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.     

Noradrenergic function and the cortisol response to dexamethasone in depression

Abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis and the noradrenergic system have been reported in depression. To study possible interrelations between these two systems, plasma free 3-methoxy-4-hydroxyphenylglycol (MPHG) was compared with the cortisol response to dexamethasone in 64 depressed patients. Postdexamethasone cortisol nonsuppressors had higher baseline plasma free MHPG values than did cortisol suppressors. Increased severity of some depressive symptoms was associated with increased postdexamethasone cortisol levels. These results indicate that depressed patients with dexamethasone nonsuppression have increased noradrenergic turnover.     

Dopaminergic function and the cortisol response to dexamethasone in psychotic depression

1. It has been hypothesized that psychotic symptoms in depression may be due to increased dopamine activity secondary to hypothalamic-pituitary-adrenal (HPA) axis overactivity. 2. To test this hypothesis, the authors examined the cortisol response to dexamethasone suppression test (DST, 1 mg orally) and multihormonal responses to apomorphine (APO, 0.75 mg s.c.)--a dopamine agonist--in 150 drug-free hospitalized patients with DSM-IV major depressive episode with psychotic features (MDEP, n=35), major depressive episode without psychotic features (MDE, n=74), or schizophrenia paranoid type (SCZ, n=41), and 27 hospitalized healthy controls (HCs). 3. MDEPs showed increased activity of the HPA system (i.e. higher post-DST cortisol levels) than HCs, SCZs and MDEs. However, there were no differences in adrenocorticotropic hormone (ACTH), cortisol, prolactin and growth hormone (GH) responses to APO between MDEPs and MDEs and HCs. On the other hand, SCZs showed lower APO-induced ACTH stimulation and a higher rate of blunted GH than HCs, MDEs and MDEPs, suggesting a functional alteration of the hypothalamic dopamine receptors in SCZs. 4. In the total sample and in each diagnostic group, DST suppressors and non-suppressors showed no differences in hormonal responses to APO. 5. These results suggest a lack of causal link between HPA axis hyperactivity and dopamine dysregulation. In contrast to schizophrenia, psychotic symptoms in depression seem not to be related to dopamine function dysregulation.     

alpha 2-Adrenergic receptor sensitivity in depression. The plasma MHPG, behavioral, and cardiovascular responses to yohimbine

alpha 2-Adrenergic receptors play a major role in the regulation of the noradrenergic system. To assess the function of these receptors relative to possible abnormalities in noradrenergic function in depression, responses to the alpha 2-antagonist yohimbine hydrochloride were investigated in 45 depressed patients and 20 healthy control subjects. Plasma 3-methoxy-4-hydroxyphenylglycol (MHPG), blood pressure (BP), pulse, subjective mood, and somatic symptoms were measured before and during yohimbine and placebo administration. The 25% increase in plasma MHPG levels produced by yohimbine did not differ between patients and controls. Mood responses also tended to be similar between groups, with patients reporting only minor improvement in depression following yohimbine. However, yohimbine caused significantly greater increases in somatic symptoms and tended to produce a greater increase in BP in patients than in controls. Evaluation of patient subgroups divided by the presence or absence of melancholia, psychosis, prominent anxiety, or personality disorder did not demonstrate consistent differences. In contrast, comparison of these findings with a prior study showed that patients with panic disorder and agoraphobia who received yohimbine manifested significantly greater increases in MHPG levels and ratings of anxiety, nervousness, and depression than depressed patients. These findings suggest that patients with major depression do not demonstrate marked abnormalities in alpha 2-adrenergic autoreceptor function.     

