ABSTRACT
The dopamine transporter (DAT) plays a pivotal role in maintaining optimal dopamine signaling. DAT-overactivity has been linked to various neuropsychiatric disorders yet so far the direct pathological consequences of it has not been fully assessed. We here generated a transgenic rat model that via pronuclear microinjection overexpresses the DAT gene. Our results demonstrate that DAT-overexpression induces multiple neurobiological effects that exceeded the expected alterations in the corticostriatal dopamine system. Furthermore, transgenic rats specifically exhibited behavioral and pharmaco-therapeutic profiles phenotypic of repetitive disorders. Together our findings suggest that the DAT rat model will constitute a valuable tool for further investigations into the pathological influence of DAT overexpression on neural systems relevant to neuropsychiatric disorders.
Subject(s)
Disease Models, Animal , Dopamine Plasma Membrane Transport Proteins/genetics , Nervous System Diseases/psychology , Up-Regulation , Animals , Male , Mice , Microinjections , Nervous System Diseases/genetics , Rats , Rats, TransgenicABSTRACT
In Parkinson's disease the loss of dopamine induces motor impairment but also leads to non-motor symptoms such as cognitive impairment, anxiety and depression. Selective serotonine reuptake inhibitors (SSRI) are so far first line therapy for mood alterations in PD and have also been shown to influence cognition, however with often insufficient results due to yet not fully understood underlying pathomechanisms of the symptoms. Deficits in the generation and maturation of new neurons in the adult hippocampus seem to be key mechanisms of major depression and cognitive decline and are robustly influenced by serotonergic pharmacotherapy. In this study we analyzed the effects of a short- and long-term treatment with the SSRI fluoxetine on changes of hippocampal precursor maturation, neurotransmitter-receptor mRNA-expression, neurotrophin levels and clinical symptoms in the MPTP-mouse model for PD. The generation of neuronal precursors as well as the absolute numbers of endogenous immature neurons increased following MPTP and were further elevated by fluoxetine. Net neurogenesis however, impaired after MPTP, remained unchanged by fluoxetine treatment. Fluoxetine induced microenvironmental changes in the hippocampus that might be involved in enhanced precursor generation involved increased contents of the neurotrophins VEGF and BDNF and decreased hippocampal expression of the 5HT1a receptor mRNA and the D2 receptor mRNA. Clinically, we were not able to detect any differences in anxiety or depressive behavior in MPTP animals compared to controls which is in line with previous studies indicating that neuropsychiatric symptoms in PD are difficult to assess in rodents due to their clinical characteristics and involvement of several brain regions. Taken together, we show that fluoxetine partially enhances brain's capacity to counteract MPTP-induced neurodegeneration by increasing the endogenous pool of immature neurons and upregulating neural precursor cell generation. The mechanisms underlying this phenomenon and the link to the clinical use of fluoxetine in PD remain to be further elucidated.
Subject(s)
Depression/drug therapy , Dopamine/metabolism , Fluoxetine/therapeutic use , Hippocampus/drug effects , MPTP Poisoning/pathology , Nerve Growth Factors/drug effects , Selective Serotonin Reuptake Inhibitors/therapeutic use , Serotonin/metabolism , Acoustic Stimulation , Analysis of Variance , Animals , Bromodeoxyuridine/metabolism , Cell Count , Conditioning, Operant/drug effects , Dark Adaptation/drug effects , Depression/etiology , Disease Models, Animal , Enzyme-Linked Immunosorbent Assay , Female , Gene Expression Regulation/drug effects , Glial Fibrillary Acidic Protein/genetics , Glial Fibrillary Acidic Protein/metabolism , Green Fluorescent Proteins/genetics , Intermediate Filament Proteins/genetics , MPTP Poisoning/complications , Mice , Mice, Transgenic , Nerve Tissue Proteins/genetics , Nestin , RNA, Messenger/metabolism , Random Allocation , Receptors, Dopamine D1/genetics , Receptors, Dopamine D1/metabolism , Receptors, Dopamine D2/genetics , Receptors, Dopamine D2/metabolism , Receptors, Serotonin, 5-HT1/genetics , Receptors, Serotonin, 5-HT1/metabolism , Reflex, Startle/drug effectsABSTRACT
BACKGROUND: The aim of the current investigation was to examine the effects of consuming a low-carbohydrate high-fat diet (LC-HFD) in combination with daily exercise on body weight, body composition, endocrine control of the energy balance system and exercise capacity in adolescent and mature rats. METHOD: Adolescent (n=23) and mature rats (n=16) were maintained on either a standard chow diet (CH) or a LC-HFD for a period of ten days prior to daily exercise training for 21 days in forced running wheel system. At the end of the 21 day training sessions all rats took part in an exercise performance test where time to exhaustion was measured. RESULTS: Rats maintained on the LC-HFD demonstrated a significant lack of body weight gain (p<0.05) compared to CH maintained rats, despite equicaloric intake and performing identical amounts of daily exercise. Body composition was significantly altered in the LC-HFD rats (p<0.05) with increased body fat (p<0.01). Leptin concentrations were higher (p<0.05) and IGF-I concentrations were lower (p<0.01) in the LC-HFD fed rats. Exercise performance was not diminished in the LC-HFD group despite the higher fat mass. Both groups irrespective of age performed equally as well in the time to exhaustion test (p>0.05). CONCLUSION: Maintenance on the LC-HFD in combination with forced daily exercise did not impact exercise capacity (total distance and meters per minute). Additionally consumption of an extreme LC-HFD in combination with daily exercise resulted in significantly less body weight gain but increased fat mass. When combined with daily exercise this diet clearly had a negative impact on body composition, but did not affect exercise capacity.
