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The Journal of Neuroscience, June 15, 2000, 20(12):4405-4413
Dopamine-Deficient Mice Are Hypersensitive to Dopamine Receptor
Agonists
Douglas S.
Kim1,
Mark
S.
Szczypka2, 3, and
Richard D.
Palmiter1, 2, 3
1 Molecular and Cellular Biology Program,
2 Department of Biochemistry, and 3 Howard
Hughes Medical Institute, University of Washington, Seattle,
Washington, 98195-7370
Dopamine-deficient (DA /) mice were created by targeted
inactivation of the tyrosine hydroxylase gene in dopaminergic neurons. The locomotor activity response of these mutants to dopamine D1 or D2
receptor agonists and L-3,4-dihydroxyphenylalanine
(L-DOPA) was 3- to 13-fold greater than the response
elicited from wild-type mice. The enhanced sensitivity of
DA/ mice to agonists was independent of changes in steady-state
levels of dopamine receptors and the presynaptic dopamine transporter
as measured by ligand binding. The acute behavioral response of DA/
mice to a dopamine D1 receptor agonist was correlated with c-fos
induction in the striatum, a brain nucleus that receives dense
dopaminergic input. Chronic replacement of dopamine to DA/ mice by
repeated L-DOPA administration over 4 d relieved the
hypersensitivity of DA/ mutants in terms of induction of both
locomotion and striatal c-fos expression. The results suggest that the
chronic presence of dopaminergic neurotransmission is required to
dampen the intracellular signaling response of striatal neurons.
Key words:
c-Fos; D1 receptor; D2 receptor; caudate putamen; dopamine; dopamine transporter; haloperidol; knock-out mice; L-3,4-dihydroxyphenylalanine (L-DOPA); nucleus
accumbens; quinpirole; SCH 23390; SKF 81297; striatum; substantia
nigra; tyrosine hydroxylase
Copyright © 2000 Society for Neuroscience 0270-6474/00/20124405-09$05.00/0
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