Abstract
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.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Autoradiography
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Benzamides / pharmacokinetics
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Brain / drug effects
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Brain / metabolism*
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Carrier Proteins / metabolism*
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Cocaine / analogs & derivatives
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Cocaine / pharmacokinetics
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Corpus Striatum / drug effects
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Corpus Striatum / metabolism
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Dopamine / deficiency*
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Dopamine Agonists / pharmacology*
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Dopamine Plasma Membrane Transport Proteins
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Dopamine beta-Hydroxylase / genetics
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Dopamine beta-Hydroxylase / metabolism*
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Iodine Radioisotopes
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Levodopa / pharmacology*
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Membrane Glycoproteins*
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Membrane Transport Proteins*
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Mice
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Mice, Knockout
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Mice, Transgenic
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Motor Activity / drug effects*
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Nerve Tissue Proteins*
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Pyrrolidines / pharmacokinetics
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Receptors, Dopamine / metabolism*
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Tyrosine 3-Monooxygenase / deficiency
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Tyrosine 3-Monooxygenase / genetics
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Tyrosine 3-Monooxygenase / metabolism*
Substances
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Benzamides
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Carrier Proteins
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Dopamine Agonists
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Dopamine Plasma Membrane Transport Proteins
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Iodine Radioisotopes
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Membrane Glycoproteins
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Membrane Transport Proteins
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Nerve Tissue Proteins
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Pyrrolidines
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Receptors, Dopamine
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epidepride
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RTI 121
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Levodopa
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Tyrosine 3-Monooxygenase
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Dopamine beta-Hydroxylase
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Cocaine
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Dopamine