Evidence that dopamine D3 receptors participate in clozapine-induced hypothermia.
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 D2/D3 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.
Millan
M J
MJ
Institut de Recherches Servier, Centre de Recherches de Croissy, Croissy-sur-Seine (Paris), France.
Audinot
V
V
Melon
C
C
Newman-Tancredi
A
A
D015081:2-Naphthylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D016466:CHO Cells; D003024:Clozapine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006224:Cricetinae; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005663:Furans / Q000494:pharmacology; D006801:Humans; D007035:Hypothermia / Q000139:chemically induced* / Q000503:physiopathology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D011954:Receptors, Dopamine / Q000187:drug effects / Q000502:physiology*; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism; D050637:Receptors, Dopamine D3; D013237:Stereoisomerism; D013764:Tetrahydronaphthalenes / Q000494:pharmacology
C493593:DRD3 protein, human; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; C493595:Drd3 protein, rat; D005663:Furans; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D013764:Tetrahydronaphthalenes; C090812:7-(N,N-dipropylamino)-5,6,7,8-tetrahydronaphtho(2,3-b)dihydro-2,3-furan; D015081:2-Naphthylamine; D003024:Clozapine; C031349:7-hydroxy-2-N,N-dipropylaminotetralin