Central Serotoninergic Activity Research Articles

A study of central serotoninergic activity in healthy subjects and patients with Type 2 diabetes treated by traditional one-to-one care or Group Care

Central serotoninergic activity may modulate glucose metabolism via neuroendocrine effectors. Group Care is a clinico-pedagogic intervention that improves metabolic control and quality of life in Type 2 diabetes through lifestyle modification and, possibly, central mechanisms. The hypothesis that central serotoninergic activity is modified in patients followed by Group Care was tested by measuring their hypothalamic- pituitary-adrenal response to citalopram, a selective serotonin reuptake inhibitor. Ten healthy controls and 17 non-obese, non-insulin-treated patients with Type 2 diabetes received, in random order, iv infusions of either 20 mg citalopram or saline. Nine patients had been longterm on Group Care and 8 had always been on traditional one-to-one care. Circulating glucose, insulin, ACTH, cortisol, DHEA, GH and PRL were measured every 15 min for 240 min. Differences between areas under the curves after citalopram and saline (Δ-AUC) were calculated. Citalopram stimulated ACTH and cortisol secretion in healthy subjects (p=0.026 and p=0.011, respectively) and patients on Group Care (p=0.056 and p=0.038) but not in patients on traditional care. In healthy subjects, basal glucose correlated with growth hormone Δ- AUC (r=0.820; p=0.004) and inversely with insulin Δ-AUC (r=-0.822; p=0.003). The former correlation was preserved in the patients (r=0.637; p=0.026). Diabetes may blunt the response of the hypothalamic-pituitary-adrenal axis to citalopram, but this is preserved in patients followed by a long-term intervention model that improves clinical as well as cognitive and emotional variables.

Association between serotonin transporter availability and overall rating scores of quality of life in healthy volunteers

Depression and impaired quality of life (QOL) are frequently observed in patients suffering from a variety of diseases. In addition, it has been reported that an enhanced degradation of the serotonin precursor tryptophan may contribute to QOL deterioration in some diseases. However, it is unclear whether the correlation between the QOL scores and the central serotonergic tone is only mediated by the severity of either the depression symptoms or the physical illness itself. The present study examined the relationship between serotonin transporter (SERT) availability and life quality as measured by the World Health Organization Quality of Life brief version questionnaire (WHO-QOL) in healthy participants in order to exclude the influence of depressive mood and disease. The SERT availability in the midbrain was approximated using SPECT with [(123)I] ADAM ligand in fifty-eight healthy volunteers. The overall rating sub scores of the WHO-QOL correlated positively with serotonin transporter availability in the males. Central serotoninergic activity may play a role in the overall rating scores of the WHO-QOL.

5-HT brain function in affective disorder: d, l-fenfluramine-induced hormone release and clinical outcome in long-term lithium/carbamazepine prophylaxis

Prolactin (PRL) and Cortisol (CORT) responses to d, l-fenfluramine (FEN) challenge (60 mg) were examined in patients with affective disorders on two occasions under euthymic conditions: drug-free before admission to prophylactic treatment and after about 9 months of medication with lithium or carbamazepine. Response to treatment was assessed by a complex algorithm using continuous ratings in outpatient clinic over a period of 2 years. In general, treatment resulted in a delayed and diminished CORT release (n.s.); subgroup analysis revealed an attenuated CORT response ( P<0.05) in responders, whereas nonresponders showed no change in CORT secretion pattern except an enhanced CORT baseline value ( P<0.05). Cross-sectional comparison of responders with nonresponders under medication yielded a trend for greater CORT stimulation in nonresponders. This result was not affected by FEN/NorFEN or lithium/carbamazepine serum levels, baseline CORT values, age, sex, diagnostic distribution, number of appointments to the outpatient clinic or duration of medication at the time of FEN test session. Before onset of prophylactic medication responders and nonresponders could not be discriminated significantly regarding stimulated hormone release, probably due to the small sample size ( n=17). CORT response to FEN was increased in drugfree unipolar patients compared to bipolar ( P<0.05) and to schizoaffective patients ( P<0.1). In accordance with its well-documented presynaptic 5-HT-agonistic action lithium medication resulted in a significantly greater increase in CORT release than carbamazepine ( P<0.05). Evaluation of PRL stimulation showed patterns of secretion quite similar to those of CORT, without reaching statistical significance in most cases. Perhaps due to methodological differences in assessing treatment response, these data do not confirm former results, which supposed an enhanced 5-HT net activity in long-term prophylactic lithium treatment. Because of high interindividual variances of hormone parameters, the FEN-test procedure is not a useful tool for the prediction of therapeutical outcome in terms of clinical routine use. Relations of stimulated hormone response as a marker of central serotoninergic activity and clinical outcome are discussed.

