Evidence that dopamine D3 receptors participate in clozapine-induced hypothermia

doi:10.1016/0014-2999(95)00250-O

European Journal of Pharmacology

Volume 280, Issue 2, 4 July 1995, Pages 225-229

https://doi.org/10.1016/0014-2999(95)00250-O Get rights and content

Abstract

In analogy to the dopamine D₃ receptor agonist, (+)-7-OH-DPAT (7-hydroxy-2-(di-n-propylamino)tetralin) (0.01–0.63 mg/kg s.c.), clozapine dose-dependently (0.63–40.0 mg/kg s.c.) elicited hypothermia in rats. Haloperidol and raclopride, mixed dopamine $D_{2} D_{3}$ receptor antagonists, failed, in contrast, to modify core temperature. Further, they dose-dependently inhibited the action of clozapine with inhibitory dose₅₀ values (ID₅₀) of 0.3 mg/kg s.c., in each case. The preferential dopamine D₃ versus D₂ receptor antagonist, (+)-AJ 76 (cis-(+)-5-methoxy-1-methyl-2-(n-propylamino)tetralin) (ID₅₀ = 2.8), and the selective dopamine D₃ versus D₂ receptor antagonist, (±)-S 11566 ((±)-[7-(N,N-dipropylamino)-5,6,7,8-tetrahydro-naphtho(2,3b) dihydro,2,3-furane]) (ID₅₀ = 1.6) likewise blocked the action of clozapine without reducing core temperature alone. The action of (±)-S 11566 was stereospecific in that its active eutomer, (+)-S 14297 (ID₅₀ = 1.0), also inhibited the action of clozapine whereas its inactive distomer, (−)-S 17777 (ID₅₀ > 10.0), was not effective. Antagonist potency for blockade of clozapine-induced hypothermia correlated powerfully both with potency for blockade of (+)-7-OH-DPAT-induced hypothermia (r = 0.98) and with affinity at cloned human dopamine D₃ receptors transfected into Chinese hamster ovary (CHO) cells (r = 0.92). In conclusion, these data suggest that dopamine D₃ receptors may be involved in the induction of hypothermia by clozapine in the rat.

References (15)

M.J. Millan et al.
(+)-S 14297, a novel selective ligand at cloned human dopamine D₃ receptors, blocks (+)-7-OH-DPAT-induced hypothermia in rats
Eur. J. Pharmacol.
(1994)
J.-M. Rivet et al.
Modulation of mesolimbic dopamine release by the selective dopamine D₃ receptor antagonist, (+)-S 14297
Eur. J. Pharmacol.
(1994)
P. Salmi et al.
Antagonism by SCH 23390 of clozapine-induced hypothermia in the rat
Eur. J. Pharmacol.
(1994)
P. Sokoloff et al.
Pharmacology of human dopamine D₃ receptor expressed in mammalian cell line: comparison with D₂ receptor
Eur. J. Pharmacol.
(1992)
M. Vasse et al.
The rise of body temperature induced by the stimulation of dopamine D₁ receptors is increased in acutely reserpinized mice
Eur. J. Pharmacol.
(1990)
P.H. Andersen et al.
Evidence for different states of the dopamine D₁ receptor: clozapine and fluperlapine may preferentially label an adenylate cyclase-coupled state of the D₁ receptor
J. Neurochem.
(1986)
J. Arnt
Behavioural studies of dopamine receptors: evidence for regional selectivity and receptor multiplicity

There are more references available in the full text version of this article.

