Platelet peripheral-type benzodiazepine receptor in major depression

doi:10.1016/0165-0327(94)00098-T

Journal of Affective Disorders

Volume 33, Issue 4, 4 April 1995, Pages 257-261

https://doi.org/10.1016/0165-0327(94)00098-T Get rights and content

Abstract

The peripheral-type benzodiazepine receptor (PBR) plays a major role in steroidogenesis. This receptor is sensitive to endocrine changes and stress. Antidepressants have been demonstrated to modulate adrenal and hepatic PBR in rats. To evaluate the relationship between depression and PBR, we measured platelet PBR in untreated depressed patients (n = 14) in comparison to normal controls (n = 13). Platelet PBR density (B_max) and the dissociation constant (k_d) of the receptor did not differ in the patients when compared with normal controls. Furthermore, no correlation was found between B_max values and the severity of the depression (as measured by the Hamilton Depression Rating Scale and Beck Depression Inventory) as well as with the severity of the anxiety (as measured by the Hamilton Anxiety Rating Scale). It seems that major depression, in contrast to stress and some anxiety disorders, is not associated with alteration of PBR.

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Cited by (37)

The translocator protein (18 kDa) and its role in neuropsychiatric disorders
2017, Neuroscience and Biobehavioral Reviews
Citation Excerpt :
Finally, schizophrenic patients with aggressive behaviour presented a lower density of platelet TSPO and scored significantly higher on hostility, anxiety, state anger, and emotional distress compared to homicidal and nonaggressive schizophrenic patients and the controls (Ritsner et al., 2003). A study by Weizman et al., demonstrated that there were no association between depression and reduced TSPO expression (Weizman et al., 1995). However, co-morbid adult separation anxiety (Abelli et al., 2010) or suicidality (Soreni et al., 1999) was associated with reduced TSPO expression in patients with depression or bipolar disorder.
Translocator protein (TSPO) is an 18 kDa translocator membrane protein expressed in the outer mitochondrial membrane of steroid-synthesizing cells in the central and peripheral nervous systems. TSPO is involved in cellular functions, including the regulation of cell proliferation, transport of cholesterol to the inner mitochondrial membranes of glial cells, regulation of mitochondrial quality control, and haem synthesis. In the brain, TSPO has been extensively used as a biomarker of injury and inflammation. Indeed, TSPO was up-regulated in several inflammatory and neurodegenerative diseases. In contrast, the expression of TSPO was decreased in peripheral blood from psychiatric patients. Since TSPO is involved in several mechanisms related to mitochondrial function and inflammatory alterations, therapeutic approaches focusing on the regulation of TSPO may provide a new avenue for the treatment of neuropsychiatric disorders. Based on the involvement of mitochondrial alterations in the neurobiology of neuropsychiatric disorders, this review will focus on the functions and physiological roles of TSPO and the potential of TSPO ligands as therapeutic strategies for the treatment of neuropsychiatric disorders.
Major depressive disorder and anxiety disorders from the glial perspective: Etiological mechanisms, intervention and monitoring
2017, Neuroscience and Biobehavioral Reviews
Citation Excerpt :
TSPO and S100beta are CNS-glia related proteins and found also in peripheral blood. Despite interesting associations with ANX and MDD (Ambree et al., 2015; Arolt et al., 2003; Schroeter et al., 2008) (Gavish et al., 1996; Johnson et al., 1998; Nakamura et al., 2002; Nudmamud et al., 2000; Rocca et al., 1998; Weizman et al., 1995), the extent to which peripheral TSPO and S100beta levels reflect CNS glia function remains to be further validated, as these proteins also appear to be produced by other cell types outside the CNS (Batarseh and Papadopoulos, 2010; Zimmer and Van Eldik, 1987). Peripheral leukocyte telomeres have been found to be significantly shorter in individuals with MDD and ANX than in matched controls (Lindqvist et al., 2015; Simon et al., 2006; Verhoeven et al., 2015).
Despite intense ongoing research efforts, the etiology of psychiatric disorders remains incompletely understood. Among biological factors playing a role in Major Depressive Disorder (MDD) and Anxiety Disorders (ANX), emerging evidence points to the relevance of different types of glia cells and efficient neuron-glia interactions. Here, we review recent findings highlighting the involvement of central nervous system (CNS) glia in MDD and ANX etiology and treatment response. Additionally, several relatively underexplored topics will be discussed: (1) glial response to non-pharmacological therapies, (2) impact of early life adversity on glia, (3) influence of lifestyle factors on glia in the context of MDD and ANX, and (4) monitoring glial functions in patients. It can be concluded that despite the sequence of events is still unclear, alterations in glial cell types are common and somewhat overlapping in ANX, MDD and corresponding animal models. Furthermore, glia are responsive to a variety of treatment and lifestyle options. Looking forward, new research developments can lead to novel types of therapeutic or symptom-relieving approaches targeting glia.
