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 activa tion of D1-like and D2-like receptors acts to intensify the expression of v arious dopamine-dependent effects, in particular the expression of the imme diate-early genes, c-fos and zif268. Using non-peptide neurotensin receptor antagonists, including SR48692, we have determined that blockade of neurot ensin receptors reduced the cooperative responses of direct acting D2-like (quinpirole) and partial D1-like (SKF38393) dopamine agonists on the expres sion 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 pal lidum. High-affinity neurotensin receptors are likely to be involved in the se D1-like/D2-like cooperative responses, as compounds structurally related to SR48692, SR48527 (3 mg/kg) and its (-)antipode, SR49711 (3 mg/kg), exer ted a stereospecific antagonism in all selected brain regions. Pretreatment with SR48692 (10 mg/kg) also diminished Fos induction by the indirect dopa mine agonist, cocaine (25 mg/kg), particularly at the rostral level of the caudate-putamen. In situ hybridization experiments in the caudate-putamen i ndicated that SR48692 (10 mg/kg) markedly reduced zif268 mRNA labelling pro duced 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 st udy indicate that neurotensin is a key element for the occurrence of cooper ative responses of D2-like and partial D1-like agonists on immediate-early gene expression.