Long-Term Treatment with Fluvoxamine Decreases Nonmotor Symptoms and Dopamine Depletion in a Postnatal Stress Rat Model of Parkinson’s Disease

Abstract

Nonmotor symptoms (NMS) such as anxiety, depression, and cognitive deficits are frequently observed in Parkinson’s disease (PD) and precede the onset of motor symptoms by years. We have recently explored the short-term effects of Fluvoxamine, a selective serotonin reuptake inhibitor (SSRI) on dopaminergic neurons in a parkinsonian rat model. Here, we report the long-term effects of Fluvoxamine, on early-life stress-induced changes in the brain and behavior. We specifically evaluated the effects of Fluvoxamine on brain mechanisms that contribute to NMS associated with PD in a unilateral 6-hydroxydopamine-lesioned rat model. A 14-day early postnatal maternal separation protocol was applied to model early-life stress followed by unilateral intracerebral infusion of 6-hydroxydopamine (6-OHDA) to model aspects of parkinsonism in rats. The anxiolytic, antidepressant, and cognitive effects of Fluvoxamine were confirmed using the elevated plus-maze (EPM) test, sucrose preference test (SPT), and Morris water maze (MWM) test. Further to that, our results showed that animals exposed to early-life stress displayed increased plasma corticosterone and malondialdehyde (MDA) levels which were attenuated by Fluvoxamine treatment. A 6-OHDA lesion effect was evidenced by impairment in the limb-use asymmetry test as well as decreased dopamine (DA) and serotonin levels in the striatum, prefrontal cortex, and hippocampus. These effects were surprisingly attenuated by Fluvoxamine treatment in all treated rats. This study is the first to suggest that early and long-term treatment of neuropsychological diseases with Fluvoxamine may decrease the vulnerability of dopaminergic neurons that degenerate in the course of PD.

Changes in depressive-like behaviors induced by spinal cord injury based on the hypothalamic-pituitary-adrenal axis and hippocampal neurogenesis

“…The levels of corticosterone in the SCI group remained high until the end of the observation period but decreased temporarily on day twentyone post injury, essentially consistent with the change in depressive behaviors. Additionally, the serum corticosterone concentration in the SCI group was strongly correlated with depressive-like behaviors in the SPT and FST, in alignment with previous research in different chronic stress models [31][32][33] and research that shows that this could be reversed by body weight-supported treadmill training [34].…”

Highlighting Immune System and Stress in Major Depressive Disorder, Parkinson’s, and Alzheimer’s Diseases, with a Connection with Serotonin

“…The study concluded that animals that were exposed to stress had high plasma levels of corticosterone and malondialdehyde, an effect that was attenuated with treatment with Fluvoxamine. Also, this drug appeared to attenuate the vulnerability of dopaminergic neurons to stress and neurotoxic treatments, such as 6-hydroxydopamine (6-OHDA) [59]. Thus, this study suggests the connection between serotonin and the stress associated with PD.…”

Rhabdomyolysis in a male adolescent associated with monotherapy of fluvoxamine

“…A study showed that acute administration of fluvoxamine inhibits the basal firing rate of dopaminergic neurons in the ventral tegmental area of rats 17. However, it was interesting to find that long-term treatment with fluvoxamine may downregulate dopamine transporters and preserve dopaminergic innervation in the striatum 18. Therefore, the dopaminergic mechanism of fluvoxamine-associated rhabdomyolysis remains unclear.…”