (YSI-402). The probe, lubricated with mucilago etalosi AF-68 (ACO La¨kemedel AB, Stockholm, Sweden), was inserted rectally (about 90 mm) in gently hand-restrained rats. The telethermometer was connected to an automatic printer device (Metod and Produkt Svenska AB, Va¨stra Fro¨lunda, Sweden) that was activated when the temperature reading had stabilized (±0.1°C) for 10 s, for further details see [11]. All experiments were carried out between 0900 and 1400 h. Statistical evaluation was performed by means of one-
Fig. 2. Antagonism of dihydrexidine-induced hypothermia in rats by SCH 23390 or NNC 687, but not by raclopride. Dihydrexidine (4.0 mg/kg, s.c.) was administered 25 min before temperature readings. SCH 23390 (0.1 mg/kg, s.c.), NNC 687 (4.0 mg/kg, s.c.) or raclopride (0.2 mg/kg, s.c.) were given 5 min before dihydrexidine. The results are presented as the mean ± SD based on 4–8 animals per group. Statistical analysis was performed by means of a one-way ANOVA, followed by the Dunnett’s t-test for comparisons with saline-treated controls, or the Student’s t-test for comparisons as indicated by brackets in the figure. Open bar, saline; fine grid, dihydrexidine; coarse grid, dihydrexidine + SCH 23390, NNC 687 or raclopride. ns P>0.05, **P , 0.01.
P. Salmi, S. Ahlenius / Neuroscience Letters 236 (1997) 57–59 Table 1 Effects of SCH 23390, NNC 687 and raclopride on core temperature in rats. SCH 23390 (0.1 mg/kg), NNC 687 (4.0 mg/kg) or raclopride (0.2 mg/kg) was administered 30 min before temperature readings Control
38.7 ± 0.3
NNC 687 SCH 23390 Raclopride
39.1 ± 0.3 38.8 ± 0.2 38.8 ± 0.1
Data are the mean ± SD based on 4–12 animals per group. Statistical analysis was performed by means of a one-way ANOVA. F3,22 = 2.76, P>0.05.
kg) (Fig. 2). By themselves, neither of the antagonists, in doses used in the present study, produced any effects on core temperature (Table 1). In agreement with an earlier study, activation of dopamine D1 receptors resulted in hypothermia in rats [10]. This hypothermia, produced by the selective full dopamine D1 receptor agonist dihydrexidine, was antagonised by either of the two dopamine D1 receptor antagonists, SCH 23390 or NNC 687, but not by the dopamine D2/3 receptor antagonist raclopride. Although SCH 23390 displays considerable affinity also for 5-HT2 receptors [6], this seems not to be of importance in the present context, since NNC 687 has a very low affinity for this 5-HT receptor sub-type [1]. Furthermore, both SCH 23390 and NNC 687 display low affinity for other receptors, as for example a1, a2 and b-adrenoceptors, as well as 5-HT1A and dopamine D2 receptors [1]. All together, this provides strong support for the notion that activation of dopamine D1 receptors by dihydrexidine induces hypothermia in rats. Previous studies on the role of dopamine D1 receptors in temperature regulation in rats have given contradictory results. These results are mainly based on the use of SKF 38393 as a dopamine D1 receptor agonist, and SKF 38393 has been shown to have no effects, to produce hyperthermia or to act synergistically with dopamine D2 receptor agonists [5,8,10,12]. One explanation for these conflicting results may be the partial dopamine D1 receptor properties of this compound. In fact, hypothermia produced by the selective full dopamine D1 receptor agonist A 68930 can be completely antagonised by SKF 38393, providing support for the partial agonistic properties of SKF 38393 [10]. In support for independent roles of dopamine D1 and D2/3 receptors in body temperature regulation in rats, we recently found that the selective dopamine D1 and D2/3 receptor agonists, A 68930 and 7-OH-DPAT, respectively, interact in an additive, rather than a synergistic, manner (Salmi, 1997, submitted). Thus, hypothermia produced by A 68930 was augmented in an additive manner by a sub-threshold dose of 7-OH-DPAT, and vice versa. Based on work with dopamine, and the non-selective dopamine receptor agonist apomorphine, the preoptic area of the anterior hypothalamus has been suggested as a likely
