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.

Abstract

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.

• Authors: David Lindenbach, Kristin B Dupre, Karen L Eskow Jaunarajs, Corinne Y Ostock, Adam A Goldenberg, Christopher Bishop
• Journal: Brain research (Brain Res) Vol. 1537 Pg. 327-39 (Nov 06 2013) ISSN: 1872-6240 [Electronic] Netherlands
• PMID: 24060645 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 Elsevier B.V. All rights reserved.

Chemical References

• Receptors, Dopamine D1
• Serotonin 5-HT1 Receptor Agonists
• Serotonin Receptor Agonists
• Receptor, Serotonin, 5-HT1A
• Levodopa
• 8-Hydroxy-2-(di-n-propylamino)tetralin
• Extracellular Signal-Regulated MAP Kinases

Topics

• 8-Hydroxy-2-(di-n-propylamino)tetralin (pharmacology)
• Animals
• Corpus Striatum (drug effects, metabolism)
• Disease Models, Animal
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Levodopa (pharmacology)
• MAP Kinase Signaling System
• Male
• Parkinson Disease (drug therapy, metabolism)
• Phosphorylation
• Rats
• Rats, Sprague-Dawley
• Receptor, Serotonin, 5-HT1A (metabolism)
• Receptors, Dopamine D1 (agonists, metabolism)
• Serotonin 5-HT1 Receptor Agonists (pharmacology)
• Serotonin Receptor Agonists (pharmacology)