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
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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- "Circle: master circadian oscillator; Oval: neuromodulators; Snip single corner rectangle: psychiatric disorders; Rectangle: sleep; Solid arrows: known interactions; Dashed arrows: tentative interactions activity in NE-containing terminals, or by a combination of both (Klimek et al. 1997). For DA, lower transporter binding potential (a correlate of receptor density) in striatum is reported in depressed patients (Meyer et al. 2001). Similar findings were also observed in depressed patients with anhedonia symptoms (Sarchiapone et al. 2006). "
ABSTRACT: Psychiatric disorders such as unipolar depression have complex pathologies, which include disruptions in circadian and sleep-wake cycles. At the neurochemical level, psychiatric diseases can also be accompanied by changes in neuromodulator systems such as orexin/hypocretin and the monoamines. Indeed, for decades the monoamine hypothesis of depression has been instrumental in driving discoveries and developments of antidepressant drugs. Recent preclinical and clinical advancement strongly suggests that neuropeptides such as orexin can play an important part in the pathophysiology of depression. Due to the complexity and extensive connectedness of neurobiological systems, understanding the biological causes and mechanisms of psychiatric disorders present major research challenges. In this chapter, we review experimental and computational studies investigating the complex relationship between orexinergic, monoaminergic, circadian oscillators, and sleep-wake neural circuitry. Our main aim is to understand how these physiological systems interact and how alteration in any of these factors can contribute to the behaviours commonly observed in depressive patients. Further, we examine how modelling across different levels of neurobiological organization enables insight into these interactions. We propose that a multiscale systems approach is necessary to understand the complex neurobiological systems whose dysfunctions are the underlying causes of psychiatric disorders. Such an approach could illuminate future treatments.Orexin and Sleep: Molecular, Functional and Clinical Aspects, 1 edited by Takeshi Sakurai, S.R. Pandi-Perumal, Jaime M. Monti, 01/2015: chapter 16: pages 299-322; Springer International Publishing., ISBN: 978-3-319-23078-8
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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]. "
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  . Contrastingly, dopaminergic hypoactivity has been recognized as a possible precursor of depression . This observation emphasizes the fact that the efficacy of fish oil potentially depends on the disease pathophysiology. "
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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