Continuous treatment with the D2 dopamine receptor agonist quinpirole decreases D2 dopamine receptors, D2 dopamine receptor messenger RNA and proenkephalin messenger RNA, and increases mu opioid receptors in mouse striatum.
Dopamine-mediated behaviors and certain biochemical and molecular events associated with these behaviors were examined following continuous infusion of the D1 dopamine agonist SKF38393 or the D2 dopamine agonist quinpirole into mice for six days. SKF38393 produced a transient grooming behavior while quinpirole initially induced stereotypy, which was followed by an increased locomotor behavior. Continuous infusion of quinpirole caused a significant down-regulation of striatal D2 dopamine receptors without significantly changing the density of D1 receptors. This was accompanied by a decrease in the level of D2 receptor messenger RNA in striatum as measured by Northern analysis. The down-regulation of dopamine receptors was selective for D2 dopamine receptors, since treatment with SKF38393 had no significant effects on either D1 or D2 dopamine receptors, nor did it alter the messenger RNAs for the D1 and D2 receptors. Continuous treatment with quinpirole resulted in a significant increase in striatal mu opioid receptor levels without significant changing delta opioid receptors. This treatment also induced a significant decrease in proenkephalin messenger RNA in striatum. Taken together, these results suggest that the down-regulation of D2 dopamine receptor and D2 receptor messenger RNA is the result of the persistent stimulation of D2 receptors and that the up-regulation of mu opioid receptors may be a compensatory response to a decreased biosynthesis of enkephalin. They suggest further that the biochemical and molecular changes that take place in dopaminergic and enkephalinergic systems following continuous treatment with dopamine agonists may underlie the mechanisms by which certain dopamine-mediated behaviors occur.
Chen
J F
JF
Department of Pharmacology, Medical College of Pennsylvania, Philadelphia 19129.
Aloyo
V J
VJ
Weiss
B
B
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000818:Animals; D001345:Autoradiography; D001522:Behavior, Animal / Q000187:drug effects; D015152:Blotting, Northern; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D015536:Down-Regulation / Q000187:drug effects; D004745:Enkephalins / Q000096:biosynthesis*; D004873:Ergolines / Q000494:pharmacology*; D007091:Image Processing, Computer-Assisted; D008297:Male; D051379:Mice; D009693:Nucleic Acid Hybridization; D015345:Oligonucleotide Probes; D011498:Protein Precursors / Q000096:biosynthesis*; D019257:Quinpirole; D012333:RNA, Messenger / Q000096:biosynthesis*; D017448:Receptors, Dopamine D2 / Q000096:biosynthesis / Q000187:drug effects*; D017465:Receptors, Opioid, delta / Q000187:drug effects; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000378:metabolism*; D013134:Spiperone / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D015259:Dopamine Agents; D065127:Dopamine D2 Receptor Antagonists; D004745:Enkephalins; D004873:Ergolines; D015345:Oligonucleotide Probes; D011498:Protein Precursors; D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; C029992:proenkephalin; D019257:Quinpirole; D013134:Spiperone; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine