Platelet alpha 2-adrenergic receptor sensitivity in major depressive disorder

We have investigated the functioning of alpha 2-adrenergic receptors in patients with major depressive disorder by measuring the specific binding of 3H-yohimbine, an alpha 2-adrenergic receptor antagonist, to platelet membranes. Bmax and Kd values for platelet 3H-yohimbine binding were normal in unmedicated patients with major depressive disorder, and did not correlate with scores on the Hamilton rating scale for depression. Platelet alpha 2-adrenergic antagonist sites were also unchanged in number or affinity in depressed patients after long-term treatment with a variety of antidepressant medications.     

Alpha 2-adrenergic receptor sensitivity in depressed patients: relation between 3H-yohimbine binding to platelet membranes and clonidine-induced hypotension

Alpha 2-adrenergic receptor changes during antidepressant treatment were studied using 3H-yohimbine binding to human platelet membranes and clonidine-induced hypotension. Twenty-six patients with major depressive disorder (MDD) participated for 4-6 weeks in a trial of imipramine (2.5 mg/kg/day), tyrosine (100 mg/kg/day), or placebo. Alpha 2-adrenergic receptors measured by 3H-yohimbine binding were not significantly changed following antidepressant treatment. Similarly, clonidine-induced hypotension did not differ significantly following treatment. No measure of alpha 2-adrenergic receptor sensitivity was significantly correlated with clinical improvement. The correlation between platelet receptor binding and clonidine-induced hypotension was not statistically significant, even though both tests are considered to be measures of alpha 2-adrenoceptor sensitivity.     

Platelet membrane alpha 2-adrenergic receptors in depression.

The platelet membrane was used as a model system to examine alpha 2-adrenergic receptors in 30 depressed patients and 30 healthy control subjects. The number of binding sites and their affinity for 3H-UK 14304 (5-bromo-6-(2-imidazoline-2-ylamino)-quinoxaline), a potent, highly selective alpha 2-adrenergic receptor agonist, was measured. Plasma magnesium and free 3-methoxy-4-hydroxyphenylglycol (MHPG) concentrations were assayed in the same sample. A decreased agonist-receptor affinity was found in depressed patients, whereas receptor density was not significantly altered compared with that in control subjects. In bipolar depressed and dysthymic patients, there was a tendency toward a higher density of alpha 2-adrenergic receptors. This trend was not apparent in unipolar, recurrent depressed subjects. Moreover, a positive correlation between Bmax and Kd values was observed in patients but not in control subjects--a finding that suggests that a compensatory phenomenon occurs in depression. After the patients were treated with antidepressant drugs, an increased affinity (decrease in Kd) was observed, together with a decrease in binding sites. Plasma magnesium concentrations were higher in drug-free depressed patients than in control subjects. In addition, magnesium concentrations were negatively correlated with the density of alpha 2-adrenergic receptor binding sites in depressed patients, both before and during treatment. Lastly, a trend toward a negative correlation between plasma MHPG concentration and the number of binding sites was also observed. These results suggest a complex multifactorial regulation of alpha 2-adrenergic receptors, which are probably hyposensitive in depressive syndromes.     

Alpha 2-adrenergic receptor in familial amyloidotic polyneuropathy

alpha 2-Adrenergic receptor binding has been studied in platelet membranes from 16 patients with type 1 familial amyloidotic polyneuropathy (FAP) at various clinical stages and 15 normal subjects. Binding of the radioligand [3H]yohimbine to platelet membranes was used to examine alpha 2-adrenergic receptors. The number of alpha 2-adrenergic receptors were significantly lower in patients of the early stage than in normal subjects. Then, the numbers tended to be higher than those of normal subjects in the intermediate stage, and they were higher in the single advanced-stage patient studied. The reduction in alpha 2-adrenergic receptor numbers in platelet membranes from patients of the early stage might be explained by the down-regulation of the receptors in vascular smooth muscle, but it remains uncertain whether a high number of alpha 2-adrenergic receptors observed in the single advanced-stage patient might be explained by the up-regulation of the receptors.     

