Destruction of Dopaminergic Neurons in the Midbrain by 6-Hydroxydopamine Decreases Hippocampal Cell Proliferation in Rats: Reversal by Fluoxetine

Background Non-motor symptoms (e.g., depression, anxiety, and cognitive deficits) in patients with Parkinson disease (PD) precede the onset of the motor symptoms. Although these symptoms do not respond to pharmacological dopamine replacement therapy, their precise pathological mechanisms are currently unclear. The present study was undertaken to examine whether the unilateral 6-hydroxydopamine (6-OHDA) lesion to the substantia nigra pars compacta (SNc), which represents a model of long-term dopaminergic neurotoxicity, could affect cell proliferation in the adult rat brain. Furthermore, we examined the effects of the selective serotonin reuptake inhibitor (SSRI) fluoxetine and the selective noradrenaline reuptake inhibitor maprotiline on the reduction in cell proliferation in the subgranular zone (SGZ) by the unilateral 6-OHDA lesion. Methodology/Principal Findings A single unilateral injection of 6-OHDA into the rat SNc resulted in an almost complete loss of tyrosine hydroxylase (TH) immunoreactivity in the striatum and SNc, as well as in reductions of TH-positive cells and fibers in the ventral tegmental area (VTA). On the other hand, an injection of vehicle alone showed no overt change in TH immunoreactivity. A unilateral 6-OHDA lesion to SNc significantly decreased cell proliferation in the SGZ ipsilateral to the 6-OHDA lesion, but not in the contralateral SGZ or the subventricular zone (SVZ), of rats. Furthermore, subchronic (14 days) administration of fluoxetine (5 mg/kg/day), but not maprotiline significantly attenuated the reduction in cell proliferation in the SGZ by unilateral 6-OHDA lesion. Conclusions/Significance The present study suggests that cell proliferation in the SGZ of the dentate gyrus might be, in part, under dopaminergic control by SNc and VTA, and that subchronic administration of fluoxetine reversed the reduction in cell proliferation in the SGZ by 6-OHDA. Therefore, SSRIs such as fluoxetine might be potential therapeutic drugs for non-motor symptoms as well as motor symptoms in patients with PD, which might be associated with the reduction in cell proliferation in the SGZ

The prevalence of psychiatric symptoms before the diagnosis of Parkinson's disease in a nationwide cohort: A comparison to patients with cerebral infarction

Objectives Psychiatric symptoms (PS) can be non-motor features in Parkinson's disease (PD) which are common even in the prodromal, untreated phase of the disease. Some PS, especially depression and anxiety recently became known predictive markers for PD. Our objective was to explore retrospectively the prevalence of PS before the diagnosis of PD. Methods In the framework of the Hungarian Brain Research Program we created a database from medical and medication reports submitted for reimbursement purposes to the National Health Insurance Fund in Hungary, a country with 10 million inhabitants and a single payer health insurance system. We used record linkage to evaluate the prevalence of PS before the diagnosis of PD and compared that with patients with ischemic cerebrovascular lesion (ICL) in the period between 2004-2016 using ICD-10 codes of G20 for PD, I63-64 for ICL and F00-F99 for PS. We included only those patients who got their PD, ICL and psychiatric diagnosis at least twice. Results There were 79 795 patients with PD and 676 874 patients with ICL. Of the PD patients 16% whereas of those with ischemic cerebrovascular lesion 9.7% had a psychiatric diagnosis before the first appearance of PD or ICL (p<0.001) established in psychiatric care at least twice. The higher rate of PS in PD compared to ICL remained significant after controlling for age and gender in logistic regression analysis. The difference between PD and ICL was significant for Mood disorders (F30-F39), Organic, including symptomatic, mental disorders (F00-F09), Neurotic, stress-related and somatoform disorders (F40-F48) and Schizophrenia, schizotypal and delusional disorders (F20-F29) diagnosis categories (p<0.001, for all). Discussion The higher rate of psychiatric morbidity in the premotor phase of PD may reflect neurotransmitter changes in the early phase of PD