Cited by (28)

Environmental and behavioral controls of the expression of clozapine tolerance: Evidence from a novel across-model transfer paradigm
2013, Behavioural Brain Research
Citation Excerpt :
The involvement of dopamine receptor-mediated processes in CLZ tolerance is also supported by early findings showing that repeated CLZ treatment leads to a suppressed firing (i.e. depolarization inactivation) of dopamine neurons in the ventral tegmental area but not in the substantia nigra and a suppressed release of dopamine in the nucleus accumbens but not in the striatum [43,44]. Since CLZ also acts on many other receptors (e.g. 5-HT2A/2C, D1, D3, α1-noradrenergic, etc.), of which some have been implicated in CLZ tolerance [45–47], future work should systematically investigate the role of these receptors in the mediation of CLZ tolerance and its contextual and behavioral controls. The present study illustrates the power of environmental and behavioral variables on the expression of CLZ tolerance.
Repeated administration of antipsychotic drugs induces a sensitization-like or tolerance-like effect in many behavioral tasks, including the conditioned avoidance response (CAR) and the phencyclidine (PCP)-induced hyperlocomotion, two rodent models with high predictive validity for antipsychotic activity. This study investigated the impacts of contextual and behavioral variables on the expression of clozapine tolerance using a recently validated across-model transfer paradigm (Zhang and Li, 2012 [1]). Male Sprague-Dawley rats were first repeatedly treated with clozapine (2.5–10.0 mg/kg, sc) in the CAR model or PCP (1.6 mg/kg, sc)-induced hyperlocomotion model for five consecutive days. They were then tested for the expression of clozapine tolerance in another model for another 5 days. Finally, all rats were switched back to the original model and tested again for the expression of clozapine tolerance. When tested in the PCP model, rats previously treated with clozapine in the CAR model did not show an immediate weaker inhibition of PCP-induced hyperlocomotion than those treated with clozapine for the first time, but showed a significantly weaker inhibition over time. In contrast, when tested in the CAR model, rats previously treated with clozapine in the PCP model showed an immediate weaker disruption of avoidance response than those treated with clozapine for the first time, but this weaker effect diminished over time. These results suggest that the expression of clozapine tolerance is strongly modulated by the test environment and/or selected behavioral response. Clozapine tolerance and its situational specificity may be related to the drug's low extrapyramidal motor side effect, its superior therapeutic efficacy and/or emergence of clozapine withdrawal syndrome.
Clozapine and olanzapine exhibit an intrinsic anxiolytic property in two conditioned fear paradigms: Contrast with haloperidol and chlordiazepoxide
2008, Pharmacology Biochemistry and Behavior
Psychotic fear and anxiety disturbances are seen at a relatively high frequency in patients with schizophrenia. Atypical anti-psychotics are believed to show superior efficacy in reducing these symptoms. However, clinical and preclinical evidence regarding their anxiolytic efficacy has been mixed. In this study, we evaluated the possible anxiolytic property of two atypicals clozapine and olanzapine and compared them with typical haloperidol and chlordiazepoxide (a prototype of sedative-anxiolytic drug) in two preclinical models of fear. In Experiment 1, we used a fear-induced passive avoidance and conditioned place aversion paradigm and examined the effects of clozapine (20 mg/kg, sc), haloperidol (0.05 mg/kg, sc) and chlordiazepoxide (10 mg/kg, ip). In Experiments 2 and 3, we used a two-way active avoidance conditioning paradigm and further compared the effects of clozapine (20 mg/kg, sc), haloperidol (0.05 mg/kg, sc), chlordiazepoxide (10 mg/kg, ip) and three doses of olanzapine (0.5, 1.0, and 2.0 mg/kg, sc). Results show that clozapine and chlordiazepoxide, but not haloperidol, significantly attenuated the shock conditioning-induced place aversion, decreased the amount of defecations and the number of the 22-kHz vocalizations. Clozapine also reduced the shock conditioning-induced hyperthermia. Similar to clozapine, olanzapine also significantly decreased the amount of defecations and reduced the shock conditioning-induced hyperthermia, but it did not inhibit the 22-kHz vocalizations. This study demonstrates that clozapine and olanzapine possess an intrinsic anxiolytic property, which is not attributable to its superior anti-“psychotic” effect or its favorable effects on motor functions or learning and memory processes. These findings also suggest that the combined use of passive avoidance and active avoidance conditioning models can be useful in better differentiating typical and atypical anti-psychotics as well as anxiolytics.