Platelet alpha 2-adrenergic receptors in schizophrenic patients before and after phenothiazine treatment

The specific binding to isolated platelet membranes of 3H-clonidine, an alpha 2-adrenergic receptor partial agonist, and 3H-yohimbine, an alpha 2-adrenergic receptor antagonist, was measured in male, drug-free schizophrenic patients. The maximum number of binding sites (Bmax) for 3H-yohimbine was significantly lower in these patients than in normal subjects. Treatment with chlorpromazine (CPZ) for 2 weeks further decreased the Bmax for both ligands. Plasma catecholamine levels were determined before and after treatment. Before treatment, levels of dopamine and norepinephrine (NE) were within a normal range, while epinephrine (E) levels were significantly elevated. CPZ treatment significantly increased plasma NE levels, but decreased E levels to a normal range. These observations suggest that schizophrenia might be associated with abnormal noradrenergic function that is reflected by a decreased number of platelet alpha 2-adrenergic receptors.     

Antidepressant drug administration modifies the interactive relationship between alpha(2)-adrenergic sensitivity and levels of TNF in the rat brain

A reciprocally permissive interaction occurs between cellular responses elicited by the pleiotropic cytokine tumor necrosis factor-alpha (TNF) and alpha(2)-adrenergic receptor activation, such that each may adapt in response to modifications in the other's effects. Changes in presynaptic adrenergic sensitivity as well as neuronal sensitivity to TNF have been implicated in the mechanism of action of antidepressant drugs. The present study examines the influence of alpha(2)-adrenergic receptor activation on levels of TNF in regions of the brain associated with adrenergic function and the expression of mood. Additionally, the role of TNF as a neuromodulator is demonstrated by in vivo microinfusion of rrTNF proximal to the hippocampus. Administration to rats of an alpha(2)-adrenergic receptor agonist (clonidine) decreases levels of TNF in homogenates of rat locus coeruleus and hippocampus within 7.5 min. Chronic (14 days) administration of the antidepressant drugs desipramine or zimelidine transforms alpha(2)-adrenergic receptor-dependent decreases in TNF levels to increases in levels of TNF in the locus coeruleus. This transformation to an increase in total levels of TNF also occurs, although transiently, in the hippocampus following acute (1 day) antidepressant drug administration. The effect of TNF on presynaptic alpha(2)-adrenergic sensitivity was also investigated. Field stimulation of hippocampal slices from rats microinfused with rrTNF proximal to the hippocampus for 14 days demonstrates a decrease in fractional release of [3H]NE and an increase in alpha(2)-adrenergic autoreceptor sensitivity. These data demonstrate a mutual dependence between alpha(2)-adrenergic receptor activation and levels of TNF in the central nervous system that would culminate in an increase in neurotransmitter release following antidepressant drug administration.     

Study of a beta-adrenergic stimulant and its antidepressant activity in man]

In animals, the psychopharmacological profile of beta-adrenergic stimulants is very similar to that of tricyclic antidepressants. In patients, more particularly in endogenous depressive patients, the antidepressant effect of salbutamol was very clear. A definite improvement was observed in all of the 22 studied patients after 1 to 3 days of intermittent venous infusion. The place of salbutamol in the therapeutic armamentarium of depressive states has still to be defined exactly. It is speculated that the antidepressant effect of imipramine-like derivatives is related to the stimulation of central beta 2-adrenergic receptors.     

