Decreased platelet alpha-2 adrenoceptor density in major depression: effects of tricyclic antidepressants and fluoxetine

Abstract

Background: It has been suggested that major depression is accompanied by a subsensitivity of central α2-adrenoceptors (α2-ARs) and, consequently, by an impaired negative feedback on the presynaptic catecholaminergic neuron, which, in turn, may induce a disinhibition of noradrenergic output and norepinephrine release in response to any activation.

Methods: The maximum number of platelet binding sites (Bmax) and their affinity for [³H]-rauwolscine, a selective α2-AR antagonist, were measured in unmedicated and medicated major depressed patients and in normal volunteers. Specific binding was defined as that inhibited by idazoxan, another α2-AR antagonist.

Results: Unmedicated major depressed patients had significantly decreased platelet [³H]-rauwolscine binding Bmax values compared to normal volunteers. [³H]-rauwolscine binding K_d values did not differ significantly between unmedicated major depressed patients and normal controls. [³H]-rauwolscine binding K_d values were significantly higher in depressed patients treated with tricyclic antidepressants than in unmedicated patients. Subchronic treatment with fluoxetine did not significantly alter either [³H]-rauwolscine binding Bmax or K_d values. [³H]-rauwolscine binding Bmax values were significantly greater in men than in women.

Conclusions: The results suggest that i) major depression is accompanied by decreased platelet α2-AR density; and that ii) subchronic treatment with tricyclic antidepressants, but not fluoxetine, results in a decreased affinity of rauwolscine for platelet α2-ARs.

Introduction

Originally proposed 30 years ago, the catecholamine hypothesis of major depression posited that some, if not all, depressions are associated with a reduced noradrenergic turnover at functionally important adrenergic receptor sites in the brain Bunney and Davis 1965, Schildkraut 1965. Accordingly, it was thought that supersensitivity of the inhibitory, presynaptic α2-adrenoreceptors (α2-ARs) may explain decreased catecholaminergic neurotransmission with resultant postsynaptic β-receptor up-regulation (Garcia-Sevilla et al 1981). Recently, the original catecholamine depletion hypothesis of major depression has been reformulated into the “dysregulation hypothesis” of depression, which emphasizes a primary subsensitivity or down-regulation in nerve terminal α2-ARs (Siever and Davis 1985). Potter and Manji (1994) suggest that a subsensitivity of α2-ARs and, consequently, an impaired negative feedback on the presynaptic neuron, could produce a disinhibition of noradrenergic output and exaggerated noradrenaline (NE) release in response to any activation of the catecholaminergic system.

The following findings support the hypotheses of Potter and Manji (1994). First, unmedicated major depressed patients excrete significantly greater amounts of NE, adrenaline, and dopamine in cerebrospinal fluid (CSF), plasma, and urine than do normal controls and patients with minor depression Lake et al 1982, Roy et al 1988, Maes et al 1990, Maes et al 1991. Depressed patients excrete disproportionally greater amounts of NE and its major extraneural metabolite, normetanephrine, relative to total catecholamine synthesis Maas et al 1987, Davis et al 1988. Esler et al (1982) found increased plasma NE appearance rates in depressed patients. These findings are compatible with reports of an exaggerated increase in plasma NE upon orthostatic challenge in depression (Rudorfer et al 1985) and significantly elevated NE appearance in extravascular and vascular compartments of depressed patients (Veith et al 1994). These findings suggest increased sympathoadrenal system (SAS) activity in major depression (Maes et al 1993). It has been argued that, since peripheral SAS and central catecholaminergic activity may be regulated in parallel, whole body catecholaminergic turnover may undergo major upheavals in major depression (Maes et al 1993).

Second, measures of peripheral blood cell receptors and neuroendocrine challenge studies suggest alterations in pre- and postsynaptic α2-ARs in depression Kafka and Paul 1986, Potter and Manji 1994. One of the most consistently reported abnormal findings in depression is a blunted growth hormone (GH) response to acute administration of clonidine, a partial α2-AR agonist Matussek et al 1980, Siever et al 1982, Ansseau et al 1984, Siever and Uhde 1984, suggesting subsensitive postsynaptic α2-ARs at the hypothalamic level (Potter and Manji 1994). Another approach has been to explore platelet α2-AR functioning through measurements of agonist-induced platelet aggregation or NE-induced inhibition of prostaglandin E1 (PGE1)-stimulated cyclic adenosine monophosphate (cAMP) production. Some of these reports suggest subsensitive platelet α2-ARs in major depression Kafka et al 1986, Roy and Kafka 1989, Kafka and Paul 1986. Platelet α2-ARs have similar kinetic and pharmacologic properties as those in the brain, suggesting that platelet α2-ARs may constitute an adequate model for the same receptors in the brain (Stahl 1985). Adrenoceptors of the α2A subtype are expressed on platelets and presynaptically on noradrenergic neurons Hieble et al 1995, Limberger et al 1995.

Direct α2-AR binding studies, however, as opposed to indirect neuroendocrine or neurochemical studies, reported either increased or normal platelet α2-AR density in depressed patients. Thus, some Garcia-Sevilla et al 1986, Piletz and Halaris 1988, Karege et al 1992, but not all (Carstens et al 1986), authors reported higher α2-AR Bmax values in depressed patients using partial agonists as ligands, i.e., clonidine, para-aminoclonidine or UK-14304. A lower platelet α2-AR agonist binding affinity (increased K_d) in depression was found in some Garcia-Sevilla et al 1986, Carstens et al 1986, Takeda et al 1989, Karege et al 1992, but not all Theodorou et al 1986, Piletz et al 1986, studies. Moreover, binding studies of α2-AR antagonist ligands to platelets of depressed patients yielded conflicting results Daiguji et al 1981, Kafka et al 1981, Wood and Coppen 1981, Healy et al 1983, Pimoule et al 1983, Braddock et al 1986, Wolfe et al 1987, Katona et al 1989, Mendlewicz et al 1989, Southwick et al 1990. There are also some reports that repeated administration of some, but not all, antidepressants induces down-regulated or subsensitive α2-ARs Spyraki and Fibiger 1980, Svensson and Usdin 1979, Stanford et al 1983, Sugrue 1983, Jimenez-Rivera et al 1996; However, possible relationships between changes in α2-AR binding characteristics in relation to treatment outcome need further examination.

The aims of the present study were to examine i) platelet [³H]-rauwolscine binding Bmax and K_d values in unmedicated major depressed patients compared to healthy volunteers; ii) the effects of subchronic treatment with antidepressive drugs on platelet α2-AR binding sites; and iii) the relationships between changes in [³H]-rauwolscine binding characteristics and treatment outcome.