Cyclic AMP responsive element binding protein phosphorylation and persistent expression of levodopa-induced response alterations in unilateral nigrostriatal 6-OHDA lesioned rats.
Activation of cAMP responsive element binding protein (CREB) has been increasingly implicated in the formation and maintenance of long-term memory. To elucidate molecular mechanisms that underlie the persisting alterations in motor response occurring with levodopa (L-dopa) treatment of parkinsonian patients, we evaluated the time course of these changes in relation to the activation of striatal CREB in 6-hydroxydopamine (6-OHDA) lesioned animals. Three weeks of twice-daily L-dopa treatment reduced the duration of the rotational response to acute L-dopa challenge in hemiparkinsonian rats, which lasted about 5 weeks after withdrawal of chronic L-dopa therapy. This shortened response duration, resembling human wearing-off fluctuations, was associated with a marked increase in Ser-133 phosphorylated CREB (pCREB) immunoreactivity in medium spiny neurons in dorsolateral striatum in response to acute dopaminomimetic challenge. Intermittent treatment with the D1 receptor-preferring agonist SKF 38393, but not the D2 receptor-preferring agonist quinpirole, produced a similar rise in CREB phosphorylation. The time course of changes in CREB phosphorylation correlated with the time course of changes in motor behavior after cessation of chronic L-dopa therapy. Both the altered motor response duration and the degree of CREB phosphorylation were attenuated by the intrastriatal administration of CREB antisense or protein kinase A inhibitor Rp-cAMPS. The results suggest that region-specific Ser-133 CREB phosphorylation in D1 receptor containing spiny neurons contributes to the persistence of the motor response alterations produced by intermittent stimulation of striatal dopaminergic receptors.
Oh
Justin D
JD
Department of Psychology, Central Michigan University, Mt. Pleasant, Michigan, USA.
Chartisathian
Karnon
K
Ahmed
Syed M
SM
Chase
Thomas N
TN
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D016627:Oxidopamine; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013375:Substance Withdrawal Syndrome / Q000235:genetics / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism
D017362:Cyclic AMP Response Element-Binding Protein; D007980:Levodopa; D016627:Oxidopamine