6-Hydroxydopamine lesions of rat substantia nigra up-regulate dopamine-induced phosphorylation of the cAMP-response element-binding protein in striatal neurons.

Cole DG, Kobierski LA, Konradi C, Hyman SE
Proc Natl Acad Sci U S A. 1994 91 (20): 9631-5

PMID: 7937819 · PMCID: PMC44867 · DOI:10.1073/pnas.91.20.9631

Destruction of the substantia nigra produces striatal D1 dopamine receptor supersensitivity without increasing receptor number or affinity, thus implicating postreceptor mechanisms. The nature of these mechanisms is unknown. Increased striatal c-fos expression ipsilateral to a unilateral lesion of the substantia nigra in rats treated with appropriate dopamine agonists provides a cellular marker of D1 receptor supersensitivity. D1 receptors are positively linked to adenylate cyclase and therefore to cAMP-dependent protein kinase. Because expression of the c-fos gene in response to cAMP- and Ca2+/calmodulin-regulated protein kinases depends on phosphorylation of cAMP-response element-binding protein (CREB) at Ser-133, we examined CREB phosphorylation after dopaminergic stimulation in cultured striatal neurons and in the striatum of rats after unilateral 6-hydroxydopamine ablation of the substantia nigra. Using an antiserum specific for CREB phosphorylated at Ser-133, we found that dopamine increases CREB phosphorylation in cultured striatal neurons. This effect was blocked by a D1 antagonist. L-Dopa produced marked CREB phosphorylation in striatal neurons in rats ipsilateral, but not contralateral, to a 6-hydroxydopamine lesion. This response was blocked by a D1 antagonist, but not a D2 antagonist, and was reproduced by a D1 agonist, but not a D2 agonist. These findings are consistent with the hypothesis that D1 receptor supersensitivity is associated with upregulated activity of cAMP-dependent or Ca2+/calmodulin-dependent protein kinases, or both, following dopamine denervation of striatal neurons.

MeSH Terms (25)

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine Animals Benzazepines Calcium-Calmodulin-Dependent Protein Kinases Cells, Cultured Corpus Striatum Cyclic AMP-Dependent Protein Kinases Cyclic AMP Response Element-Binding Protein Dopamine Embryo, Mammalian Ergolines Gene Expression Genes, fos Levodopa Male Neurons Oxidopamine Phosphorylation Quinpirole Rats Rats, Sprague-Dawley Receptors, Dopamine D1 Receptors, Dopamine D2 Salicylamides Substantia Nigra

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