Platelet adrenoceptors and prostaglandin responses in depressed patients.

Platelet alpha 2-adrenergic receptor binding and prostaglandin responsivity were measured in depressed patients. Depressed patients had significantly higher platelet 3H-dihydroergocryptine (3H-DHE) binding values than controls. Depressed patients also showed significantly reduced prostaglandin E1-stimulated cyclic adenosine 3',5'-monophosphate (cAMP) production and significantly decreased % inhibition of cAMP production by norepinephrine. These results support the suggestion that there may be a dissociation between alpha 2-adrenergic receptor binding and responsivity in depression. There were no significant correlations between platelet adrenergic variables and other indices of noradrenergic function. However, there was a significant correlation between 3H-DHE binding values and basal plasma levels of cortisol.

Alpha 2-adrenergic receptor function in patients with unipolar and bipolar affective disorders.

Alpha 2-adrenergic receptor function was measured in platelets from unipolar (UP) depressed, bipolar (BP) depressed, and bipolar euthymic patients and normal control subjects. Only the platelets from UP depressed patients were different from control in having an increased number of alpha 2-receptors, a decreased percent norepinephrine inhibition of prostaglandin E1 (PGE1)-stimulated cyclic AMP (cAMP) production, and a decrease in PGE1 stimulation of cAMP production. Platelets from BP patients, depressed or euthymic, were not significantly different from control subjects. These preliminary data suggest that alpha 2-adrenergic receptor function and PGE1 stimulation of cAMP production are diminished in UP patients.

Alpha-adrenergic receptors and cyclic AMP production in a group of schizophrenic patients.

Alpha 2-adrenergic receptor function was measured in platelets from chronic schizophrenic patients and normal controls. The number of alpha 2-receptors was greater in patients' platelets, and the prostaglandin E1 (PGE1)-stimulated cyclic AMP (cAMP) production lower, when compared with the normal controls. The changes measured may occur only in the platelet, but if central nervous system neurons share with platelets these changes, one might speculate that an increase in the number of alpha 2-receptors and a decrease in cAMP production may relate to the psychopathology of schizophrenia.

Circadian rhythms in catecholamine metabolites and cyclic nucleotide production.

Circadian rhythms in noradrenergic (NE) and dopaminergic (DA) metabolites and in cyclic nucleotide production were measured in discrete regions of rat brain. A circadian rhythm was found in the concentration of the NE metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), in the hippocampus. No MHPG rhythm was found in frontal, cingulate, parietal, piriform, insular or temporal cortex, or in hypothalamus. Circadian rhythms in the concentration of the NE metabolite, 3,4-dihydroxyphenylglycol (DHPG), occurred in occipital and parietal cortex and hypothalamus, with no rhythm observable in temporal or insular cortex, hippocampus, pons-medulla or cerebellum. The 24-hr mean concentration of MHPG varied 3.5-fold, highest in cingulate and lowest in parietal, temporal and occipital cortex. The 24-hr mean concentration of DHPG varied 6-fold, highest in hypothalamus and lowest in parietal cortex. Circadian rhythms in the concentration of the DA metabolite, homovanillic acid (HVA), were found in olfactory tubercle, amygdala and caudate-putamen, but not in nucleus accumbens. A circadian rhythm in the concentration of the DA metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), occurred in nucleus accumbens, but not in olfactory tubercle or caudate-putamen. The mean 24-hr concentration of HVA was highest in caudate-putamen, intermediate in nucleus accumbens, and lowest in olfactory tubercle and amygdala. The mean 24-hr concentration of DOPAC was highest in nucleus accumbens and lower in olfactory tubercle and caudate-putamen. Circadian rhythms were found in the concentration of cyclic GMP (cGMP) in all regions measured except parietal cortex. The mean 24-hr concentration varied 128-fold, highest in nucleus accumbens, frontal poles, and hypothalamus and lowest in cingulate cortex. Circadian rhythms in cyclic AMP (cAMP) concentration were found in piriform, temporal, occipital, cingulate, and parietal cortex, amygdala and nucleus accumbens. No rhythms were found in frontal or insular cortex, hypothalamus, hippocampus, caudate-putamen or olfactory tubercle. The 24-hr mean cAMP concentration varied 4-fold, highest in parietal cortex and lowest in caudate-putamen and amygdala. Norepinephrine metabolites and dopamine metabolites were rhythmic in few regions. It is, therefore, unlikely that the rhythmicity measured in adrenergic receptors is, in general, a response to rhythmic changes in adrenergic transmitter release. The putative second messenger response systems, especially cGMP, were more often rhythmic. The rhythms in cGMP are parallel in form and region to those in the alpha 1-adrenergic receptor and may act as 2nd messenger for that receptor.(ABSTRACT TRUNCATED AT 400 WORDS)

Relationships between behavioral rhythms, plasma corticosterone and hypothalamic circadian rhythms.

