Parkinson’s disease (PD) is a neurodegenerative disorder causedby the loss of dopaminergic neurons in the basal ganglia (BG). PD patients exhibit motorsymptoms, including slowness of movement, rigidity and resting tremor. The most common treatment for PD is L-dopa, a precursor to dopamine (DA), which readily crosses the blood-brain barrierto restore dopamine levels. While L-dopa therapy is initially effective in alleviating the motor symptomsof PD, prolonged L-dopa treatment often leads to the development and expression of abnormal involuntary movements, otherwise known as L-dopa-induced dyskinesia (LID). Although the underlying mechanisms of LID are not fully understood, previous studies have identified the serotonergic dorsal raphe nucleus (DRN) as a possible contributor to its cause. Research suggests that DRN neurons compensate for the loss of dopaminergic neurons by converting and releasing L-dopa-derived DA. Previous studies have reported high gamma oscillatory activity (70-110 Hz) within the BG during L-dopa treatment of PD patients. More recently, similar activity in the motor cortex has been linked to the expression of dyskinetic symptoms in a rodent model of PD. The present study’s objectives were two-fold: 1) Determine the relationship between dyskinetic behavior and gamma activity within the motor cortex and BG, and 2) investigate the contribution of the serotonin (5-HT) system to this high gamma cortical activity, using a rodent model of PD.
To accomplish these goals, hemiparkinsonian rats were chronically implanted with electrode bundles located in the primary motor cortex in conjunction witheither the DRN or substantianigra pars reticulata (SNpr), a BG structure known to exhibitstrong coherence with the motor cortex in other frequency ranges in parkinsonian rats during walk. Rats were administered a high dose of L-dopa for 7 days with neuronal recordings and behavioral ratings occurring on the first and last days of treatment. Following this priming regimen, dyskinetic rats were tested with the5-HT1A receptor agonist8-OH-DPAT, a compound known to diminish LID and DRN neuronal activity. As expected, high gamma activity was positively correlated with the severity of dyskinetic behaviors (in both dominant peak frequency and total power). Our findings indicate that the power of high gamma activity within the motor cortex increases between days 1 and 7 of L-dopa priming. Further, administration of 8-OH-DPAT concurrently eliminated high gamma cortical activity and the expression of LID, and importantly, these effects were reversed with the 5-HT1A receptor antagonist WAY100635. Finally, high gamma cortical activity displayed mild coherence with the SNpr, suggesting that this oscillatory activity may be entrained in the BG thalamocorticalcircuit. Although there was no apparent coherence with the DRN, findings assert the role of 5-HT in the modulation of high gamma cortical activity and dyskinetic behavior. Collectively, these findings support a relationship between high gamma activity in the motor cortex and BG, and the progression and expression of LID. Potential therapies targeting the 5-HT system may prove effective at reducing LID by normalizing this aberrant oscillatory activity. Further investigation into this high gamma phenomenon is paramount for understanding the mechanisms of LID and may ultimately lead to more effective treatment for PD patients.
Last updated December 14, 2012