Neuroendocrine and mood responses to intravenous L-tryptophan in 3,4-methylenedioxymethamphetamine (MDMA) users. Preliminary observations

3,4-Methylenedioxymethamphetamine (MDMA; "ecstasy") is a selective serotonin (5-HT) neurotoxin in laboratory animals. To assess its effects on 5-HT function in humans, serum prolactin (PRL) and mood responses to intravenous L-tryptophan were measured in nine recreational users of MDMA and compared with findings from nine matched healthy controls. L-Tryptophan induced a rise in the PRL concentration in controls, but not in MDMA users. Peak change and the area under the curve of the PRL response appeared to be blunted in MDMA users, but the difference from controls did not reach statistical significance. This study provides suggestive evidence of altered 5-HT function in MDMA users, but more definitive studies clearly are needed.     

Neuroendocrine abnormalities in bulimia

The authors examined the relationship of clinical variables, family history, and neuroendocrine function in 18 bulimic patients. Twelve of 18 patients (67%) showed abnormalities of cortisol suppression, and 8 of 10 (80%) showed blunted thyrotropin-releasing hormone (TRH) tests. These findings suggest that neuroendocrine abnormalities identified previously in anorexia nervosa are not solely an artifact of low weight and, further, that eating disorders and affective disorders may share neurochemical similarities.     

Neuroendocrine profile in bulimia nervosa

The neuroendocrinology of bulimia nervosa has only recently been investigated, with initial research suggesting some biological overlap with both anorexia nervosa (AN) and depression. Similarities among AN, depression, and bulimia include a nonsuppressed Dexamethasone Suppression Test and an abnormal growth hormone (GH) response to thyrotropin-releasing hormone (TRH). Bulimics and anorectics both tend to have a delayed thyrotropin (TSH) response to TRH and elevated basal GH levels. Bulimics, however, have a normal GH response to clonidine, a nonblunted TSH response to TRH, low basal prolactin (PRL) levels, and may have an exaggerated PRL response to TRH. Unpublished data suggest bulimics may have a gonadotropin profile distinct from either AN or depression, as well as a variety of other endocrinopathies. Although many of these abnormalities may reflect malnutrition despite normal weight, other factors that are as yet unidentified are likely to be contributing to the neuroendocrine abnormalities seen in bulimia.     

Neuroendocrine responses to serotonergic agents in alcoholics.

Previous studies have suggested a possible deficit in serotonergic function in alcoholism. In order to further assess the serotonergic system in alcoholism, the plasma cortisol and prolactin (PRL) responses following 6-chloro-2-[1-piperazinyl]pyrazine (MK-212), a direct-acting serotonin2 (5-HT2)/5-HT1c receptor agonist, L-5-hydroxytryptophan (L-5-HTP), a precursor of 5-HT, and placebo were compared in male alcoholics and normal controls. The increase in plasma cortisol following L-5-HTP was significantly lower in the alcoholic subjects compared with the normal controls. The plasma PRL, but not the plasma cortisol response, following MK-212 was also significantly lower in the alcoholics. L-5-HTP had no significant effect on plasma PRL levels in either group. The basal plasma cortisol and PRL concentrations of the alcoholics and normal controls were not significantly different. These data are consistent with previous reports of a serotonergic abnormality in alcoholism.     

Neuroendocrine responses to carbidopa in primary affective dosorders.

(1) Measurement of hypothalamic-pituitary function in patients with affective disorders can indicate altered neurotransmitter activity since biogenic amines are involved in the control of these hormones. (2) We studied 18 patients with primary affective disorders, 11 bipolar and 7 unipolar and 10 normal controls for 10 days each. (3) On the first 2 days fasting resting 0900 hr samples were taken for measurement of growth hormone (GH), prolactin, thyroid stimulating hormone (TSH) and cortisol. These measures were repeated on the 9th and 10th days of the study while subjects were on carbidopa. Carbidopa is a peripheral inhibitor of l-aromatic amino acid decarboxylase and therefore inhibits extracerebral synthesis of serotonin and catecholamines. (4) We found bipolar depressed females to show a failure to respond to carbidopa with the normal prolactin elevation and their levels on carbidopa were significantly less than controls. (5) Moreover, bipolar depressed females had higher levels of plasma TSH than controls. (6) No such differences between groups were evident in males. (7) These results support the concept of altered neurotransmitter activity in some groups of patients with primary affective disorder.     

