Involvement of the direct striatonigral pathway in levodopa-induced sensitization in 6-hydroxydopamine-lesioned rats.
Induction of dopamine D3 receptor gene expression in 6-hydroxydopamine-lesioned rats by repeated administration of levodopa had been suggested to be responsible for behavioural sensitization developing in these animals. Using double in situ hybridization techniques, we show that D3 receptor mRNA induction after repeated administration of levodopa took place mainly in dynorphin/substance P-expressing neurons of the direct striatonigral pathway. In agreement, induction of D3 receptor binding sites was evidenced, using 7-[3H]hydroxy-N,N-di-propyl-2-aminotetralin ([3H]7-OH-DPAT), in substantia nigra pars reticulata, the projection area of the direct nigrostriatonigral pathway. Changes in D3 receptor binding and behavioural sensitization during intermittent administration of levodopa paralleled changes in prodynorphin/preprotachykinin rather than preproenkephalin/prodynorphin and preproenkephalin/preprotachykinin mRNA ratios. Behavioural sensitization, induction of D3 receptor binding and changes in prodynorphin/preprotachykinin ratio were all prevented together when levodopa was continuously delivered or intermittently delivered in combination with R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepine (SCH 23390), a selective D1 receptor antagonist. Our results indicate that functional changes of the direct striatal output pathway, possibly through an interaction between D1 and D3 receptors at the level of terminals in the substantia nigra pars reticulata, are important for the development of behavioural sensitization.
Bordet
R
R
Unité de Neurobiologie et Pharmacologie Moléculaire (INSERM U 109), Centre Paul Broca, 2ter rue d'Alésia, 75014, Paris, France.
Ridray
S
S
Schwartz
J C
JC
Sokoloff
P
P
D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D001552:Benzazepines / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive / Q000502:physiology; D003342:Corpus Striatum / Q000166:cytology*; D003714:Denervation; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018491:Dopamine Agonists / Q000378:metabolism / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000378:metabolism / Q000494:pharmacology; D004745:Enkephalins / Q000235:genetics; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D015870:Gene Expression / Q000502:physiology; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D009434:Neural Pathways; D009474:Neurons / Q000737:chemistry / Q000502:physiology; D018847:Opioid Peptides / Q000378:metabolism; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology*; D011498:Protein Precursors / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000032:analysis / Q000235:genetics; D050637:Receptors, Dopamine D3; D013378:Substantia Nigra / Q000166:cytology*; D013565:Sympatholytics; D015320:Tachykinins / Q000235:genetics; D013764:Tetrahydronaphthalenes / Q000378:metabolism / Q000494:pharmacology; D014316:Tritium; D017557:Ventral Tegmental Area / Q000166:cytology
D000978:Antiparkinson Agents; D001552:Benzazepines; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; C493595:Drd3 protein, rat; D004745:Enkephalins; D018691:Excitatory Amino Acid Antagonists; D018847:Opioid Peptides; D011498:Protein Precursors; D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D013565:Sympatholytics; D015320:Tachykinins; D013764:Tetrahydronaphthalenes; C044206:preprotachykinin; D014316:Tritium; D007980:Levodopa; D016291:Dizocilpine Maleate; D016627:Oxidopamine; C033660:preproenkephalin; C031349:7-hydroxy-2-N,N-dipropylaminotetralin