Brain stimulation and morphine reward deficits in dopamine D2 receptor-deficient mice.
BACKGROUND
The rewarding effects of lateral hypothalamic brain stimulation, various natural rewards, and several drugs of abuse are attenuated by D1 or D2 dopamine receptor (D1R or D2R) antagonists. Much of the evidence for dopaminergic involvement in rewards is based on pharmacological agents with limited or "relative" selectivity for dopamine receptor subtypes. Genetically engineered animal models provide a complementary approach to pharmacological investigations.


OBJECTIVE
In the present study, we explored the contribution of dopamine D2Rs to (1) brain stimulation reward (BSR) and (2) the potentiation of this behavior by morphine and amphetamine using D2R-deficient mice.


METHODS
Wild-type (D2Rwt), heterozygous (D2Rhet), and D2R knockout (D2Rko) mice were trained to turn a wheel for rewarding brain stimulation. Once equivalent rate-frequency curves were established, morphine-induced (0, 1.0, 3.0, and 5.6 mg/kg s.c.) and amphetamine-induced (0, 1.0, 2.0, and 4.0 mg/kg i.p.) potentiations of BSR were determined.


RESULTS
The D2Rko mice required approximately 50% more stimulation than the D2Rwt mice did. With the equi-rewarding levels of stimulation current, amphetamine potentiated BSR equally across the three genotypes. In contrast, morphine potentiated rewarding stimulation in the D2Rwt, had no effect in the D2Rhet, and antagonized rewarding stimulation in the D2Rko mice.


CONCLUSIONS
D2R elimination decreases, but does not eliminate, the rewarding effects of lateral hypothalamic stimulation. After compensation for this deficit, amphetamine continues to potentiate BSR, while morphine does not.
Elmer
G I
GI
Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland, Maple and Locust Streets, Baltimore, MD 21228, USA. gelmer@mprc.umaryland.edu
Pieper
J O
JO
Levy
J
J
Rubinstein
M
M
Low
M J
MJ
Grandy
D K
DK
Wise
R A
RA
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects*; D001931:Brain Mapping; D003216:Conditioning, Operant / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006579:Heterozygote; D007026:Hypothalamic Area, Lateral / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology*; D009042:Motivation; D017447:Receptors, Dopamine D1 / Q000172:deficiency* / Q000235:genetics; D017448:Receptors, Dopamine D2 / Q000172:deficiency* / Q000235:genetics; D012201:Reward; D012653:Self Stimulation / Q000187:drug effects*
D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D009020:Morphine; D000661:Amphetamine