Blockade of neurotensin receptors suppresses the dopamine D1/D2 synergism on immediate early gene expression in the rat brain.
A remarkable feature of dopamine functioning is that the concomitant activation of D1-like and D2-like receptors acts to intensify the expression of various dopamine-dependent effects, in particular the expression of the immediate-early genes, c-fos and zif268. Using non-peptide neurotensin receptor antagonists, including SR48692, we have determined that blockade of neurotensin receptors reduced the cooperative responses of direct acting D2-like (quinpirole) and partial D1-like (SKF38393) dopamine agonists on the expression of Fos-like antigens and zif268 mRNA. Pretreatment with SR48692 (3 and 10 mg/kg) reduced the number of Fos-like immunoreactive cells produced by the combined administration of SKF38393 (20 mg/kg) and quinpirole (1 mg/kg) in the caudate-putamen, nucleus accumbens, globus pallidus and ventral pallidum. High-affinity neurotensin receptors are likely to be involved in these D1-like/D2-like cooperative responses, as compounds structurally related to SR48692, SR48527 (3 mg/kg) and its (-)antipode, SR49711 (3 mg/kg), exerted a stereospecific antagonism in all selected brain regions. Pretreatment with SR48692 (10 mg/kg) also diminished Fos induction by the indirect dopamine agonist, cocaine (25 mg/kg), particularly at the rostral level of the caudate-putamen. In situ hybridization experiments in the caudate-putamen indicated that SR48692 (10 mg/kg) markedly reduced zif268 mRNA labelling produced by SKF38393 plus quinpirole in cells not expressing enkephalin mRNA, but was unable to affect the concomitant decrease of zif268 mRNA labelling in enkephalin-positive cells. Taken together, the results of the present study indicate that neurotensin is a key element for the occurrence of cooperative responses of D2-like and partial D1-like agonists on immediate-early gene expression.
Alonso
R
R
Sanofi Recherche, Department of Neuropsychiatry, 371 rue du Pr. J. Blayac, 34184 Montpellier Cedex 04, France. richard.aloso@tls.elfsanofi.fr
Gnanadicom
H
H
Fréchin
N
N
Fournier
M
M
Le Fur
G
G
Soubrié
P
P
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000818:Animals; D001923:Brain Chemistry / Q000502:physiology*; D003042:Cocaine / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics; D018491:Dopamine Agonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D051766:Early Growth Response Protein 1; D004745:Enkephalins / Q000032:analysis; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D017781:Genes, Immediate-Early / Q000502:physiology*; D017874:Immediate-Early Proteins; D017403:In Situ Hybridization; D008297:Male; D017072:Neostriatum / Q000737:chemistry / Q000166:cytology / Q000502:physiology; D009474:Neurons / Q000737:chemistry / Q000187:drug effects / Q000502:physiology; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D011720:Pyrazoles / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D019257:Quinpirole / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000502:physiology*; D017448:Receptors, Dopamine D2 / Q000502:physiology*; D018028:Receptors, Neurotensin / Q000037:antagonists & inhibitors*; D014157:Transcription Factors / Q000235:genetics
D004268:DNA-Binding Proteins; D018491:Dopamine Agonists; D018765:Dopamine Uptake Inhibitors; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D004745:Enkephalins; D017874:Immediate-Early Proteins; D016760:Proto-Oncogene Proteins c-fos; D011720:Pyrazoles; D011804:Quinolines; D012333:RNA, Messenger; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D018028:Receptors, Neurotensin; C114947:SR 142948; C086487:SR 48527; D014157:Transcription Factors; C079087:SR 48692; D019257:Quinpirole; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D003042:Cocaine