Neuroendocrine responses to physostigmine in Alzheimer's disease

To assess central nervous system cholinergic neuroendocrine regulation in Alzheimer's disease (AD), we measured plasma arginine vasopressin, beta-endorphin, and epinephrine responses to a cholinergic challenge elicited by intravenous administration of the acetylcholinesterase inhibitor physostigmine (0.0125 mg/kg) in male patients with AD (n = 12) and compared their responses with those of age-matched normal control subjects (n = 12). Physostigmine promptly increased plasma arginine vasopressin (tenfold), beta-endorphin (twofold to threefold) and epinephrine (threefold) levels in elderly control subjects. In contrast, patients with AD showed attenuated responses to physostigmine. When controls and patients with AD who experienced nausea (n = 2 and n = 6, respectively) were excluded, the arginine vasopressin, beta-endorphin, and epinephrine responses of patients with AD were significantly less than those of control subjects. These data suggest that the central nervous system cholinergic deterioration of AD results in decreased responsiveness of neuroendocrine systems that are regulated by central cholinergic mechanisms.     

L-tryptophan and neuroendocrine regulation in neurologic patients: hormone responses to L-tryptophan loading in patients with hypothalamic lesions

1. Oral administration of 2 g of l-tryptophan induced a marked plasma elevation of total and free tryptophan during the 2 hr of sampling in both normal subjects and in neurologic patients. Plasma free trytophan concentration showed a peak about 60 min after loading with l-tryptophan. 2. Plasma immunoreactive follitrophin (FSH) and lutrophin (LH) levels were not altered after l-tryptophan treatment. 3. Plasma immunoreactive somatotrophin (growth hormone, GH) levels showed a statistically significant elevation after l-tryptophan loading in both normal subjects and in neurologic control patients. In two acromegalic patients there was a very marked elevation of plasma somatotrophin levels 90 min after loading. No responses of plasma somatotrophin to l-tryptophan were observed in patients with hypothalamic lesion or with hypopituitarism. 4. Plasma cortisol levels showed significant morning decline during loading either with l-tryptophan or with l-leucine as placebo in normal subjects and in neurologic control patients. In patients with hypothalamic lesion the monitoring of plasma cortisol concentrations during l-tryptophan loading revealed a primary elevation with a subsequent slight decline. No variation of plasma cortisol was found in patients with hypopituitarism. 5. It was concluded that the brain serotoninergic system can be activated by l-tryptophan treatment which results in alterations of the hypothalamic regulation of somatotrophin secretion. When neuroendocrine dysfunction is due to structural lesions in the hypothalamus or in related regions, l-tryptophan loading is unable to modify somatotrophin secretion. The normal morning decline of plasma cortisol levels is lacking in such patients.     

Serotonergic function in obsessive-compulsive disorder. Behavioral and neuroendocrine responses to oral m-chlorophenylpiperazine and fenfluramine in patients and healthy volunteers.

To evaluate serotonergic (5-hydroxytryptamine) function in obsessive-compulsive disorder, behavioral and neuroendocrine responses to m-chlorophenylpiperazine (m-CPP; 0.5 mg/kg orally) and fenfluramine hydrochloride (60 mg orally) were examined in 20 patients and 10 healthy controls under double-blind, placebo-controlled conditions. Following m-CPP, but not fenfluramine or placebo, 55% (11/20) of the patients with obsessive-compulsive disorder experienced a transient exacerbation of obsessive-compulsive disorder. Prolactin response was blunted in patients following m-CPP but not following fenfluramine. Patients with greater behavioral response to m-CPP had smaller prolactin responses. Cortisol response to m-CPP and fenfluramine did not significantly differ between the groups. Behavioral and neuroendocrine responses appeared divergent. This does not suggest simply upregulation or downregulation of 5-hydroxytryptamine receptors, but rather complex mechanisms involving multiple neurotransmitter and neuromodulator systems.     