Circadian rhythms in physiological processes and behaviors were compared with hypothalamic circadian rhythms in norepinephrine (NE) metabolites, adrenergic transmitter receptors, cAMP, cGMP and suprachiasmatic nucleus (SCN) arginine vasopressin (AVP) in a single population of rats under D:D conditions. Eating, drinking and locomotor activity were high during the subjective night (the time when lights were out in L:D) and low during the subjective day (the time when lights were on in L:D). Plasma corticosterone concentration rose at subjective dusk and remained high until subjective dawn. Binding to hypothalamic alpha 1- and beta-adrenergic receptors also peaked during the subjective night. Cyclic cGMP concentration was elevated throughout the 24-hr period except for a trough at dusk, whereas DHPG concentration peaked at dawn. Arginine vasopressin levels in the suprachiasmatic nucleus peaked in the middle of the day. No rhythm was found either in binding to the alpha 2-adrenergic receptor, or in MHPG or cAMP concentration. Behavioral and corticosterone rhythms, therefore, are parallel to rhythms in hypothalamic alpha 1- and beta-receptor binding and NE-release. Cyclic GMP falls only at dusk, suggesting the possibility that cGMP inhibits activity much of the day and that at dusk the inhibition of nocturnal activity is removed. SCN AVP, on the other hand, peaking at 1400 hr, may play a role in the pacemaking function of the SCN that drives these other rhythms.

The Genain Quadruplets 25 years later: a diagnostic and biochemical followup.

A biological and clinical followup of the Genain Quadruplets was initiated as a multilaboratory collaborative effort at the National Institute of Mental Health (NIMH). The quadruplets are 51-year-old monozygotic women previously studied with a battery of psychological and physiological tests 25 years ago at the NIMH. The present article (the first of a series of three) details the clinical history and course of the schizophrenic illness in each of the quadruplets and describes the biochemical measures determined. The findings of elevated urinary phenylethylamine excretion, decreased plasma dopamine-beta-hydroxylase activity, and increased alpha-adrenergic receptor concentrations in all quadruplets warrant further genetic studies.

Alpha-adrenergic receptors in orthostatic hypotension syndromes.

Alpha-adrenergic receptor function was measured in platelets from patients with orthostatic hypotension and normotensive controls. Patients with idiopathic orthostatic hypotension (IOH) or multiple system atrophy (MSA) had more alpha-receptors than controls. Patients with IOH, but not MSA, produced less prostaglandin E1 (PGE1)-stimulated cyclic AMP (cAMP) than controls. Patients with sympathotonic orthostatic hypotension (SOH) were similar to controls in receptor number and cAMP production. The percent norepinephrine (NE) inhibition of PGE1-stimulated cAMP production was similar in patients and controls. An increase in alpha-receptor number may result from decreased peripheral NE secretion in IOH and MSA. Increased alpha-receptor number and decreased cAMP production, which accompany essential hypertension, may contribute to the supine hypertension of IOH, and an increase in alpha-receptor number may contribute to the supine hypertension of MSA. SOH patients appear to have no abnormalities of alpha-receptor function.

Platelet alpha-adrenergic binding and biochemical responsiveness in depressed patients and controls.

In a study of platelet alpha 2-adrenergic receptor number in depressed patients, binding of tritiated dihydroergocriptine (3H-DHE) to platelet membranes was measured in 23 depressed patients and 51 controls. To examine the functional responsiveness of the platelet alpha 2-adrenergic receptor, basal cyclic adenosine 3',5'-monophosphate (cAMP) production, prostaglandin E1 (PGE1) stimulation of cAMP production, and norepinephrine (NE) inhibition of PGE1-stimulated cAMP production were measured in 23 depressed patients and 53 control subjects. Finally, plasma NE concentration was measured in 20 patients to explore the possible relationship between this endogenous agonist and platelet alpha 2-adrenergic receptor function. 3H-DHE binding to platelet membranes was significantly increased in the depressed patients compared to control subjects. Both the PGE1-stimulated cAMP response and the inhibition of this response by NE were significantly reduced in the depressed patients compared to the control subjects. Thus, an apparent dissociation between alpha 2-adrenergic receptor binding and functional responsiveness was observed. Plasma NE concentrations were neither significantly different in the depressed patients than in the controls nor correlated with any of the measures of cAMP responsiveness. They were, however, significantly negatively correlated with 3H-DHE binding in depressed patients with adequate PGE1 stimulation of cAMP production.

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

Platelet alpha 2-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 alpha 2-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 alpha 2-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 alpha 2-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 alpha 2-adrenergic receptors as a model for central alpha 2-adrenergic receptor adaptation.

alpha-Adrenergic receptor function in schizophrenia. Receptor number, cyclic adenosine monophosphate production, adenylate cyclase activity, and effect of drugs.

alpha-Adrenergic receptor function was assessed in platelets from drug-free schizophrenic patients and control subjects. The number of alpha-receptors was similar in platelet membranes from schizophrenic patients and control subjects. In intact platelets from schizophrenic male, but not female, patients, prostaglandin E1 (PGE1)-stimulated cyclic adenosine monophosphate (cAMP) level was less than in control subjects. This defect may be due, at least in part, to decreased adenylate cyclase activity. In platelet lysates from schizophrenic patients, but not from normal control subjects, adenylate cyclase activity was diminished and PGE1-stimulated adenylate cyclase activity could be restored partially by the addition of guanosine triphosphate. Treatment with neuroleptic drugs or lithium carbonate did not change alpha-receptor number or cAMP production in platelets from schizophrenic patients, but high doses of propranolol hydrochloride increased cAMP production without affecting the number of alpha-receptors. If the production of cAMP in neurons is similar to that in platelets, diminished cAMP production may be associated with a vulnerability to schizophrenia.

