Dopamine is required for hyperphagia in Lep(ob/ob) mice.
Feeding is a complex process responsive to sensory information related to sight and smell of food, previous feeding experiences, satiety signals elicited by ingestion and hormonal signals related to energy balance. Dopamine released in specific brain regions is associated with pleasurable and rewarding events and may reinforce positive aspects of feeding. Dopamine also influences initiation and coordination of motor activity and is required for sensorimotor functions. Thus, dopamine may facilitate integration of sensory cues related to hunger, initiating the search for food and its consumption. Dopaminergic neurons in the substantia nigra and ventral tegmental area project to the caudate putamen and nucleus accumbens, where they modulate movement and reward. There are projections from the nucleus accumbens to the lateral hypothalamus that regulate feeding. Dopamine-deficient mice (Dbh(Th/+), Th-/-; hereafter DD mice) cannot synthesize dopamine in dopaminergic neurons. They gradually become aphagic and die of starvation. Daily treatment of DD mice with L-3,4-dihydroxyphenylalanine (L-DOPA) transiently restores brain dopamine, locomotion and feeding. Leptin-null (Lep(ob/ob)) mice exhibit obesity, decreased energy expenditure and hyperphagia. As the hypothalamic leptin-melanocortin pathway appears to regulate appetite and metabolism, we generated mice lacking both dopamine and leptin (DD x Lep(ob/ob)) to determine if leptin deficiency overcomes the aphagia of DD mice. DD x Lep(ob/ob) mice became obese when treated daily with L-DOPA, but when L-DOPA treatment was terminated the double mutants were capable of movement, but did not feed. Our data show that dopamine is required for feeding in leptin-null mice.
Szczypka
M S
MS
Howard Hughes Medical Institute and Department of Biochemistry, Box 357370, University of Washington, Seattle, Washington, USA.
Rainey
M A
MA
Palmiter
R D
RD
D000818:Animals; D004298:Dopamine / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D005247:Feeding Behavior / Q000502:physiology; D006963:Hyperphagia / Q000235:genetics* / Q000503:physiopathology; D020738:Leptin / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008820:Mice, Obese / Q000235:genetics*
D020738:Leptin; D004298:Dopamine