Neuroendocrine and behavioral responses to mCPP in Obsessive-Compulsive Disorder

Patients with Obsessive-Compulsive Disorder (OCD) have been shown to demonstrate blunted cortisol and prolactin responses along with an exacerbation of obsessive-compulsive symptoms in response to oral administration of the pharmacological probe, meta-chlorophenylpiperazine (mCPP). In an attempt to replicate these findings, mCPP was administered orally in the dose of 0.5 mg/kg body weight in a randomized double-blind design to 34 OCD patients who were either drug-naive or drug-free for a minimum period of four weeks. The cortisol and prolactin responses were contrasted with those of 18 drug-free healthy subjects. The OCD patients showed significantly blunted cortisol and prolactin responses to mCPP challenge as compared to normal subjects. However, mCPP did not produce any significant exacerbation of obsessive-compulsive symptoms in the patient group. The results are suggestive of a serotonin (5-HT) receptor hyporesponsivity in the HPA axis. Even though previous studies indicate a hyperresponsivity of the 5-HT receptor system in the orbitofrontal-striatal-pallido-thalamo-cortical pathway as shown by significant symptom worsening following serotonergic challenge, the present study failed to replicate those results. 5-HT receptor hyporesponsivity in the HPA axis may be considered as a biological "trait marker" of OCD, and may not be directly involved in the mediation of symptomatology of the disorder.     

Neuroendocrine responses to intravenous tryptophan in major depression

The increases in plasma levels of prolactin (PRL) and growth hormone (GH) following intravenous administration of the 5-hydroxytryptamine precursor tryptophan (100 mg/kg) were assessed in 30 depressed patients and 30 control subjects. In depressed patients who lost less than 10 lb, PRL responses were significantly reduced compared with controls. In contrast, the PRL responses of patients with weight loss exceeding 10 lb were significantly greater than those of either controls or the other depressed patients. Growth hormone responses to tryptophan were significantly decreased in patients who lost less than 10 lb. Prolactin, but not GH, responses correlated significantly with the postdexamethasone plasma cortisol concentration; however, an apparent relationship between GH and PRL responses and suicidal behavior was probably due to the common factor of weight loss. The results suggest that depressed patients have different types of abnormal 5-hydroxytryptamine-mediated neuroendocrine responses that correlate with the presence or absence of severe weight loss and cortisol hypersecretion. Further investigations are needed to establish if these abnormalities are central to the depressive disorder or have implications for treatment response.     

Effect of amitriptyline on endocrine responses to intravenous L-tryptophan

The endocrine responses to the 5-hydroxytryptamine (5HT) precursor, L-tryptophan, were assessed in 10 depressed patients before and after at least 4 weeks of treatment with amitriptyline. Overall, amitriptyline did not alter either prolactin or growth hormone responses to L-tryptophan. When three subjects with severe pretreatment weight loss were excluded, however, the remaining seven patients showed a significant increase in the prolactin response to L-tryptophan, consistent with other published studies. The findings suggest that severe recent weight loss may alter the effects of tricyclic antidepressants on 5HT-mediated prolactin release.     

Neuroendocrine responses to fenfluramine and its relationship to personality in alcoholism

Summary. This study investigates the relationship between personality and serotonergic reactivity in alcohol dependence. Personality characteristics were assessed according to the Temperament and Character model of Cloninger, the five-factor model of McCrae and Costa, Zuckerman's Sensation Seeking as well as Eysenck's impulsiveness/venturesomeness. Placebo-controlled prolactin response to the serotonin (5-HT) reuptake inhibitor/releaser fenfluramine served as an indicator for the reactivity of serotonergic neurotransmission. Forty abstinent alcohol-dependent men were subdivided into high and low prolactin responders according to their level of neuroendocrine response. High responders were characterized by decreased harm avoidance while their extraversion and venturesomeness scores were increased in comparison to low responders. The data demonstrates that harm avoidance on the one hand and extraversion/venturesomeness on the other are inversely correlated to serotonergic neurotransmission. These results support a specific relationship between personality traits and the serotonergic system. Received March 20, 2001; accepted May 22, 2001     

Neuroendocrine responses to cold stress in normal subjects and depressives

In order to assess the effects of cold stress on neuroendocrine function in persons with affective disorders, 11 normal subjects and eight depressed patients were subjected to a well-defined thermal stress in a cold chamber at 10° C. Metabolic rate, skin and rectal temperature, and TSH, T4, T3, growth hormone, prolactin, and cortisol were measured simultaneously for 45 minutes prior to cold exposure and for 60 minutes in the cold. All subjects experienced robust changes in skin temperature and metabolic rate during cold exposure, while maintaining core temperature throughout. There were no changes in any of the neuroendocrine parameters during exposure to cold stress in either the controls or the depressives, although depressives had somewhat higher T4 and lower T3, TSH, and GH throughout the study. These findings indicate that hormones of these neuroendocrine axes are unresponsive to acute, moderate cold stress in normal man and that depressives show no greater reactivity than normals.     

