Involvement of the direct striatonigral pathway in levodopa-induced sensitization in 6-hydroxydopamine-lesioned rats

• Published in: The European journal of neuroscience 2000-06, Vol.12 (6), p.2117-2123
• Main Authors: Bordet, Régis, Ridray, Sophie, Schwartz, Jean-Charles, Sokoloff, Pierre
• Format: Article
• Language: English
• Subjects: Animals; Antiparkinson Agents - pharmacology; Benzazepines - metabolism; Benzazepines - pharmacology; Binding, Competitive - physiology; Corpus Striatum - cytology; Denervation; Dizocilpine Maleate - pharmacology; Dopamine Agonists - metabolism; Dopamine Agonists - pharmacology; Dopamine Antagonists - metabolism; Dopamine Antagonists - pharmacology; dopamine D3 receptor; Enkephalins - genetics; Excitatory Amino Acid Antagonists - pharmacology; Gene Expression - physiology; Levodopa - pharmacology; Male; Neural Pathways; Neurons - chemistry; Neurons - physiology; Opioid Peptides - metabolism; Oxidopamine; Parkinson Disease, Secondary - chemically induced; Parkinson Disease, Secondary - drug therapy; Parkinson Disease, Secondary - pathology; Parkinson's disease; preprotachykinin; prodynorphin; Protein Precursors - genetics; Rats; Rats, Wistar; Receptors, Dopamine D2 - analysis; Receptors, Dopamine D2 - genetics; Receptors, Dopamine D3; RNA, Messenger - analysis; Substantia Nigra - cytology; Sympatholytics; Tachykinins - genetics; Tetrahydronaphthalenes - metabolism; Tetrahydronaphthalenes - pharmacology; Tritium; Ventral Tegmental Area - cytology
• ISSN: 0953-816X; 1460-9568
• DOI: 10.1046/j.1460-9568.2000.00089.x

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.