The neuroinflammation marker translocator protein is not elevated in individuals with mild-to-moderate depression: A [<sup>11</sup>C]PBR28 PET study
2013, Brain, Behavior, and Immunity
Citation Excerpt :
Anxiety is associated with lower levels of platelet TSPO in healthy individuals (Nudmamud et al., 2000; Nakamura et al., 2002), and lower TSPO binding in platelets has been found in panic disorder, posttraumatic stress disorder, generalized anxiety disorder, and social anxiety disorder (Johnson et al., 1998; Rocca et al., 1998). Lower TSPO binding in platelets has also been found in individuals who attempted suicide (Soreni et al., 1999), but not in depression (Weizman et al., 1995), except when co-morbid with adult separation anxiety disorder (Chelli et al., 2008). Interestingly, TSPO agonists have anxiolytic properties in animal models and in humans (Rupprecht et al., 2010; Costa et al., 2011; Venneti et al., 2013).
Depression is associated with systemic inflammation. In animals, systemic inflammation can induce neuroinflammation and activation of microglia; however, postmortem studies have not convincingly shown that there is neuroinflammation in depression. The purpose of this study was to use positron emission tomography (PET) with [¹¹C]PBR28, which binds to the neuroinflammation marker translocator protein 18 kDa (TSPO), to compare the level of TSPO between individuals with depression and control subjects. Ten individuals who were in an acute episode of major depression and 10 control subjects matched for TSPO genotype and other characteristics had a PET scan with arterial input function to quantify levels of TSPO in brain regions of interest (ROIs). Total volume of distribution (V_T) of [¹¹C]PBR28 was used as a measure of total ligand binding. The primary outcome was the difference in V_T between the two groups; this was assessed using a linear mixed model with group as a between-subject factor and region as a within-subject factor. There was no statistically significant difference in [¹¹C]PBR28 binding (V_T) between the two groups. In fact, 7 of 10 individuals with depression had lower [¹¹C]PBR28 binding in all ROIs compared to their respective genotype-matched control subjects. Future studies are needed to determine whether individuals with mild-to-moderate depression have lower TSPO levels and to assess whether individuals with severe depression and/or with elevated levels of systemic inflammation might have higher TSPO levels than control subjects.
Lifetime manic-hypomanic symptoms in post-traumatic stress disorder: Relationship with the 18 kDa mitochondrial translocator protein density
2010, Psychiatry Research
Initially explored in military settings, post-traumatic stress disorder (PTSD) has shown increasing prevalence in the general population. The high comorbidity rates between bipolar disorder (BD) and PTSD have raised the issue of whether some characteristics of BD could represent risk factors for PTSD. In combat-related PTSD, the 18 kDa mitochondrial translocator protein (TSPO), essential for steroid synthesis, was found to be decreased. Aims of the present study were: 1) the assessment of the TSPO mitochondrial density in lymphomonocytes from civilian patients with non-combat-related PTSD, without current or lifetime Axis I mood comorbidity, versus controls; 2) the exploration of the correlations between TSPO density and the presence of comorbid manic/hypomanic lifetime spectrum symptoms. Assessments included the Structured Clinical Interview for DSM-IV (SCID), the Impact of Event Scale (IES), and the lifetime Mood Spectrum Self-Report (MOODS-SR). Blood samples were processed to assess TSPO binding parameters in lymphomonocyte mitochondrial membranes. PTSD patients showed a significant decrease in TSPO density, without changes in mitochondrial citrate synthase activity. Further, TSPO density correlated with the number of lifetime manic/hypomanic spectrum symptoms. For the first time, TSPO density was found to be decreased in non-war-related PTSD and such decreases correlated with comorbid manic/hypomanic spectrum symptoms, indicating a possible role of sub-threshold bipolar comorbidity in PTSD-related neurobiological dysregulation.
Effects of long-term low-dose hormone replacement therapy on the binding capacity of platelet peripheral-type benzodiazepine receptor in postmenopausal women
2008, Psychoneuroendocrinology
Citation Excerpt :