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.

Indomethacin increases leucocyte beta-adrenoreceptors in man.

1. The effect of indomethacin, an inhibitor of prostaglandin synthesis, on number and sensitivity of alpha- and beta-adrenoreceptors was studied in normal healthy volunteer subjects. 2. The subjects were studied under metabolic conditions. To achieve inhibition of prostaglandin synthesis indomethacin (2 mg day-1 kg-1) was given orally for 7 days. This dose decreased urinary excretion of prostaglandin E-like immunoreactivity by 70%. 3. The number or alpha-adrenoreceptors was measured by the specific binding of [3H]dihydroergocryptine to platelet membranes and that of beta-adrenoreceptors by the binding of [3H]dihydroalprenolol to leucocyte membranes. 4. The number of alpha-adrenoreceptors did not change with indomethacin, nor did basal, prostaglandin E1- or noradrenaline-stimulated cyclic AMP production by platelet membranes. In contrast, the number of beta-adrenoreceptors increased by 92%. Indomethacin did not affect, however, basal, 1-isoprenaline- or prostaglandin E1-stimulated cyclic AMP production in leucocyte membranes. 5. These results suggest that a reflex-mediated decrease in sympathetic discharge in response to an indomethacin-induced decrease in release of vasodilator prostaglandins may lead to an 'up-regulation' of beta-adrenoreceptor sites.

Effect of inhibition of prostaglandin synthesis on sympathetic nervous system function in man.

The effect of inhibition of prostaglandin synthesis by indomethacin on the function of the peripheral sympathetic nervous system was studied in eight normotensive subjects. Sympathetic nervous function was assessed by measurement of plasma norepinephrine, alpha-adrenergic receptor sites on platelet membranes, and urinary excretion of epinephrine and norepinephrine. Treatment with indomethacin for 7 days resulted in significant decreases in basal plasma norepinephrine from 134 +/- 7 to 99 +/- 6 (SEM) pg/ml (P less than 0.01), a 26% decrease. Posturally stimulated norepinephrine concentrations (337 +/- 14 pg/ml in control studies) were 255 +/- 18 pg/ml (P less than 0.02), 25% lower, with indomethacin. Plasma norepinephrine after 5-min compression of hand grip (468 +/- 47 pg/ml in control) was 331 +/- 30 pg/ml (P less than 0.005), 29% lower, with indomethacin. The number of platelet alpha-adrenergic receptor sites did not change with indomethacin, nor did prostaglandin E1-stimulated cAMP production by platelet membranes. In addition, indomethacin produced no change in urinary excretion of norepinephrine or epinephrine. It is suggested that inhibition of prostaglandin synthesis may lead, via baroreceptor feedback, to a decrease in plasma norepinephrine concentration.

Reduced cyclic AMP production in the blood platelets from schizophrenic patients.

The authors assessed alpha-adrenergic receptor function in blood platelets from chronic schizophrenic patients and normal control subjects. The number of receptors was measured by the specific binding of the alpha-adrenergic antagonist [3H]dihydroergocryptine to the platelets. A physiological response of the platelets to agonist occupancy of the alpha-adrenergic receptors was measured by the norepinephrine inhibition of prostaglandin E1(PGE1)-stimulated cyclic AMP (cAMP) production. cAMP production in male schizophrenic patients was lower than in normal male subjects. alpha-Adrenergic receptor function was similar in patients and normal control subjects of both sexes. Normal male subjects had about 1.5 times the number of alpha-adrenergic receptors as normal females and generated about 1.8 times the quantity of PGE1-stimulated cAMP.

Adrenergic receptor function is different in male and female patients with essential hypertension.

As plasma norepinephrine (NE) levels may be similar in hypertensive and normotensive subjects, the sensitivity of adrenergic receptors was investigated in patients with essential hypertension and normotensive subjects of similar age and sex. Alpha-adrenergic receptor sensitivity was measured in platelets by the specific binding of [3H]dihydroergocryptine and the NE inhibition of prostaglandin E1 (PGE1)-stimulated cyclic AMP (cAMP) production. The number of alpha-adrenergic receptors in platelets from hypertensive women was 1.5 times that in the platelets from normotensive ones, with no differences between hypertensive and normotensive women or between men and women in the affinity of the alpha-adrenergic receptor for [3H]dihydroergocryptine. PGE1-stimulated cAMP production was half as great in hypertensive as in normotensive men, while NE inhibition of PGE1-stimulated cAMP production was similar in hypertensive and normotensive men and women. [3H]Dihydroergoeryptine binding in female hypertensives, and PGE1-stimulated cAMP in male hypertensives did not differ from that in sex-matched controls. The sensitivity of the beta-adrenergic receptor, measured by [3H]dihydroalprenolol binding and cAMP production was similar in hypertensive and normotensive subjects.