Dopamine D-2 receptor knock-out mice are insensitive to the hypolocomotor and hypothermic effects of dopamine D-2/D-3 receptor agonists

The dopamine (DA) D2-like family of receptors is comprised of three subtype s, the D-2, D-3, and D-4 receptors. It has been suggested that the potency of DA receptor agonists to produce hypothermia and hypolocomotion in rodent s correlates more strongly with the in vitro affinity for, or potency (mito genesis test) at the D-3 than at the D-2 subtype. However, it has recently been reported that when tested in DA D-3 receptor knock-out mice, several D A D-2/D-3 receptor agonists (7-OH-DPAT, PD 128907 and quinelorane) induced levels of hypothermia and decreases of locomotor activity similar to those obtained in control (wild-type) mice. These results do not argue in favour of an implication of DA D-3 receptors in these in vivo effects. In order to investigate whether the DA D-2 receptor is the subtype that mediates hypot hermia and hypolocomotion produced by DA D-2/D-3 receptor agonists, we test ed the effects of ip administration of the DA D-2/D-3 receptor agonists 7-O H-DPAT and PD 128907, on core temperature and locomotor activity in DA D-2 receptor knock-out mice (homozygotes: D-2(-/-) and heterozygotes: D-2(+/-)) , and in wild-type (D-2(+/+)) mice. 7-OH-DPAT (0.1-3 mg/kg) and PD 128907 ( 1-10 mg/kg) induced hypothermia and decreased locomotion in D-2(+/+) mice, but had no effects in D-2(-/-) mice; the magnitude of the hypothermic and l ocomotor-reducing effects of these two agonists in D-2(+/-) mutants was app roximately half that of D-2(+/+) mice. During the first 10 min in the activ ity chambers, the level of spontaneous locomotor activity of D-2(-/-) indiv iduals was almost 50% below that of D-2(+/+) mice; basal locomotor activity of D-2(+/-) mice was between that of D-2(-/-) and D,+'+individuals. Neithe r type of mutant showed spontaneous catalepsy or deficits in forelimb muscl e strength (grip-strength test). These results show that the presence of DA D-2 receptors is necessary for the expression of the locomotor- and core t emperature-decreasing effects of DA D-2/D-3 receptor agonists such as 7-OH- DPAT and PD 128907. (C) 1999 Elsevier Science Ltd. All rights reserved.