Alpha 2-adrenergic and opiate receptor blockade. Synergistic effects on anxiety in healthy subjects

To evaluate interactions between the opiate and adrenergic systems in healthy humans, concomitant administration of the opiate antagonist, naloxone hydrochloride, and the alpha 2-adrenergic receptor antagonist, yohimbine hydrochloride, was compared with the administration of placebo and of each drug separately. A synergistic effect of the combination (larger than the sum of the effects of the two drugs separately) was observed on subject ratings of nervousness, anxiety, tremors, palpitations, nausea, hot and cold flashes, and increased plasma cortisol concentrations. In addition, following the combination, each of the male subjects studied reported a full penile erection lasting at least 60 minutes, an effect not reported when each drug was given separately. These results demonstrate that interactions between the opiate the adrenergic systems have important implications for our understanding of the cause and treatment of anxiety disorders and male impotence.     

Platelet alpha 2-adrenergic receptor function in psychiatric disorders

The inhibitory effects of norepinephrine (NE) on the cyclic adenosine-3',5'-monophosphate (cAMP) response to prostaglandin E1 (PGE1), a measure of alpha 2-adrenergic receptor function, have been compared in platelets from drug-free schizophrenic patients, depressive patients, and normal controls. The absolute value of the inhibition by NE of the cAMP response to PGE1 was smaller in platelets from schizophrenic and depressive patients than in controls. However, this result was secondary to the smaller baseline platelet cAMP response to PGE1 in patients with these disorders. Effects of NE on cAMP production did not discriminate between actively ill and remitted patients with either schizophrenia or depression. Platelet alpha 2-receptor sensitivity, as measured by the effects of NE on cAMP production, does not appear to be altered in these psychiatric disorders.     

Alpha 2-adrenergic receptor inhibition of cAMP accumulation is transformed to facilitation by tumor necrosis factor-alpha

Activation of the alpha(2)-adrenergic receptor on neurons regulates the activity of neurons. Inhibition of forskolin-stimulated cAMP accumulation induced by alpha(2)-adrenergic receptor activation is altered following exposure of the neuron SH-SY5Y cell line to tumor necrosis factor-alpha (TNF). Acute (5 and 15 min) exposure to TNF induces a transformation in alpha(2)-adrenergic regulation of cAMP accumulation from inhibition to facilitation. These findings support an autocrine role for the regulation of TNF production from neurons.     

The cortisol awakening response in patients remitted from depression

An impressive number of data has been accumulated on dysfunctions of the hypothalamo-pituitary–adrenal (HPA) axis and cortisol hypersecretion in depression. To assess the dynamic HPA functioning, the cortisol awakening response (CAR) is an easily accessible and reliable approach. Some data suggest that elevated CAR in depressed patients has trait-like characteristics. Therefore we investigated whether patients in remission from a depressive episode have elevated CAR compared to control subjects. CAR of thirty-eight patients in remission from depression (11 men, 27 women, age range 24–66) and 52 control participants were analyzed (18 men, 34 women, age range 24–63). All patients had experienced ≥3 previous depressive episodes and were off psychotropic medication since at least 3 months. Saliva samples were collected only once, at home, either on weekend or weekday at 0, 15, 30, 45 and 60 min post-awakening.The area under the curve (AUC) above minimum cortisol concentration displayed large interindividual variability (6.4-fold in remitted patients and 8.1-fold in controls, based on 80% range). Investigation of possible variability factors showed that percent explained variance increased from 3.9% when group was considered alone to 8.8%, 12.3% and 19.2% after adjusting for significant effects of weekday vs. weekend, wake-up time and sleep duration, respectively. According to the latter model, AUC was estimated to be 51% higher in remitted patients than in controls (p = 0.007), while a 21% AUC decrease was associated with a 1-h longer sleep duration (p < 0.001). In future studies, detection of between-group differences might benefit from adjusting for sleep duration and other possible confounders.     

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.     

Monoamine oxidase and cortisol response in depression and schizophrenia.