PBR has also been strongly considered to participate in the regulation of apoptosis (Susin et al., 1997). As a result, it may be sensitive to endocrine changes (Weizman et al., 1995). Animal studies have demonstrated that the expression of PBR in hippocampus synaptosomes decreases, which was possibly associated with spatial learning-memory impairments induced by d-galactose (Chen et al., 2006b).
The effects of long-term low-dose hormone replacement therapy (HRT) on the level of hormone in plasma and on the binding capacity of peripheral-type benzodiazepine receptor (PBR) on the platelet membranes were investigated among women. This study was a retrospective and case-controlled study where 64 women using long-term low-dose HRT for over 4 years entered the study and 99 women, age and education matched, were enrolled as control. Plasma hormone level and platelet PBR binding capacity of two groups were analyzed. A significant increase in plasma estradiol level in women using HRT was observed, compared to those in the control group. Meanwhile, women in the HRT group displayed higher platelet PBR binding capacity. Further analysis demonstrated that the binding capacity of platelet PBR was closely related to estradiol plasma level in all subjects. These results suggest that long-term low-dose HRT could relieve the decrease of estradiol level in plasma and PBR binding capacity on platelets in postmenopausal women, alleviate the endocrine imbalance process, and might be beneficial for reducing the risks of some diseases.
Platelet 18 kDa Translocator Protein density is reduced in depressed patients with adult separation anxiety
2008, European Neuropsychopharmacology
Citation Excerpt :
We found that TSPO platelet density was significantly decreased in the overall sample of MDD patients with respect to healthy controls. These results are apparently contradictory to those of Weizman et al. (1995) who found no significant differences in [3H]PK 11195 dissociation constant values or TSPO density in MDD patients, with or without associated anxiety, as compared to healthy subjects. Consistently with this study, in our group of MDD patients without ASAD, TSPO density did not differ from healthy controls.
Recent studies indicate that Adult Separation Anxiety Disorder (ASAD) may represent a discrete diagnostic entity worthy of attention. Adults with separation anxiety report extreme anxiety and fear about separations from major attachment figures (partner, children or parents). These symptoms affect individual's behavior, lead to severe impairment in social relationships and are not better accounted for by the presence of agoraphobia. In a previous study we found platelet expression reduction of the 18 kDa Translocator Protein (TSPO) (the new nomenclature for the peripheral-type benzodiazepine receptor) in patients with panic disorder who also fulfilled the diagnostic criteria for ASAD.
To explore whether separation anxiety might be a factor differentiating TSPO expression in a sample of patients with major depression.
The equilibrium binding parameters of the specific TSPO ligand [³H]PK 11195 were estimated on platelet membranes from 40 adult outpatients with DSM-IV diagnosis of MDD, with or without separation anxiety symptoms, and 20 healthy controls. Patients were assessed by SCID-I, HAM-D, the Structured Clinical Interview for Separation Anxiety Symptoms (SCI-SAS-A) and the Adult Separation Anxiety Self-report Checklist (ASA-27).
A significant reduction of platelet TSPO density mean value was found in depressed patients with associated ASAD symptoms, while no significant differences were found between depressed patients without ASAD and the control group. Individual TSPO density values were significantly and negatively correlated with both SCI-SAS-A and ASA-27 total scores, but not with HAM-D total score or HAM-D anxiety/somatization factor score.
The reduction of platelet TSPO density in our sample of patients with depression was specifically related to the presence of ASAD. These data suggest that TSPO expression evaluation is a useful biological marker of ASAD.

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¹: Submitted in partial fulfillment of the requirements for the DSc degree of Ruth Burgin at the Technion-Israel Institute of Technology.

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Research paperPlatelet peripheral-type benzodiazepine receptor in major depression

Abstract

Trends Pharmacol. Sci.

J. Biol. Chem.

Life Sci.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Mol. Cell. Endocrinol.

J. Biol. Chem.

J. Biol. Chem.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

An inventory for measuring depression

Arch. Gen. Psychiatry

Effects of peripheral benzodiazepine receptor ligands on hypothalamic-pituitary-adrenal axis function in the rat

J. Pharmacol. Exp. Ther.

Research paper
Platelet peripheral-type benzodiazepine receptor in major depression