59
target for hypothermic effects produced by systemically administered dopamine receptor agonists [2,3]. However, the involvement of this brain area for effects produced by dihydrexidine remains to be demonstrated. In conclusion, the dopamine D1 receptor agonist dihydrexidine produced hypothermia that was antagonised by either of the dopamine D1 receptor antagonists SCH 23390 or NNC 687, but not by the dopamine D2/3 receptor antagonist raclopride. This supports the notion that activation of dopamine D1 receptors induces hypothermia in rats. The animal experiments were approved by the Stockholm South Local Committee on Ethics of Animal Experimentation. This study was generously supported by Astra Arcus AB, So¨derta¨lje, Sweden. [1] Andersen, P.H., Grønvald, F.C., Hohlweg, R., Hansen, L.B., Guddal, E., Braestrup, C. and Nielsen, E.B., NNC-112, NNC687 and NNC-756, new selective and highly potent dopamine D1 receptor antagonists, Eur. J. Pharmacol., 219 (1992) 45–52. [2] Colboc, O. and Costentin, J., Evidence for thermoregulatory dopaminergic receptors located in the preopticus medialis nucleus of the rat hypothalamus, J. Pharm. Pharmacol., 32 (1980) 624–629. [3] Cox, B., Kerwin, R. and Lee, T.F., Dopamine receptors in the central thermoregulatory pathways of the rat, J. Physiol., 282 (1978) 471–483. [4] DeNinno, M.P., Schoenleber, R., Mackenzie, R., Britton, D.R., Asin, K.E., Briggs, C., Trugman, J.M., Ackerman, M., Artman, L., Bednarz, R., Bhatt, R., Curzon, P., Gomez, E., Kang, C.H., Stittsworth, J. and Kebabian, J.W., A 68930: a potent agonist selective for the dopamine D1 receptor, Eur. J. Pharmacol., 199 (1991) 209–219. [5] Faunt, J.E. and Crocker, A.D., The effects of selective dopamine receptor agonists on body temperature in rats, Eur. J. Pharmacol., 133 (1987) 243–247. [6] Hyttel, J., SCH 23390 – the first selective dopamine D-1 receptor antagonist, Eur. J. Pharmacol., 91 (1983) 153–154. [7] Mottola, D.M., Brewster, W.K., Cook, L.L., Nichols, D.E. and Mailman, R.B., Dihydrexidine, a novel full efficacy D1 dopamine receptor agonist, J. Pharmacol. Exp. Ther., 262 (1992) 383– 393. [8] Nagashima, M., Yamada, K., Kimura, H., Matsumoto, S.-I. and Furukawa, T., Hyperthermia induced by the dopamine D1 receptor agonist SKF 38393 in combination with the dopamine D2 receptor agonist talipexole in the rat, Pharmacol. Biochem. Behav., 43 (1992) 993–997. ¨ gren, S.-O. and Fuxe, K., Apomorphine and pergolide induce [9] O hypothermia by stimulation of dopamine D2 receptors, Acta Physiol. Scand., 133 (1988) 91–95. [10] Salmi, P., Jimenez, P. and Ahlenius, S., Evidence for specific involvement of dopamine D1 and D2 receptors in the regulation of body temperature in the rat, Eur. J. Pharmacol., 236 (1993) 395–400. [11] Salmi, P., Karlsson, T. and Ahlenius, S., Antagonism by SCH 23390 of clozapine-induced hypothermia in the rat, Eur. J. Pharmacol., 253 (1994) 67–73. [12] Verma, A. and Kulkarni, S.K., Dopamine receptor mediated hypothermic action of B-HT 920 in rats, J. Pharm. Pharmacol., 43 (1991) 421–424. [13] Winer, B.J., Statistical Principles in Experimental Design, McGraw-Hill, New York, 1971.