The relationship between hypothalamic-pituitary-adrenal (HPA) axis function and platelet monoamine oxidase (MAO) activity was examined in drug-free depressed (n = 32) and schizophrenic (n = 36) inpatients. HPA function was measured by determining plasma cortisol levels at 8:30 a.m. and 11 p.m. before, and 8:30 a.m., 4 p.m., and 11 p.m. after administration of 1 mg of dexamethasone (DEX). There was a significant correlation between platelet MAO activity and all post-DEX cortisol levels (8:30 a.m., 4 a.m., and 11 p.m.) in depressed patients, and MAO activity and pre-DEX cortisol levels (11 p.m.) in schizophrenic patients. MAO activity was significantly higher in depressed DST nonsuppressors than in suppressors, and there were more DST nonsuppressors in high-MAO groups as compared with low-MAO groups. Our results thus suggest a strong relationship between platelet MAO activity and HPA function in depressed patients. These biochemical markers are potentially useful in the identification of biochemically and clinically homogeneous subgroups of depressed patients.     

Nonsuppression of cortisol in depression and immune function

Eighteen depressive patients and twenty-five healthy control subjects were studied using a comprehensive immunological test system and the dexamethasone suppression test (DST) as well as some additional neuroendocrine parameters. In addition, immune functions of six of the patients were studied serially three times at 1-2 month's intervals. The OKT 4+/8+ ratio (OKT 4+ = helper/inducer phenotype; OKT 8+ = suppressor/cytotoxic phenotype) was slightly higher in those ten depressive patients showing suppression in the DST than in healthy controls, but there were no significant differences between the nonsuppressor and suppressor groups or between the nonsuppressor and suppressor groups or between nonsuppressors and control subjects. Lymphocyte transformation responses induced by phytohaemagglutinin (PHA) were similar in the nonsuppressors and suppressors, but lower in both groups than in control subjects. The number of Ig-secreting cells measured in the absence and presence of pokeweed mitogen (PWM) were similar in the nonsuppressor and suppressor groups. Four of the depressive patients tested repeatedly exhibited an abnormal response in the DST at the beginning of the study. During the follow-up period two of them recovered completely from depression as well as the patients with a normal suppression in the DST. The proportions of T and B lymphocytes and regulatory T lymphocyte subsets as well as the functions of T and B lymphocytes of the nonsuppressors and suppressors in the DST were within normal ranges before and after recovery from depression and comparable to healthy controls in repeated testing. The results indicate that in spite of the importance of cortisol in immunoregulation, the increased cortisol secretion and typical resistance to dexamethasone suppression in endogenously depressive patients is not profoundly and consistently reflected in immune functions. Neither does normalization of cortisol responses induce any major changes in immune status during a patient's recovery from depression. Previous work indicates that suppressed immunity may play an important role in the increased morbidity and mortality associated with bereavement. In the light of present findings we suggest that endogenous depression differs also in this respect from grief reactions.     

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.     

Neuroendocrine evidence for decreased function of alpha 2-adrenergic receptor after electroconvulsive therapy.

Growth hormone (GH) and hypotensive responses to clonidine (150 micrograms, i.v.) were investigated before and after electroconvulsive therapy (ECT) in 16 depressed patients. Because of high baseline serum GH concentrations, results from only 10 patients could be evaluated. The level of GH secretion induced by clonidine was significantly reduced after ECT, but the hypotensive responses to clonidine remained unchanged. The results indicate downward regulation of the sensitivity of alpha 2-adrenergic receptors in the hypothalamus after ECT.     

Alpha(2A)-adrenergic receptors are present in mu-opioid receptor containing neurons in rat medial nucleus tractus solitarius.