Investigation of peptide YY and ghrelin responses to a test meal in bulimia nervosa.

BACKGROUND: Gut-derived peptides, such as peptide YY (PYY) and ghrelin that regulate the initiation and termination of meals, could play a role in the altered eating behavior of patients with bulimia nervosa (BN). Therefore, we aimed to assess plasma PYY and ghrelin responses to a test meal in symptomatic bulimics. METHODS: Ten healthy women and nine women with BN underwent blood sample collections before and after the ingestion of a test meal of 1300 Kcal (with 15% carbohydrates, 10% proteins, and 75% fat) at 12:00 noon. Plasma total PYY, ghrelin, insulin, and glucose were assayed. RESULTS: As compared with healthy women, bulimics exhibited a significantly blunted increase of circulating PYY (p < .007) and a significantly reduced suppression of plasma ghrelin (p < .0004) after the test meal. No significant differences emerged in food-induced plasma insulin and glucose changes between the two groups. Plasma ghrelin suppression after the meal was significantly correlated with plasma PYY increase. CONCLUSIONS: We replicated our previous findings of an altered ghrelin response to food ingestion in people with BN and showed for the first time a blunted PYY increase after food consumption in these patients. These findings support the occurrence in BN of a profound dysregulation of some peripheral regulatory mechanisms involved in the short-term regulation of feeding behavior that might be involved in the pathophysiology of their binge eating behavior.     

Neuroendocrine responses to experimentally-induced psychological stress in healthy humans

Previous studies of hormonal and neurophysiological changes in response to psychological stress in humans have produced contrasting findings due to differing experimental procedures and consistent individual variability. Habituation effects, which influence physiological coping in response to exposure to repeated stress, need to be investigated more extensively. In the present study, twenty healthy male subjects were each exposed twice to the same psychosocial stressor (Stroop Color Word Interference task, public speaking and mental arithmetic in front of an audience) during a first session (day 1) and a second session (day 8). Plasma concentrations of norepinephrine (NE), epinephrine (EPI), adrenocorticotropic hormone (ACTH), cortisol (CORT) and prolactin (PRL) were measured immediately before the beginning of the tests and at their end, 30 min later, on both experimental days. For the total group, NE, EPI, ACTH, and CORT levels were significantly elevated, and PRL levels were significantly decreased, after stress exposure on day 1. ACTH and CORT levels showed less significant increases after stress on day 8. In contrast, NE and EPI responses to stress were not significantly blunted, and PRL response was unchanged on day 8. Cluster analysis revealed two groups of subjects who showed different habituation patterns for ACTH and CORT. The first group (n=12) of subjects showed a reduction of ACTH and CORT responses to stress on day 8. The subjects of the second group (n=8) displayed a significant increase of ACTH and cortisol in response to stress on day 8, without any habituation effect. These results increase the evidence concerning the involvement of the HPA axis and catecholamines in response to psychological stress, and suggest that possible individual differences in the neuroendocrine coping mechanisms may affect mood regulation and the state of health.     

Neuroendocrine responses to intravenous infusion of physostigmine in patients with Alzheimer disease.

We have reported that physostigmine, a reversible cholinesterase inhibitor, enhances verbal memory in patients with Alzheimer disease (AD). To elucidate the mechanism of cognition enhancement, plasma hormones were measured during high-dose acute and low-dose chronic steady-state intravenous infusions of physostigmine in nine subjects with AD. High-dose hormone responses were measured during and for 24 h after the infusion of physostigmine 1-1.5 mg over 45-60 min. Chronic responses were measured during continuous intravenous infusions of physostigmine at doses (0.5-25 mg/day) that escalated over 2 weeks, and then during 1 week infusion of the dose that optimized cognition (2-12 mg/day) or placebo administered in a randomized, double-blind, cross-over design. A replicable improvement in verbal memory was found in five subjects. High-dose physostigmine infusion that produced noxious side effects resulted in significant elevation above baseline in plasma levels of adrenocorticotrophic hormone (ACTH) (p = 0.0001), cortisol (p = 0.0001), and beta-endorphin (p = 0.0001). Chronic physostigmine administration, in the absence of adverse effects, produced no significant elevation in ACTH (p = 0.08), cortisol (p = 0.70), or beta-endorphin (p = 0.82). These results indicate that high-dose physostigmine activates the hypothalamic-pituitary-adrenal (HPA) axis, likely representing a "stress response." In contrast, cognition-enhancing doses do not produce a peripheral corticosteroid response. Thus, physostigmine-induced memory improvement is independent of the activation of the HPA axis.     

