Viral gene delivery selectively restores feeding and prevents lethality ofdopamine-deficient mice

Dopamine-deficient mice (DA(-/-)), lacking tyrosine hydroxylase (TH) in dop aminergic neurons, become hypoactive and aphagic and die by 4 weeks of age. They are rescued by daily treatment with LB, Q-dihydroxyphenylalanine (L-D OPA); each dose restores dopamine (DA) and feeding for less than 24 hr. Rec ombinant adeno-associated viruses expressing human TH or GTP cyclohydrolase 1 (GTPCH1) were injected into the striatum of DA(-/-) mice. Bilateral coin jection of both viruses restored feeding behavior for several months. Howev er, locomotor activity and coordination were partially improved. A virus ex pressing only TH was less effective, and one expressing GTPCH1 alone was in effective. TH immunoreactivity and DA were detected in the ventral striatum and adjacent posterior regions of rescued mice, suggesting that these regi ons mediate a critical DA-dependent aspect of feeding behavior.