Dopamine-dependent desensitization of dopaminergic signaling in the developing mouse striatum.
The dynamics of dopamine receptor signaling efficacy were characterized in developing mice by measuring striatal c-Fos expression after dopaminergic agonist treatment at postnatal day 4 (P4) to P18. Control mice and mutant mice, in which dopamine production is inactivated in dopaminergic neurons by gene targeting, were treated with saline; a synthetic dopamine precursor, L-3,4-dihydroxyphenylalanine (L-DOPA) methyl ester; a direct dopamine D(1) receptor agonist, N-allyl-SKF 38393; or a dopamine reuptake inhibitor, cocaine. L-DOPA methyl ester treatment failed to induce striatal c-Fos immunoreactivity in control and mutant mice deficient in dopamine production at P4 and P6 compared with saline treatment. However, at P10 through P18 it induced abundant c-Fos expression in mutants. At these later stages, c-Fos expression remained at basal levels in control mice after L-DOPA methyl ester treatment. Control and mutant mice responded to D1 receptor agonist administration to a similar degree at P4 and P6, but the responses were greatly enhanced in mutants at later stages. Cocaine treatment elicited expression in control mice at P10 through P18 but not at P4 and P6. Mutant mice were largely unresponsive to cocaine treatment. The results suggest that striatal dopamine receptors are capable of transducing extracellular signals at P4 and P6, but dopaminergic neurotransmission begins thereafter. Dopaminoceptive neurons appear to reduce their sensitivity to dopamine as dopaminergic terminals innervate the striatum and functional neurotransmission begins.
Kim
Douglas S
DS
Molecular and Cellular Biology Program, University of Washington, Seattle, Washington 98195-7370, USA.
Froelick
Glenda J
GJ
Palmiter
Richard D
RD
D000375:Aging / Q000378:metabolism; D000818:Animals; D001142:Aromatic-L-Amino-Acid Decarboxylases / Q000096:biosynthesis; D001522:Behavior, Animal; D001835:Body Weight; D003042:Cocaine / Q000494:pharmacology; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D004298:Dopamine / Q000172:deficiency / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D007150:Immunohistochemistry; D007980:Levodopa / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D017447:Receptors, Dopamine D1 / Q000096:biosynthesis; D017450:Receptors, Opioid, mu / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D012965:Sodium Chloride / Q000494:pharmacology
D018491:Dopamine Agonists; D016760:Proto-Oncogene Proteins c-fos; D017447:Receptors, Dopamine D1; D017450:Receptors, Opioid, mu; D012965:Sodium Chloride; D007980:Levodopa; D001142:Aromatic-L-Amino-Acid Decarboxylases; D003042:Cocaine; C035420:levodopa methyl ester; D004298:Dopamine