Abstract
Depression is a common comorbid condition in Parkinson’s disease (PD). Patients with depression have a two-fold increased risk to develop PD. Further, depression symptoms often precede motor symptoms in PD and are frequent at all stages of the disease. However, the influence of a depressive state on the responses to antiparkinson treatments is largely unknown. In this study, the genetically inbred depression-like flinders sensitive line (FSL) rats and control flinders resistant line (FRL) rats were studied in models of experimental parkinsonism. FSL rats showed a potentiated tremorgenic response to tacrine, a cholinesterase inhibitor used experimentally to induce 6 Hz resting tremor reminiscent of parkinsonian tremor. We also studied rats lesioned with 6-OHDA to induce hemiparkinsonism. No baseline differences in dopaminergic response to acute apomorphine or L-DOPA was found. However, following chronic treatment with L-DOPA, FRL rats developed sensitization of turning and abnormal involuntary movements (AIMs); these effects were counteracted by the anti-dyskinetic 5-HT1A agonist/D2 partial agonist sarizotan. In contrast, FSL rats did not develop sensitization of turning and only minor AIMs in response to L-DOPA treatment. The roles of several non-dopamine systems underlying this discrepancy were studied. Unexpectedly, no differences of opioid neuropeptides or serotonin markers were found between FRL and FSL rats. The marked behavioral difference between the FRL and FSL rats was paralleled with the striatal expression of the established marker, c-fos, but also the GABAergic transporter (vGAT), and a hitherto unknown marker, tamalin, that is known to regulate mGluR5 receptor function and postsynaptic organization. This study demonstrates that behavioral and transcriptional responses of non-dopaminergic systems to experimental parkinsonism and L-DOPA are modified in a genetic rat model of depression.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disorder and is diagnosed based on the presence of bradykinesia, rigidity and tremor (Kalia and Lang, 2015)
This result indicates that movement responses reminiscent of parkinsoniam 6 Hz tremor are exaggerated in flinders sensitive line (FSL) compared to flinders resistant line (FRL) rats
FSL rats were found to be more responsive to tacrine-induced tremorous jaw movements which is consistent with their supersensitivity toward cholinergic compounds (Overstreet et al, 2005)
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disorder and is diagnosed based on the presence of bradykinesia, rigidity and tremor (Kalia and Lang, 2015). Experimental Parkinsonism in FSL Rats from other chronic motor disabilities, parkinsonian individuals score higher in rating scales for depression (Robins, 1976).depression symptoms appear to be a part of PD pathology and a reaction to the somatic disease manifestations. Unipolar depressed patients have a two-fold increased risk of being diagnosed with PD when compared to other groups with chronic illness that need continuous treatment (Nilsson et al, 2001; Leentjens et al, 2003). The flinders sensitive line (FSL) of rats is commonly used as a genetic animal model of depression with the flinders resistant line (FRL) serving as control (Overstreet et al, 2005). FRL rats exhibit low sensitivity to DFP. FSL rats have good face validity and exhibit increased immobility in the forced swim test. The FSL rats possess predictive validity, since all so far tested antidepressant therapies show antidepressant-like effects in these rats (Overstreet and Wegener, 2013)
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