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. 2013 Nov 6:1537:327-39.
doi: 10.1016/j.brainres.2013.09.020. Epub 2013 Sep 21.

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

David Lindenbach  1 , Kristin B Dupre, Karen L Eskow Jaunarajs, Corinne Y Ostock, Adam A Goldenberg, Christopher Bishop
Affiliations

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

David Lindenbach et al. Brain Res. .

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.

Keywords: 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.

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Figures

Figure 1
Figure 1
A) Timeline for experiment 1. Six treatment groups were created based on forepaw adjusting steps scores. Half the rats were given daily L-DOPA (6 mg/kg) for 10 days while half were given VEH. On day 11, DPAT (1 mg/kg), SCH (1 mg/kg) or VEH were given prior to L-DOPA or VEH and sacrificed 20 min later. B) Timeline for experiment 2. Six treatment groups were created based on amphetamine-induced rotation scores. Between days 1 and 7, half the rats were given three doses of the D1 agonist SKF (0.8 mg/kg) while the other half were given VEH. On day 8, rats received DPAT (1 mg/kg) or VEH prior to SKF or VEH and were sacrificed 20 min later.
Figure 2
Figure 2
Results from behavioral testing during the chronic treatment phase for experiments 1 and 2. A) Timecourse of dyskinesia development among all rats injected with chronic L-DOPA (6 mg/kg) in experiment 1. B) Median AIMs on each test day for each of the six treatment groups in experiment 1. C) Dyskinesia development timecourse for all rats that received chronic SKF (0.8 mg/kg) treatment in experiment 2. B) Median AIMs on each test day for each of the six treatment groups in experiment 2. § p < .05 vs. 1st day.
Figure 3
Figure 3
Immunohistological analysis of the number of striatal cells expressing pERK for rats in experiment 1. Rats were treated daily with L-DOPA (6 mg/kg) or VEH for 10 days. The next day, each rat was given two of the following treatments and sacrificed 20 min later: L-DOPA, the 5-HT1AR agonist DPAT (1 mg/kg), the D1R antagonist SCH (1 mg/kg) or VEH. Photomicrographs were analyzed from four regions of each striatal hemisphere: A) dorsomedial B) dorsolateral C) ventromedial and D) ventrolateral. The location of each photomicrograph is indicated by a black box in the schematic insets to the bar graphs (created using a section from the brain atlas of Paxinos and Watson [1998] at 1 mm anterior to bregma). E) Samples of representative histology from the lesioned-side ventromedial striatum. * p<.05 vs. chronic VEH and VEH+VEH; @ p<.05 vs. chronic L-DOPA and VEH+L-DOPA.
Figure 4
Figure 4
Immunohistological analysis of the number of M1 cells expressing pERK for rats in experiment 1. Rats were treated daily with L-DOPA (6 mg/kg) or VEH for 10 days. The next day, each rat was given two of the following treatments and sacrificed 20 min later: L-DOPA, the 5-HT1AR agonist DPAT (1 mg/kg) the D1R antagonist SCH (1 mg/kg) or VEH. Photomicrographs were analyzed from two regions of each M1 hemisphere: A) dorsal and B) ventral. The location of each photomicrograph is indicated by a black box in the schematic insets to the bar graphs (created using a section from the brain atlas of Paxinos and Watson [1998] at 1 mm anterior to bregma). C) Samples of representative histology from the lesioned-side dorsal M1. Only ¼ of each photomicrograph is shown in order to make cells visible. # p<.05 vs. chronic VEH and VEH+L-DOPA; @ p<.05 vs. chronic L-DOPA and VEH+L-DOPA.
Figure 5
Figure 5
Number of striatal cells positively-labeled for pERK among rats in experiment 2. Rats were treated with SKF (0.8 mg/kg) or VEH for 3 days. The next day, each rat was given two of the following treatments and sacrificed 20 min later: SKF, the 5-HT1AR agonist DPAT (1 mg/kg) or VEH. Four photomicrographs were quantified from each striatal hemisphere, covering the A) dorsomedial B) dorsolateral C) ventromedial and D) ventrolateral regions. The location of each photomicrograph is indicated by a black box in the schematic insets to the bar graphs (created using a section from the brain atlas of Paxinos and Watson [1998] at 1 mm anterior to bregma). E) Samples of representative histology from the lesioned-side dorsolateral striatum. * p<.05 vs. chronic VEH and VEH+VEH; # p<.05 vs. chronic VEH and VEH+SKF; ¶ p<.05 vs. chronic SKF and VEH+VEH.
Figure 6
Figure 6
Number of M1 cells positively-labeled for pERK among rats in experiment 2. Rats were treated with SKF (0.8 mg/kg) or VEH for 3 days. The next day, each rat was given two of the following treatments and sacrificed 20 min later: SKF, the 5-HT1AR agonist DPAT (1 mg/kg) or VEH. Photomicrographs were analyzed from two regions of each M1 hemisphere: A) dorsal and B) ventral. The location of each photomicrograph is indicated by a black box in the schematic insets to the bar graphs (created using a section from the brain atlas of Paxinos and Watson [1998] at 1 mm anterior to bregma). C) Samples of representative histology from the lesioned-side ventral M1. Only ¼ of each photomicrograph is shown in order to make cells visible. # p<.05 vs. chronic VEH and VEH+SKF.
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