Lower Dopamine Transporter Binding Potential in Striatum During Depression

PET Imaging Centre, and Mood Division, Centre for Addiction and Mental Health, Department of Psychiatry and University of Toronto, 250 College St., Toronto, Ont. M5T1R8, Canada.
Neuroreport (Impact Factor: 1.52). 01/2002; 12(18):4121-5. DOI: 10.1097/00001756-200112210-00052
Source: PubMed


Previous studies suggest that there is a dopamine lowering process during major depressive episodes (MDE). To investigate this, we measured the dopamine transporter binding potential (DAT BP) in the striatum of depressed and healthy subjects using [(11)C]RTI-32 PET. The DAT, a predominantly presynaptic receptor, decreases in density after chronic dopamine depletion and the BP is proportional to receptor density. In all striatal regions, subjects with MDE had significantly lower DAT BP. Low striatal DAT BP in MDE is consistent with a downregulation of DAT in response to a dopamine lowering process. There was also a strong, highly significant, inverse correlation between striatal DAT BP and neuropsychological tests of dopamine-implicated symptoms in patients (i.e. patients with lower DAT BP performed better). Lower DAT BP itself reduces extracellular clearance of dopamine. Patients who did not decrease their striatal DAT BP failed to compensate for low dopamine and showed greater impairment on dopamine related tests.

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    • "In other studies, DRD4 levels in postmortem brain tissue from MDD and schizophrenia patients were found to be elevated [51, 52]. Variations in peripheral and postmortem levels of DRD3 and dopamine transporter have also been observed, suggesting broad dysregulation of dopaminergic pathways in depressive disorders [53, 54]. "
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    ABSTRACT: Objective. To evaluate leukocyte gene expression for 9 selected genes (mRNAs) as biological markers in patients with medication refractory depression before and after treatment with ECT or isoflurane anesthesia (ISO). Methods. In a substudy of a nonrandomized open-label trial comparing effects of ECT to ISO therapy, blood samples were obtained before and after treatment from 22 patients with refractory depression, and leukocyte mRNA was assessed by quantitative PCR. Patients' mRNAs were also compared to 17 healthy controls. Results. Relative to controls, patients before treatment showed significantly higher IL10 and DBI and lower ADRA2A and ASIC3 mRNA (P < 0.025). Both ECT and ISO induced significant decreases after treatment in 4 genes: IL10, NR3C1, DRD4, and Sult1A1. After treatment, patients' DBI, ASIC3, and ADRA2A mRNA remained dysregulated. Conclusion. Significant differences from controls and/or significant changes after ECT or ISO treatment were observed for 7 of the 9 mRNAs studied. Decreased expression of 4 genes after effective treatment with either ECT or ISO suggests possible overlap of underlying mechanisms. Three genes showing dysregulation before and after treatment may be trait-like biomarkers of medication refractory depression. Gene expression for these patients has the potential to facilitate diagnosis, clarify pathophysiology, and identify potential biomarkers for treatment effects.
    Depression research and treatment 04/2014; 2014(2):582380. DOI:10.1155/2014/582380
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    • "The activities of GABA families and dopaminergic hyperactivity are positively correlated with the prevalence of bipolar disorder and schizophrenia [105] [106]. Contrastingly, dopaminergic hypoactivity has been recognized as a possible precursor of depression [107]. This observation emphasizes the fact that the efficacy of fish oil potentially depends on the disease pathophysiology. "
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    ABSTRACT: The health benefits of fish oil enriched with high omega-3 polyunsaturated fatty acids (n-3 PUFA) are widely documented. Fish oil as dietary supplements, however, show moderate clinical efficacy, highlighting an immediate scope of systematic in vitro feedback. Our transcriptomic study was designed to investigate the genomic shift of murine brains fed on fish oil enriched diets. A customized fish oil enriched diet (FD) and standard lab diet (SD) were separately administered to two randomly chosen populations of C57BL/6J mice from their weaning age until late adolescence. Statistical analysis mined 1,142 genes of interest (GOI) differentially altered in the hemibrains collected from the FD- and SD-fed mice at the age of five months. The majority of identified GOI (∼40%) encodes proteins located in the plasma membrane, suggesting that fish oil primarily facilitated the membrane-oriented biofunctions. FD potentially augmented the nervous system's development and functions by selectively stimulating the Src-mediated calcium-induced growth cascade and the downstream PI3K-AKT-PKC pathways. FD reduced the amyloidal burden, attenuated oxidative stress, and assisted in somatostatin activation-the signatures of attenuation of Alzheimer's disease, Parkinson's disease, and affective disorder. FD induced elevation of FKBP5 and suppression of BDNF, which are often linked with the improvement of anxiety disorder, depression, and post-traumatic stress disorder. Hence we anticipate efficacy of FD in treating illnesses such as depression that are typically triggered by the hypoactivities of dopaminergic, adrenergic, cholinergic, and GABAergic networks. Contrastingly, FD's efficacy could be compromised in treating illnesses such as bipolar disorder and schizophrenia, which are triggered by hyperactivities of the same set of neuromodulators. A more comprehensive investigation is recommended to elucidate the implications of fish oil on disease pathomechanisms, and the result-driven repositioning of fish oil utilization may revitalize its therapeutic efficacy.
    PLoS ONE 03/2014; 9(3):e90425. DOI:10.1371/journal.pone.0090425 · 3.23 Impact Factor
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    • "As with the 5-HT studies summarized above, however, imaging studies of DA systems have produced conflicting results. In PET and SPECT studies of DAT, MDD has been associated with both lower [72] and higher [73-75] binding potential in the striatum. Interestingly, all studies reporting DAT increases have used SPECT, which has much lower sensitivity than PET [76] and often employed tracers that have equal affinity for the SERT and DAT (for example, β-CIT) and thus do not allow conclusive interpretations. "
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    ABSTRACT: The neuroimaging literature of Major Depressive Disorder (MDD) has grown substantially over the last several decades, facilitating great advances in the identification of specific brain regions, neurotransmitter systems and networks associated with depressive illness. Despite this progress, fundamental questions remain about the pathophysiology and etiology of MDD. More importantly, this body of work has yet to directly influence clinical practice. It has long been a goal for the fields of clinical psychology and psychiatry to have a means of making objective diagnoses of mental disorders. Frustratingly little movement has been achieved on this front, however, and the 'gold-standard' of diagnostic validity and reliability remains expert consensus. In light of this challenge, the focus of the current review is to provide a critical summary of key findings from different neuroimaging approaches in MDD research, including structural, functional and neurochemical imaging studies. Following this summary, we discuss some of the current conceptual obstacles to better understanding the pathophysiology of depression, and conclude with recommendations for future neuroimaging research.
    Biology of Mood and Anxiety Disorders 03/2014; 4(1):5. DOI:10.1186/2045-5380-4-5
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