Dopamine is required for hyperphagia in Lep(ob/ob) mice

Feeding is a complex process responsive to sensory information related to s ight and smell of food, previous feeding experiences, satiety signals elici ted by ingestion and hormonal signals related to energy balance. Dopamine r eleased in specific brain regions is associated with pleasurable and reward ing events(1,2) and may reinforce positive aspects of feeding. Dopamine als o influences initiation and coordination of motor activity and is required for sensorimotor functions(3-5). Thus, dopamine may facilitate integration of sensory cues related to hunger, initiating the search for food and its c onsumption. Dopaminergic neurons in the substantia nigra and ventral tegmen tal area project to the caudate putamen and nucleus accumbens, where they m odulate movement and reward(2,6-8). There are projections from the nucleus accumbens to the lateral hypothalamus that regulate feeding(9). Dopamine-de ficient mice (Dbh(Th/s+), Th-/-; hereafter DD mice) cannot synthesize dopam ine in dopaminergic neurons. They gradually become aphagic and die of starv ation. 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 hyperph agia. As the hypothalamic leptin-melanocortin pathway appears to regulate a ppetite and metabolism(10), we generated mice lacking both dopamine and lep tin (DDxLep(ob/ob)) to determine if leptin deficiency overcomes the aphagia of DD mice. DDxLep(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.