Desipramine-yohimbine combination treatment of refractory depression. Implications for the beta-adrenergic receptor hypothesis of antidepressant action

Preclinical investigations have shown that combined administration of the alpha 2-adrenergic receptor antagonist yohimbine hydrochloride and the tricyclic antidepressant desipramine hydrochloride produces a reduction in brain beta-adrenergic receptor function within four days. Since the ability of antidepressant treatments to reduce beta-adrenergic receptor function has been hypothesized to mediate antidepressant efficacy, it was predicted that combined desipramine-yohimbine treatment would be a more rapid-acting and potent antidepressant regimen than desipramine alone. In the present investigation, the effects of desipramine (N = 11) and desipramine-yohimbine (N = 10) treatment on depressive symptoms, norepinephrine turnover, and blood pressure were determined in patients with major depression who had a history of nonresponse to standard antidepressant treatments. Neither desipramine nor desipramine-yohimbine proved to be an effective treatment, although concomitant yohimbine administration did attenuate the ability of desipramine to decrease plasma free and 24-hour urinary 3-methoxy-4-hydroxyphenyl-ethyleneglycol levels and blood pressure. Fifteen of the 21 patients eventually had a good response to pharmacologic treatments, particularly a desipramine-lithium carbonate or lithium carbonate-tranylcypromine sulfate combination treatment (11 of 14 responded). This study provides evidence against the beta-adrenergic receptor hypothesis of antidepressant action.     

三环类抗抑郁药对抑郁症患者淋巴细胞β受体的作用

本文以内源性抑郁症患者为实验对象，研究三环类药物对淋巴细胞肾上腺能β受体的作用．结果提示治疗前抑郁症患者淋巴细胞β受体最大结合（Ｂｍａｘ）明显低于正常，治疗后与正常对照无显著差异，且这一改变与临床疗效一致。受体亲和力无改变。本研究对三环类抗抑郁药的机理探讨，及抑郁症病因研究提供依据。     

Some behavioural effects of antidepressant drugs are time-dependent

1. The effects of repeated administration of antidepressant drugs (imipramine, IMI and citalopram, CIT) on the beta- and alpha2-adrenergic as well as dopaminergic D3 receptors were compared with time-dependent changes in the receptor responsiveness after acute treatment. 2. Repeated treatment with IMI or CIT (administered at a dose of 10 mg/kg p.o. twice a day for 14 days) induced down-regulation of beta-adrenergic receptors, demonstrated by behavioural experiment using salbutamol-induced hypoactivity and by binding studies using [3H]CGP12177. The changes in alpha2-adrenergic receptors were studied using clonidine-induced hypoactivity, which was attenuated by repeated treatment with IMI or CIT. Behavioural responsiveness of dopamine D3 receptors was investigated using two doses of 7-OH-DPAT. This drug at a dose of 0.05 mg/kg s.c. induced locomotor hypoactivity (interpreted as a result of stimulation of presynaptic dopamine D3 receptors), which was reversed by repeated administration of IMI or CIT, while 7-OH-DPAT at a dose of 3 mg/kg s.c. (which stimulated postsynaptic dopamine D3 receptors) induced significant hyperactivity, which was markedly enhanced by repeated administration of antidepressant drugs. 3. The effect of acute administration of IMI or CIT measured 14 days after drug treatment were similar to the described above alterations at the level of alpha2 adrenoreceptors and presynaptic dopamine D3 receptors, i.e. the drugs attenuated clonidine-induced hypoactivity and reversed locomotor hypoactivity evoked by low dose of 7-OH-DPAT. To induce the down-regulation of beta-adrenergic receptors or up-regulation of the behavioural responsiveness of dopaminergic D3 postsynaptic receptors, the repeated administration of IMI or CIT was necessary. 4. Therefore it has been concluded that presynaptic dopaminergic D3 and alpha2-adrenergic receptors are more sensitive to the acute treatment with antidepressant drugs than postsynaptic D3 and beta-adrenergic receptors.     