Neuroendocrine and leukocyte responses and pulmonary function to acute stressors

Although stress is linked to asthma exacerbation, underlying mechanisms are unclear. Given the shared relevance to stress and asthma, select neuroendocrine and immune responses to acute stressors and their impact on pulmonary function were examined, comparing responses between students with (n = 20) and without childhood asthma (n = 16). Students were challenged with speech and math tasks. Blood samples were collected five times: before tasks, immediately after first and second tasks, and 15 and 60 minutes posttasks. Pulmonary function was measured four times, excluding midtask point. Stress reactivity patterns did not differ between two groups. However, all measures showed significant changes across the challenge. Plasma epinephrine and norepinephrine rose during tasks and declined after tasks, p < .001. Cortisol mainly declined after tasks, p = .03. Leukocyte count increased during tasks with increased lymphocyte percentage that declined after tasks, while neutrophil percentage changed opposite to lymphocytes, p < .001 each. Changes in pulmonary function were significant, p < .05, but were not predicted by the magnitude of neuroendocrine and immune changes. Instead, neuroendocrine and immune levels explained 33%-51% of variance on concurrent pulmonary function. Findings indicate that acute stress induces significant neuroendocrine and immune changes that can affect pulmonary function. However, stress reactivity needs further investigation with larger samples and people with a more severe form of asthma.     

Lithium treatment and serotoninergic function. Neuroendocrine and behavioral responses to intravenous tryptophan in affective disorder

Evidence suggests that lithium treatment alters serotoninergic (5-HT) function in laboratory animals and humans. Since 5-HT function may be abnormal in patients with affective disorders, we studied 23 such patients by measuring responses to intravenous infusion of the 5-HT precursor tryptophan before and during short-term (less than one week) or long-term (greater than three weeks) lithium treatment. The prolactin response to tryptophan was significantly enhanced after short-term lithium treatment; long-term lithium treatment had no effect. Other studies have shown that the prolactin response to tryptophan is also enhanced after long-term tricyclic antidepressant treatment in depressed patients and after short- and long-term lithium treatment in healthy subjects. The present findings suggest that lithium treatment enhances 5-HT function, but that homeostatic responses of the 5-HT system to long-term lithium treatment may differ in patients with affective disorder and healthy subjects.     

Neuroendocrine responses to psychological stress in adolescents with anxiety disorder

Neurotransmitter-neuroendocrine and cardiovascular responses to the administration of a psychologically stressful mixed-model test (Mental Arithmetic, Stroop Color Word Interference Task, Trier Social Stress Test) were examined in 20 male peripubertal subjects affected by anxiety disorder (group A: 14 with generalized anxiety disorder, 6 with generalized anxiety disorder and separation anxiety disorder) and 20 junior school adolescents, matched for age, without overt psychological disorders (group B). Plasma levels of norepinephrine (NE), epinephrine (EPI), adrenocorticotropic hormone (ACTH), beta-endorphin (beta-EP), cortisol (CORT), growth hormone (GH), prolactin (PRL) and testosterone (Te) were measured immediately before the beginning of the tests and 30 min later at their end. Mean prestress values of GH, PRL, beta-EP and ACTH were significantly higher in anxious subjects than in controls. There was no difference in NE, EPI, CORT and Te prestress levels in the two groups. After the psychological stress session NE, GH and Te concentrations increased significantly in anxious subjects (A), but not in controls. In contrast, beta-EP and PRL decreased significantly during the psychological stress session in anxious subjects, and were unaffected by stress in the subjects without anxiety. No significant changes were found in ACTH, CORT and EPI during the challenge either in anxious subjects or in controls, which may be attributed to the late time of poststress blood sampling. In contrast to controls, heart rate and systolic blood pressure increased significantly in anxious subjects after psychological stress testing. Our data support the hypothesis that the hyperactivity of the noradrenergic system in response to stress is associated with anxiety disorders in adolescents and might influence the responses of GH and Te. High prestress basal values of stress hormones seem to be induced in anxious subjects by the anticipation of the task or by a persistent hyperactivity of the noradrenergic system. Further studies are needed to investigate in more detail the involvement of the HPA axis in anxious adolescents by a more refined resolution of time points of blood sampling.