Agonists of the alpha-2A-adrenergic- (alpha(2A)-AR) and the mu-opioid-receptor (muOR) jointly affect autonomic functions that are also disregulated in animals undergoing withdrawal from chronic administration of the muOR agonist morphine. Cardiovascular and gastrointestinal reflexes are mediated, in part, by the medial nucleus of the solitary tract (mNTS) at caudal (cNTS) and intermediate (iNTS) subregions. Together, this evidence suggests that alpha(2A)-AR and muOR may be colocalized within many of the same neuronal profiles in both the intermediate and caudal mNTS. In order to examine whether alpha(2A)-AR and muOR are present within common somata, dendrites, or axon terminals in the mNTS, we used electron microscopic immunocytochemistry for the detection of antisera against each receptor at intermediate and caudal levels of this brain region. Most of the dually labeled profiles were somata and dendrites. Of all dual-labeled profiles in the iNTS 49% were somata and were 47% dendrites, whereas in the cNTS 61% were somata and 32% were dendrites. Within dual-labeled profiles, the intracellular distribution of alpha(2A)-AR and muOR differed. MuOR was more frequently associated with the plasmalemma, whereas alpha(2A)-AR was often affiliated with vesicular organelles. Few axon terminals, and even fewer glia, contained both markers. We also frequently observed single-labeled alpha(2A)-AR glia that apposed exclusively muOR-containing dendrites or axon terminals. These findings indicate that somata and dendrites contain functional sites for convergent muOR and alpha(2A)-AR activation. In addition, each receptor is positioned for involvement in intercellular signaling between apposed neurons and glia. Activation of alpha(2A)-AR on muOR-containing somata or dendrites, or on glia apposed to muOR-containing neurons, may help to account for the efficacy of alpha(2A)-AR agonists in relieving some of the autonomic symptoms of opiate withdrawal.     

Platelet MAO activity and the cortisol response to dexamethasone in major depression

Previous studies have sometimes found a positive relationship between platelet monoamine oxidase (MAO) activity and dexamethasone nonsuppression in depressed patients. To assess this relationship in more detail, we examined the association between these two biological variables in unmedicated depressed patients. A positive correlation between platelet MAO activity and 8:00 AM serum cortisol levels following an overnight dexamethasone test (1 mg) was observed. The relationship between high and low platelet MAO activity (median split) and suppression of serum cortisol levels was also significant. These relationships were stronger in bipolar patients. Multiple regression revealed that postdexamethasone 8:00 AM dexamethasone levels and platelet MAO activity were independent predictors of the 8:00 AM cortisol levels following dexamethasone. The possibility that platelet MAO activity may be a peripheral marker of brain serotonergic activity which in turn may affect various aspects of the hypothalamo-pituitary-adrenal axis activity, is discussed. We also found that all nine depressed patients studied greater than or equal to 15 days after admission were suppressors. Platelet MAO activity, but not 8:00 AM pre- or postdexamethasone serum cortisol, was related to the severity of depression.     

Major depression in young girls is related to altered cortisol awakening response

Background

There is evidence that clinical depression is associated with elevated basal cortisol levels in adult patients.

Objective

The present investigation tries to find out, whether this relationship also holds true in adolescents with major depression.

Methods

For 131 female subjects (63 MDD, 68 controls) the cortisol awakening response (CAR) was measured at 0, 30, 45, and 60 min after awakening. All subjects provided saliva cortisol.

Results

A significantly higher CAR was found in patients. The global mean difference was due to differences 60 and 45 min after awakening.

Limitations

A causal interpretation of the data is restricted, because of its cross-sectional nature. The effect size of the mean differences is rather small.

Conclusion

The observed HPA hyperactivity may be a cause as well as a consequence of depression in childhood.     

Alpha2 antagonist yohimbine suppresses maintained firing of rat prefrontal neurons in vivo

As a general alpha2 adrenergic antagonist, yohimbine has been widely used for research needs and in the therapy of malfunction of the noradrenergic system. In this study we analysed the effects of iontophoretically applied yohimbine on 79 prefrontal cortical (PFC) neurons of the rat in vivo. Our results indicate the inhibitory effect of norepinephrine on PFC neurons, which was simulated by yohimbine. The effect of yohimbine was not blocked by known alpha1 or postsynaptic alpha2 receptor agents. These results indicate that yohimbine exerts its antagonising and hyperpolarising effect on presynaptic rather than postsynaptic alpha2 receptors. Since these receptors have a permissive role in maintaining neural activity, their malfunction may contribute to the behavioural deficits observed in prefrontal disorders.