Alpha 2-adrenergic receptors in platelet membranes of depressed patients: increased affinity for 3H-yohimbine

Specific binding to alpha 2-adrenergic receptors was studied in the platelets of 31 patients with major depressive disorder and 18 normal controls using the selective antagonist 3H-yohimbine. Receptor density for depressed patients (Bmax = 88 +/- SD 45.1 fmoles/mg) was not significantly lower than that for controls (124 +/- SD 78.1 fmoles/mg). The affinity of the receptor for yohimbine was significantly greater in depressed patients (Kd = 1.05 +/- SD 0.47 nM) than in controls (Kd = 1.47 +/- SD 0.63 nM). This is consistent with the hypothesis of increased alpha 2-adrenergic receptor sensitivity in depressive disorders. Past studies of alpha 2-adrenergic receptors on platelets are reviewed, and the importance of designing studies with sufficient statistical power is discussed.     

Clinical studies of monoamine receptors in the affective disorders and receptor changes with antidepressant treatment

Pre-clinical and clinical studies suggest that the responsiveness of monoamine and cholinergic receptors may be altered in the affective disorders and that antidepressants may modify the sensitivity of these receptors. The growth hormone response to clonidine is reduced in depressed patients compared to controls according to several independent studies, suggesting that post-synaptic alpha 2-adrenergic receptors may be less responsive in depressed patients. The cortisol response to clonidine is enhanced in depressed patients compared to controls in our study raising the possibility that cortisol hypersecretion in depressed patients may be related to noradrenergic dysfunction. The hypotensive response to clonidine is blunted in patients on chronic antidepressant treatment with either clorgyline or desipramine suggesting that pre-synaptic alpha 2-adrenergic receptors may subsensitize with chronic antidepressant treatment. The prolactin increase in response to fenfluramine is less in depressed patients compared to controls suggesting decreased functional activity of the serotonergic system in depression. Platelet alpha 2-adrenergic receptor number as measured by tritiated dihydroergocriptine (3H-DHE) binding is increased in depressed patients compared to controls, while cyclic 3'-5' adenosine monophosphate (cAMP) production in response to prostaglandin E1 (PGE1) and norepinephrine (NE) inhibition of PGE1-stimulated cAMP production are reduced in the platelets of depressed patients. Thus, it is not clear that increased 3H-DHE binding reflects increased functional responsiveness and might in fact be compensatory to decreases in functional responses of alpha 2-adrenergic receptors.     

Platelet alpha 2 adrenoreceptors are decreased in number after antidepressant therapy

Specific binding of 3H-clonidine to alpha 2 adrenoreceptors upon human blood platelet membranes is increased in patients with major depressive disorder (endogenous depression). Specific binding of 3H-yohimbine to the platelet adrenoreceptor is not altered in endogenously depressed patients. Other psychiatric disorders are not associated with alterations in the specific binding of either 3H-clonidine or 3H-yohimbine. In patients with severe congestive heart failure or with symptomatic coronary artery disease the number of platelet alpha 2 adrenoreceptors is actually decreased. Treatment of endogenously depressed patients with tricyclic antidepressants, lithium salts or electroconvulsive therapy results in a decrease in the number of alpha 2 adrenoreceptors on blood platelet membranes. These studies suggest that a supersensitivity of the alpha 2 adrenoreceptor might exist in patients with endogenous depression and that effective forms of therapy lead to a decrease in the number of neural alpha 2 adrenoreceptors which is reflected by a decrease in the number of these receptors upon blood platelet membranes.     

