Elsevier

Brain Research

Volume 210, Issues 1–2, 6 April 1981, Pages 413-418
Brain Research

α2-Adrenoreceptors in rat brain are decreased after long-term tricyclic antidepressant drug treatment

https://doi.org/10.1016/0006-8993(81)90919-7Get rights and content

Summary

After two weeks of twice-daily administration of amitriptyline to rats, the binding of [3H]clonidine to presynaptic α2-adrenoreceptors was decreased in membranes isolated from 5 areas of the rat brain. After one day of treatment, binding did not differ from saline treated controls. In vitro, a high concentration of amitriptyline caused a competitive inhibition of [3H]clonidine binding but did not alter the number of binding sites. The decrease in the number of α2-adrenoreceptor binding sites after two weeks of amitriptyline treatment would explain the subsensitivity of these receptors which occurs after prolonged administration of antidepressant drugs.

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    Indeed, suicide victims treated with antidepressants have however significantly lower levels of α2-adrenoceptors in cortex, hippocampus, caudate and amygdala compared to antidepressant-free suicides (De Paermentier et al., 1997). Chronic antidepressant treatment has also repeatedly been shown to induce down-regulation of α2-adrenoceptors in rat brain (Barturen and Garcia-Sevilla, 1992; Cottingham et al., 2011; Smith et al., 1981). However, it must be noted that post-mortem changes in binding do not always correlate with the in vivo functional response of receptors and increased sensitivity of amygdaloid neurons to monoaminergic transmitters has been found following antidepressant treatment (Wang and Aghajanian, 1980).

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    By contrast, there are few reports about the status of brain β-adrenoceptors in major depressive disorder and the majority of them correspond to suicide victims with unknown psychiatric diagnosis. Antidepressant treatment on animals (represented by tricyclic antidepressants, monoamine oxidase inhibitors (MAOi) or electroconvulsive shock) induces a down-regulation and/or desensitisation of brain α2- (Esteban et al., 1999; Giralt and García-Sevilla, 1989; Mateo et al., 2001; Mongeau et al., 1994; Pilc and Vetulani, 1982; Sacchetti et al., 2001; Smith et al., 1981) and β-adrenoceptors (Duncan et al., 1985; Gillespie et al., 1979; Heal et al., 1989; Holoubek et al., 2004; Ordway et al., 1991). However, information about the effect of antidepressant treatment on α2- and β-adrenoceptors in postmortem human brain of subjects with major depressive disorder is scarce.

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    Given the clinical evidence, it is possible to draw a fairly clear connection between experimental studies investigating the phenomenon of antidepressant-induced adaptive alterations in α2AR density and the therapeutic mechanism. Indeed, several studies have reported downregulation of cortical and hippocampal α2ARs through direct assays of receptor expression levels following chronic exposure of rodents to antidepressant drugs (Barturen and García-Sevilla, 1992; Cottingham et al., 2011b; Giaroni et al., 2008; Giralt and García-Sevilla, 1989; Smith et al., 1981; Subhash et al., 2003). Further, studies have reported functional α2AR downregulation in the form of decreased α2AR-mediated responses following chronic exposure of rodents to antidepressant drugs (Esteban et al., 1999; Mateo et al., 2001; Menargues et al., 1990; Nomura et al., 1987).

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