Dopamine-deficient mice are hypersensitive to dopamine receptor agonists.
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.
Kim
D S
DS
Molecular and Cellular Biology Program, Department of Biochemistry, and Howard Hughes Medical Institute, University of Washington, Seattle, Washington, 98195-7370, USA.
Szczypka
M S
MS
Palmiter
R D
RD
D000818:Animals; D001345:Autoradiography; D001549:Benzamides / Q000493:pharmacokinetics; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D003042:Cocaine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000172:deficiency*; D018491:Dopamine Agonists / Q000494:pharmacology*; D050483:Dopamine Plasma Membrane Transport Proteins; D004299:Dopamine beta-Hydroxylase / Q000235:genetics / Q000378:metabolism*; D007457:Iodine Radioisotopes; D007980:Levodopa / Q000494:pharmacology*; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects*; D009419:Nerve Tissue Proteins; D011759:Pyrrolidines / Q000493:pharmacokinetics; D011954:Receptors, Dopamine / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D001549:Benzamides; D002352:Carrier Proteins; D018491:Dopamine Agonists; D050483:Dopamine Plasma Membrane Transport Proteins; D007457:Iodine Radioisotopes; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D011759:Pyrrolidines; D011954:Receptors, Dopamine; C063525:epidepride; C079213:RTI 121; D007980:Levodopa; D014446:Tyrosine 3-Monooxygenase; D004299:Dopamine beta-Hydroxylase; D003042:Cocaine; D004298:Dopamine