Dopamine D3 receptor agonists produce similar decreases in body temperature and locomotor activity in D3 knock-out and wild-type mice.
The function of the dopamine (DA) D3 receptor, a member of the D2-like family, has not been firmly established. It has been reported that the potency of DA receptor agonists in producing hypothermia and hypolocomotion in rodents correlates more strongly with the in vitro affinity for, or potency (mitogenesis test) at the D3 than the D2 subtype. In order to investigate further the role of D3 receptors in hypothermia and hypolocomotion, we tested the effects of ip administration of three DA receptor agonists reported to be selective for the D3 receptor subtype (7-OH-DPAT, quinelorane and PD 128907) on core temperature and spontaneous locomotor activity in homozygous (D3-/-), heterozygous (D3+/-) mutant and wild-type (D3+/+) mice. Quinelorane (0.003-0.3 mg/kg), PD 128907 (1-10 mg/kg) and 7-OH-DPAT (0.1-3 mg/kg) induced hypothermia and decreased locomotion to a similar extent in the three genotypes. Additionally, the putatively selective DA D3 receptor antagonist PNU 99194A (3-20 mg/kg i.p.) increased locomotor activity in habituated mice and reversed the hypothermia induced by 30 microg/kg of quinelorane, with no apparent difference between D3-/-, D3+/- and D3+/+ genotypes. The spontaneous level of locomotor activity of mutants (D3-/- or D3+/-) was found to be either at, below, or above that of controls, with no consistent trend between different batches of mice. These results show that the presence of DA D3 receptors is not necessary for the expression of these effects induced by the three agonists or the antagonist supposedly selective for the D3 receptor subtype. This raises the question of the involvement of the D3 receptor in these behavioural effects and the issue of the in vivo selectivity of these four compounds for the D3 receptor subtype. Alternatively, possible adaptive mechanisms taking place in D3-/- mice might have compensated for the absence of DA D3 receptors.
Boulay
D
D
Synthélabo Recherche, Bagneux, France.
Depoortere
R
R
Rostene
W
W
Perrault
G
G
Sanger
D J
DJ
D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D001831:Body Temperature / Q000187:drug effects*; D002940:Circadian Rhythm / Q000187:drug effects; D018491:Dopamine Agonists / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D007189:Indans / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects*; D010078:Oxazines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000235:genetics*; D050637:Receptors, Dopamine D3; D013764:Tetrahydronaphthalenes / Q000494:pharmacology
D001578:Benzopyrans; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; C493594:Drd3 protein, mouse; D007189:Indans; D010078:Oxazines; D011804:Quinolines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D013764:Tetrahydronaphthalenes; C062458:3,4,4a,10b-tetrahydro-4-propyl-2H,5H-(1)benzopyrano(4,3-b)-1,4-oxazin-9-ol; C086335:(5,6-dimethoxyindan-2-yl)dipropylamine; C031349:7-hydroxy-2-N,N-dipropylaminotetralin; C047726:quinelorane