Amitriptyline administration transforms tumor necrosis factor-alpha regulation of norepinephrine release in the brain

The present study demonstrates that the mixed action antidepressant drug amitriptyline enhances norepinephrine (NE) release by transforming the nature of the response of neurons to both tumor necrosis factor-alpha (TNF) as well as to an alpha(2)-adrenergic agonist in an area of the central nervous system (CNS) rich in adrenergic neurons. Administration of the antidepressant drug amitriptyline for 1 day or 14 days to rats significantly increases TNF bioactivity in total homogenates of the locus coeruleus (LC) and the hippocampus as assessed by the WEHI-13VAR bioassay. Superfusion and electrical field stimulation of rat hippocampal brain slices were used to study the regulation of NE release. Exposure to TNF, as well as activation of the alpha(2)-adrenergic autoreceptor inhibits stimulation-evoked norepinephrine (NE) release from adrenergic neurons of the CNS from na?ve rats. Superfusion of hippocampal slices isolated from rats chronically (14 days) administered amitriptyline demonstrates that TNF inhibition of NE release is transformed, such that TNF facilitates NE release, dependent upon alpha(2)-adrenergic activation. Furthermore, chronic administration of amitriptyline increases stimulation-evoked NE release and decreases alpha(2)-adrenergic autoreceptor inhibition of NE release, an effect not observed with acute drug administration. These data support the hypothesis that chronic antidepressant drug administration, through regulation of TNF expression, transforms alpha(2)-adrenergic receptors such that they function to facilitate NE release, suggesting a mechanism of action of antidepressant drugs.     

Effect of long-term clorgyline administration on human platelet alpha-adrenergic receptor binding and platelet cyclic AMP responses

Platelet α₂-adrenergic receptor number and physiologic responsiveness, as well as plasma norepinephrine (NE), were evaluated in psychiatric patients with major depressive disorder before and during chronic clorgyline treatment. The α₂-adrenergic receptor number was determined by measuring the binding of tritiated dihydroergocriptine (³H-DHE) to platelet membranes. Physiologic responsiveness was determined by measuring the response of cyclic adenosine 3'-5' monophosphate (cAMP) to prostaglandin E₁ (PGE₁), and the inhibition of the PGE₁-stimulated cAMP response by NE in intact platelets. No significant differences from pretreatment values were observed in platelet α₂-adrenergic binding or responsiveness during clorgyline treatment. Baseline platelet cAMP production and plasma NE levels were significantly decreased after chronic clorgyline treatment. Previous studies on animals and humans have suggested that brain α₂-adrenergic receptor responsiveness decreases during chronic clorgyline treatment. The present findings therefore suggest that such changes may represent adaptations induced by long-term clorgyline administration which may differ between the brain and the platelet, thus illustrating potential limitations of the study of platelet α₂-adrenergic receptors as a model for central α₂-adrenergic receptor adaptation.     

Desipramine treatment in normal subjects. Effects on neuroendocrine responses to tryptophan and on platelet serotonin (5-HT)-related receptors

Normal subjects took the tricyclic antidepressant, desipramine hydrochloride, for 16 days. Following treatment there was an increase in the number of specific binding sites on the platelet for both tritiated imipramine and tritiated LSD, the latter site probably representing a platelet serotonin (5-HT) receptor. During desipramine treatment the prolactin response to tryptophan (L-tryptophan) was enhanced, and this enhancement correlated with the increase in platelet LSD binding. The results confirm previous observations that desipramine administration increases certain 5-HT-mediated neuroendocrine responses. Our findings further indicate that desipramine may alter both 5-HT uptake and 5-HT receptor sensitivity, and suggest that the platelet LSD receptor may in certain conditions provide a useful model of 5-HT receptors in the brain.     

Interaction of neuroleptics and antidepressants with rat brain alpha 2-receptors: a possible relationship between alpha 2-receptor antagonism and antidepressant action

The relative potencies of a variety of neuroleptic drugs and antidepressant agents in competing for the binding of 3H-clonidine and 3H-yohimbine to alpha 2-adrenergic receptors of the rat cerebral cortex were quantified. The rank order of potencies of neuroleptics tested in competing for both ligand bindings is: clocapramine, carpipramine much greater than perphenazine, fluphenazine, alpha,beta-flupentixol greater than propericiazine, levomepromazine greater than chlorpromazine, pimozide greater than moperone much greater than haloperidol, sulpiride. Among the antidepressants, mianserin is the most potent antidepressant. Amitriptyline has a substantial affinity, while desipramine, imipramine, and clomipramine are the least potent. It is concluded that a number of neuroleptics and antidepressant agents display a potent or moderate affinity to alpha 2-receptor sites. These findings support the suggestion that some neuroleptics enhance the release of norepinephrine (NE) mainly by acting on presynaptic alpha 2-receptors, and that the alpha 2-receptor blocking property may have an important role in the mechanism of the antidepressant effect of some neuroleptic compounds.     

