Effects of 5-HT1A receptor stimulation on striatal and cortical M1 pERK induction by L-DOPA and a D1 receptor agonist in a rat model of Parkinson's disease.
Motor symptoms of Parkinson's disease are commonly treated using l-DOPA although long-term treatment usually causes debilitating motor side effects including dyskinesias. A putative source of dyskinesia is abnormally high levels of phosphorylated extracellular-regulated kinase (pERK) within the striatum. In animal models, the serotonin 1A receptor agonist ±8-OH-DPAT reduces dyskinesia, suggesting it may exhibit efficacy through the pERK pathway. The present study investigated the effects of ±8-OH-DPAT on pERK density in rats treated with l-DOPA or the D1 receptor agonist SKF81297. Rats were given a unilateral dopamine lesion with 6-hydroxydopamine and primed with a chronic regimen of l-DOPA, SKF81297 or their vehicles. On the final test day, rats were given two injections: first with ±8-OH-DPAT, the D1 receptor antagonist SCH23390 or their vehicles, and second with l-DOPA, SKF81297 or their vehicles. Rats were then transcardially perfused for immunohistological analysis of pERK expression in the striatum and primary motor cortex. Rats showed greater dyskinesia in response to l-DOPA and SKF81297 after repeated injections. Although striatal pERK induction was similar between acute and chronic l-DOPA, SKF81297 caused the largest increase in striatal pERK after the first exposure. Neither compound alone affected motor cortex pERK. Surprisingly, in the ventromedial striatum, ±8-OH-DPAT potentiated l-DOPA-induced pERK; in the motor cortex, ±8-OH-DPAT potentiated pERK with l-DOPA or SKF81297. Our results support previous work that the striatal pERK pathway is dysregulated after dopamine depletion, but call into question the utility of pERK as a biomarker of dyskinesia expression.
Behavioral Neuroscience Program, Department of Psychology, Binghamton University - State University of New York, Binghamton, NY, USA.
David
D
Lindenbach
Kristin B
KB
Dupre
Karen L
KL
Eskow Jaunarajs
Corinne Y
CY
Ostock
Adam A
AA
Goldenberg
Christopher
C
Bishop
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D007980:Levodopa / Q000494:pharmacology*; D020935:MAP Kinase Signaling System; D008297:Male; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000378:metabolism; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
D017447:Receptors, Dopamine D1; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; D007980:Levodopa; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D048049:Extracellular Signal-Regulated MAP Kinases
5-HT; 5-HT(1A)R; 6-OHDA; 6-hydroxydopamine; AIMs; D(1) receptor; D(1)R; DA; DPAT; Dopamine; ERK; Extracellular-regulated kinase; LID; M.A.D.; M1; Motor cortex; PD; Parkinson's disease; S.E.M.; SCH; SCH23390; SKF; SKF81297; Serotonin; Striatum; VEH; abnormal involuntary movements; dopamine; extracellular-regulated kinase; l-DOPA-induced dyskinesia; median absolute deviation; pERK; phosphorylated extracellular-regulated kinase; primary motor cortex; serotonin; serotonin 1A receptor; standard error of the mean; vehicle; ±8-OH-DPAT