Decreased in vivo α2 adrenoceptor binding in the Flinders Sensitive Line rat model of depression

Abstract

Depression is a debilitating heterogeneous disorder and the underlying mechanisms remain elusive. Alterations in monoaminergic neurotransmission, including noradrenergic, have been implicated in the etiology of depression. Although depression is difficult to model in animals, the availability of animal models with face, predictive and construct validity permits more in-depth investigations resulting in a greater understanding of the disease. We investigated the role of noradrenaline (NA) and α2 adrenoceptors in vivo in a genetic model of depression, the Flinders Sensitive Line (FSL) rat. We determined baseline differences in NA receptor volume of distribution to α2 adrenoceptors in FSL, in comparison with two routinely used controls, Flinders Resistant Line (FRL) and Sprague-Dawley (SD) rats using positron emission tomography (PET) imaging and the carbon-11 labeled radioligand yohimbine. We demonstrate a 42-47% reduction in the binding of the tracer in the cortex, striatum, cerebellum, thalamus and pons of FSL rats compared to the two control groups. Our results suggest that the behavioral deficits expressed in the FSL depression model are associated with functional over-activity of the NA system.

Sex differences in the locus coeruleus-norepinephrine system and its regulation by stress

“…However, in parallel with these effects, estrogens also reduce postsynaptic adrenergic receptors, decreasing the ability of NE to affect downstream structures. A similar pattern of high NE levels and decreased α2 adrenergic receptors is observed in the Flinders Sensitive Line, which is a genetic model of depressive-like behavior (Landau et al, 2015; Zangen et al, 1999). In this model, the decreased receptors are thought to reflect receptor downregulation following a persistently high NE tone (Landau et al, 2015).…”

“…A similar pattern of high NE levels and decreased α2 adrenergic receptors is observed in the Flinders Sensitive Line, which is a genetic model of depressive-like behavior (Landau et al, 2015; Zangen et al, 1999). In this model, the decreased receptors are thought to reflect receptor downregulation following a persistently high NE tone (Landau et al, 2015). Estrogen-induced reductions in adrenergic receptors could similarly be compensatory in females, allowing them to maintain NE function at a level comparable to males under normal circumstances.…”

Dexmedetomidine Alleviates Postpartum Depressive Symptoms following Cesarean Section in Chinese Women: A Randomized Placebo‐Controlled Study

“…The LC is the major source of brain noradrenergic activity, with raised levels of LC neuronal activity associated with a lower LC density of G protein‐coupled inhibitory α 2 ‐adrenoceptors (α 2 ‐AR) in stressed animals, with the LC α 2 ‐AR functionally blocked in stress‐induced depression models that is reversed by the LC infusion of the α 2 ‐AR agonist, clonidine . Three α 2 ‐AR subtypes, α 2A ‐AR, α 2B ‐AR, and α 2C ‐AR, are present in the mammalian brain, with α 2A ‐AR the predominant inhibitory autoreceptor in noradrenergic neurons .…”

Radioligand binding analysis of α2 adrenoceptors with [11C]yohimbine in brain in vivo: Extended Inhibition Plot correction for plasma protein binding

“…The labeling of yohimbine with carbon-11 provided new opportunities to measure noradrenergic transmission in pathological conditions. [ 11 C]yohimbine so far has been applied to image α 2 adrenoceptor in vivo in different species, including humans 12 , pigs 13 , 14 , and rats 15 – 17 . However, the wide anatomical distribution of noradrenergic receptors complicates the quantification of receptor occupancy and receptor density.…”