Safety pharmacology assessment of central nervous system function in juvenile and adult rats: Effects of pharmacological reference compounds
2008, Journal of Pharmacological and Toxicological Methods
Recent EU/US pediatric legislation and FDA/EMEA guidelines recognize the potential differences in safety profiles of drugs in adults versus young patients. Hence safety studies are recommended to investigate key functional domains of e.g. the developing CNS. Methods: Selected psychoactive stimulants (caffeine, d-amphetamine, scopolamine) and depressants (baclofen, diazepam, haloperidol, chlorpromazine, imipramine, morphine) were characterized upon single administration with regard to behavioural parameters, locomotor activity, body temperature, pro-/anti-convulsive activity (pentylenetetrazole, PTZ), and nocifensive responses (hotplate) in neonatal (2 weeks), juvenile (4 weeks) and adult rats (8–9 weeks). Results: In vehicle-treated rats, behavioural patterns matured with age, locomotor activity and handling-induced rise in body temperature were enhanced, whereas PTZ convulsion threshold dose and nocifensive response latency decreased. Single test compound treatment elicited behavioural effects characteristic for psychoactive drugs with stimulating and depressing properties regardless of age. However, incidence of certain behaviours, and magnitude of effects on locomotor activity and body temperature varied with age and became generally more pronounced in adult rats. Pro-/anti-convulsive effects and delayed nocifensive responses did not differ between juvenile and adult rats. Conclusion: CNS effects of selected psychoactive reference compounds were qualitatively similar, but quantitatively different in neonatal, juvenile and adult rats.
Clozapine does not induce a motor impairment in operant responding for heat reinforcement
2000, Pharmacology Biochemistry and Behavior
This experiment examined the effects of intraperitoneal (i.p.) clozapine (CLZ) compared to haloperidol (HAL) on operant responding for heat reinforcement in a cold environment (−8°C). Three doses of CLZ (1, 3 and 5 mg/kg) were found to dose-dependently increase responding for heat while lowering core temperature (T_c) only at the highest dose. Three doses of HAL (0.1, 0.3 and 0.5 mg/kg) dose-dependently decreased operant responding which resulted in a dose-dependent decrease in T_c. The highest dose of CLZ was then tested in two other paradigms: a reinforcement schedule in which heat was available as long as the lever was held down, and a temperature gradient (range 7–45°C) in which access to heat required minimal motor effort. The ad libitum reinforcement schedule still did not provide enough heat to overcome the hypothermic effects of CLZ. However, in the gradient, rats receiving CLZ selected a warmer region of the gradient, and T_c was higher than that of controls. These data support CLZ's reputation for having minimal motor side effects. Unlike HAL, the hypothermic effects of CLZ appear to be unrelated to effects of the drug on movement.
Clozapine is a partial agonist at cloned, human serotonin 5-HT<inf>1A</inf> receptors
1996, Neuropharmacology
Clozapine exhibited 10-fold higher affinity than haloperidol for human 5-HT_1A receptors expressed in Chinese Hamster Ovary cells (CHO-h5-HT_1A) (K_is = 160 and 1910 nM respectively). Whereas haloperidol did not alter the basal binding of [³⁵S]GTPγS to CHO-h5HT_1A membranes, clozapine stimulated it with an EC₅₀ of 2320 nM and an efficacy of 49% (compared to 5-HT). The stimulation was antagonized by the selective 5-HT_1A receptor antagonist, WAY 100635 (1 nM).
A case report of acute hypothermia during initial inpatient clozapine titration with review of current literature on clozapine-induced temperature dysregulations
2020, BMC Psychiatry

View all citing articles on Scopus

View full text

Short communicationEvidence that dopamine D3 receptors participate in clozapine-induced hypothermia

Abstract

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Evidence for different states of the dopamine D1 receptor: clozapine and fluperlapine may preferentially label an adenylate cyclase-coupled state of the D1 receptor

J. Neurochem.

Behavioural studies of dopamine receptors: evidence for regional selectivity and receptor multiplicity

Short communication
Evidence that dopamine D₃ receptors participate in clozapine-induced hypothermia

Evidence for different states of the dopamine D₁ receptor: clozapine and fluperlapine may preferentially label an adenylate cyclase-coupled state of the D₁ receptor