Platelet imidazoline receptors as state marker of depressive symptomatology

Abstract

Objective-Previous studies have shown that imidazoline receptors (IR-1) are increased in platelets and frontal cortex of depressed patients, and this up-regulation is normalized (down-regulated) after antidepressant drug treatments. It has been hypothesized that IR-1 up-regulation during the depressive episode may be a state marker for depressive symptomatology. The goal of the present study was to address the state versus trait question.Method-Twelve healthy subjects (6 males and 6 females) met stringent inclusion and exclusion criteria for physical and mental health. They received desipramine for six weeks in order to simulate the length of time and dosing used previously to obtain an IR-1 down-regulation and a therapeutic response in depressed patients. Outcome and safety measures included clinical, psychological, and cardiovascular assessments obtained throughout the study. Plasma concentrations of desipramine were measured throughout the six weeks of treatment and again after 2 weeks following tapered discontinuation of desipramine. Platelet receptors were assessed by Western blotting and radioligand binding assays.Results-Healthy subjects taking desipramine experienced mild dysphoric effects but there were no adverse events. The binding of 8 nM p-[ 125 I] clonidine to IR-1 and α 2 -adrenoceptors in healthy subjects did not change during desipramine treatment. The immunodensity of the 33 kD band associated with IR-1 gradually increased to a maximum, by week-6, of 26% higher than baseline (p < 0.01 compared to baseline). Two weeks after desipramine discontinuation, there was a decline in α 2 -adrenoceptor binding and 33 kD band's immunodensity (p = 0.04).Conclusions-The findings support the hypothesis that platelet IR-1 binding sites are a marker of mood state rather than of antidepressant-induced pharmacological regulation. By comparison, platelet α 2 -adrenoceptors appear to be regulated by desipramine as a pharmacological effect independent of mood state.

A Biomarker to Differentiate between Primary and Cocaine-Induced Major Depression in Cocaine Use Disorder: The Role of Platelet IRAS/Nischarin (I1-Imidazoline Receptor)

“…Also, these biomarkers would improve the knowledge of neurobiological mechanisms of both types of depression associated to CUD and facilitate the appropriate treatment. In addition, comparable results (Trp depletion: 86–87%) have been reported in studies using a similar protocol in pure MDD ( 19 , 33 ).…”

“…Before starting the sessions, urine was screened for cocaine and other substances to exclude consumption prior to testing. During one session, in randomized form, the subjects were given an amino acid mixture lacking Trp (ATD session; i.e., l -alanine 4.1 g, l -arginine 3.7 g, l -cysteine 2.0 g, glycine 2.4 g, l -histidine 2.4 g, l -isoleucine 6.0 g, l -leucine 10.1 g, l -lysine 6.7 g, l -methionine 2.3 g, l -proline 9.2 g, l -phenylalanine 4.3 g, l -serine 5.2 g, l -threonine 4.9 g, l -tyrosine 5.2 g, and l -valine 6.7 g) and in the other session a similar amino acid mixture but containing Trp (non-ATD; 3.0 g) ( 19 ). Blood samples were obtained prior, during and after the test.…”

“…( 11 ), which combines platelet 5-HT 2A receptor binding and plasma tryptophan/amino acid ratio in MDD]. Notably, the I 1 -IR was recently shown to participate in the prevention of cue-induced cocaine relapse in rats ( 17 ) and has been proposed as a state marker of MDD ( 18 , 19 ). In a recent post-mortem human brain study, the basal content of I 1 -IR was marginally increased and then downregulated by antidepressant drugs (AD) in the prefrontal cortex of subjects with MDD ( 15 ), further suggesting a role of this novel receptor in MDD and in the action mechanisms of AD, including the selective 5-HT re-uptake inhibitors (SSRI) which were the predominant drugs in the medicated depressed patients of the present study.…”

Modulation of stress by imidazoline binding sites: Implications for psychiatric disorders

“…This would suggest that the down-regulation/normalization of platelet I1 IBS is limited to treated depressed patients and is likely to be related to antidepressant-induced mood improvement. However, a platelet 33 kDa band is upregulated during desipramine treatment of healthy subjects (Piletz et al, 2008). This conflicts directly with findings in antidepressant-treated patients (Zhu et al, 1999).…”

“…Indeed, patients with bipolar depression that were treated with lithium showed normal IRBP-immunodensities (Garcia-Sevilla et al, 1996;Garcia-Sevilla et al, 1999). The down regulation of bands associated with I1 IBS occurred only in depressed patients and not in healthy control subjects that received the antidepressant treatment (Piletz et al, 2008). This would suggest that the down-regulation/normalization of platelet I1 IBS is limited to treated depressed patients and is likely to be related to antidepressant-induced mood improvement.…”