Possible subsensitization of alpha 2-adrenergic receptors by chronic monoamine oxidase inhibitor treatment in psychiatric patients

Clonidine was administered to nine psychiatric patients before and after chronic treatment (3 to 4 weeks) with clorgyline, a selective monoamine oxidase type A inhibitor with antidepressant efficacy. The hypotensive response to clonidine, believed to be mediated by brain alpha 2-adrenergic receptors, was significantly attenuated by chronic but not acute (2 to 3 days) clorgyline treatment, with a time course similar to the onset of its clinical efficacy. This study supports the hypothesis that subsensitization of alpha 2-adrenergic receptors plays an important role in clorgyline's antidepressant effects and may constitute a key contribution to the mode of action of other antidepressant treatments as well.     

Biological alterations in the primary affective disorders and other tricyclic-responsive disorders

Noradrenergic function was studied in patients with primary affective disorder and other tricyclic-responsive disorders including obsessive-compulsive disorder, anorexia nervosa and panic attack/agoraphobia in medication-free states. Pre-synaptic noradrenergic activity was assessed by assaying plasma concentrations of norepinephrine (NE) and its metabolite 3-methoxy,4-hydroxyphenylglycol (MHPG). Noradrenergic receptor responsiveness was evaluated by measuring plasma growth hormone (GH), MHPG, and NE responses to clonidine. Binding of tritiated dihydroergocriptine (3H-DHE) and biochemical responsiveness of alpha 2-adrenergic receptors were measured in platelet preparations. These studies suggest that noradrenergic activity may be altered in several tricyclic-responsive disorders and are consistent with the possibility that tricyclic antidepressants may serve to stabilize a dysregulated noradrenergic system in patients from several diagnostic categories.     

Enhanced signal transduction by adenylate cyclase in platelet membranes of patients showing antidepressant responses to alprazolam: preliminary data

The triazolobenzodiazepine, alprazolam, was administered to 11 depressed patients over a period of six weeks, and six patients showed a favorable antidepressant response. There were no significant differences between responders and nonresponders in age, pretreatment Hamilton Depression Rating Scores, 4 p.m. postdexamethasone plasma cortisol levels, or platelet monoamine oxidase activities. Blood levels of alprazolam were not meaningfully different in responders and nonresponders when measured on treatment day 8. However, on treatment day 8, significantly enhanced prostaglandin D2-stimulated platelet adenylate cyclase activity, greater suppression of prostaglandin D2-stimulated platelet adenylate cyclase activity by epinephrine, and enhanced sodium fluoride-stimulated platelet adenylate cyclase activity were seen in the six patients who went on to respond to alprazolam, but not in the five nonresponders. In contrast, there were no significant changes in prostaglandin D2, (-)-isoproterenol, or fluoride ion-stimulated leukocyte adenylate cyclase activity in responders or nonresponders. No meaningful changes were observed in the mean densities of either the high-affinity platelet alpha 2-adrenergic receptor (for 3H-p-aminoclonidine) or the leukocyte beta-adrenergic receptor (for 3H-dihydroalprenolol) in responders or nonresponders. The present findings, taken in conjunction with findings from other recent studies, suggest that enhanced coupling between certain neurotransmitter or hormone receptors and adenylate cyclase through the guanine nucleotide regulatory proteins may help explain the antidepressant effects of alprazolam and possibly other forms of antidepressant treatment.