Locomotor and discriminative-stimulus effects of cocaine in dopamine D5 receptor knockout mice.
BACKGROUND
Dopamine D1-like antagonists block several effects of cocaine, including its locomotor-stimulant and discriminative-stimulus effects. Because these compounds generally lack selectivity among the dopamine D1 and D5 receptors, the specific roles of the subtypes have not been determined.


OBJECTIVE
Dopamine D5 receptor knockout (DA D5R KO), heterozygous (HET) and wild-type (WT) mice were used to study the role of D5 dopamine receptors in the effects of cocaine. In addition, effects of the D1-like antagonist, SCH 39166 were also studied to further clarify the roles of D1 and D5 dopamine receptors in the discriminative-stimulus effects of cocaine.


METHODS
DA D5R KO, HET and WT mice were treated with cocaine (3-30 mg/kg) or vehicle and their horizontal locomotor activity was assessed. The mice were also trained to discriminate IP injections of saline from cocaine (10 mg/kg) using a two-lever food-reinforcement (FR10) procedure. Doses of cocaine (1.0-10 mg/kg) were administered 5 min before 15-min test-sessions.


RESULTS
Cocaine dose-dependently stimulated activity in each genotype, with the highest level of activity induced in the DA D5R WT mice. Both DA D5R KO and HET mice showed reduced levels of horizontal activity compared to WT mice. All three genotypes acquired the discrimination of 10 mg/kg cocaine; doses of 1.0-10.0 mg/kg produced dose-related increases in the number of cocaine-appropriate responses. SCH 39166, at inactive to fully active doses (0.01-0.1 mg/kg) produced predominately saline-appropriate responding. SCH 39166 produced a dose-dependent rightward shift in the cocaine dose-effect curve in all genotypes, with similar apparent affinities.


CONCLUSIONS
The present data suggest an involvement of DA D5R in the locomotor stimulant effects of cocaine. In addition, the data indicate that there is little involvement of the DA D5R in the discriminative-stimulus effects of cocaine. In addition, the antagonism data suggest a role of the D1 receptor in the behavioral effects of cocaine.
Elliot
Elizabeth E
EE
Department of Public Health, Adelaide University, 5005 South Australia, Australia.
Sibley
David R
DR
Katz
Jonathan L
JL
D000818:Animals; D001552:Benzazepines / Q000008:administration & dosage / Q000493:pharmacokinetics; D003042:Cocaine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004193:Discrimination Learning / Q000187:drug effects; D004192:Discrimination, Psychological / Q000187:drug effects*; D018492:Dopamine Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D006579:Heterozygote; D008297:Male; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics* / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects*; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000235:genetics* / Q000502:physiology; D050641:Receptors, Dopamine D5
D001552:Benzazepines; D018492:Dopamine Antagonists; C493606:Drd5 protein, mouse; D017447:Receptors, Dopamine D1; C058081:ecopipam; D050641:Receptors, Dopamine D5; D003042:Cocaine