The m-chlorophenylpiperazine test in cluster headache: a study on central serotoninergic activity.

The central serotoninergic agonist m-chlorophenylpiperazine (m-CPP) stimulates several 5HT receptor subtypes. It induces the release of both cortisol and prolactin (PRL). In this study we investigated central serotoninergic responsiveness in cluster headache by monitoring cortisol and PRL responses to m-CPP administration. Twenty-three patients with episodic cluster headache and 17 sex-matched and age-matched healthy subjects were studied. The cluster headache patients were tested during a cluster period, and none were receiving prophylaxis. A single oral dose of m-CPP, 0.5 mg/kg, was given at time 0. Blood samples were drawn at -30, 0, 30, 60, 90, 120, 150 and 180 min. PRL and cortisol levels were assayed in the samples. PRL and cortisol delta maxima (delta maximum = maximum response - baseline level at time 0/baseline level at time 0) were evaluated in each patient and mean values compared. Serum levels of m-CPP were detected by HPLC and correlated to hormonal responses. Reduced cortisol (p < 0.02) and increased PRL (p < 0.05) delta maxima were observed in cluster headache patients. Increased basal cortisol plasma levels (p < 0.05) and reduced basal PRL plasma levels (p = 0.06) also characterized cluster headache patients. This is the first study evaluating central serotoninergic responsiveness to m-CPP in cluster headache and these data suggest impaired central serotoninergic function in this pathology.

Fluoxetine in the treatment of premenstrual syndrome

Background: Premenstrual syndrome (PMS) is defined as the disabling and cyclic occurrence of emotional and behavioral symptom complex during the latter half of the menstrual cycle. Although its etiology is unknown, it has been speculated that premenstrual syndrome is linked to a deficiency of central serotoninergic activity. Method: The study consisted of a double-blind, placebo controlled trial of fluoxetine at a dose of 20 mg/day or placebo for three menstrual cycles. The 440 women who appeared to meet the eligibility criteria were instructed to record the ‘Calendar of Premenstrual Experiences’ (CPE) scale for two complete menstrual cycles. Of 410 women who successfully completed two cycles of recording their symptoms daily only 35 met the criteria for PMS. These criteria included psychiatric interviews which were made before treatment. Thirty-five PMS patients were randomized into placebo or fluoxetine treatment groups. Results: Our study suggests that fluoxetine at a dose of 20 mg per day was significantly superior to placebo in alleviating the symptoms of PMS. The most common side effects were gastrointestinal irritability (15%), insomnia (11%) and sexual dysfunction (8.5%). Conclusion: Fluoxetine is an effective and well-tolerated drug and appears to have considerable promise in treating a range of symptoms in women with PMS.

Blunted growth hormone (GH) responsiveness to GH-releasing hormone in obese patients: Influence of prolonged administration of the serotoninergic drug fenfluramine

The aim of the present study was to ascertain if reduced central serotoninergic activity might contribute to the well-known blunted growth hormone (GH) response to GH-releasing hormone (GHRH) in obese patients. Thus, we studied the effect of prolonged stimulation of the serotoninergic system by fenfluramine (FF; 60 mg twice daily for 7 days) on GHRH-induced GH release in nine obese and seven normal subjects. In controls, GHRH (100 μg intravenously [IV]) injection increased GH levels from 2.3 ± 1.8 (±SE) to 18.5 ± 2.8 mU/L, P < .002. FF administration enhanced both basal and GHRH-stimulated GH levels (peak, 38.4 ± 8.3 v 6.9 ± 2.6 mU/L, P < .002). This response was significantly higher ( P < .02) than in pretreatment. In obese patients, GH responsiveness to GHRH was slight (peak, 7.1 ± 2.0 v 0.6 ± 0.18 mU/L, P < .01) and lower ( P < .01) than in controls. FF administration did not affect this response. In controls, the enhanced FF-induced GH release after a maximal dose of GHRH indicates that serotoninergic activation influences GH secretion and that the mechanism involved is independent of endogenous GHRH. In obese patients, we found a blunted GH responsiveness to GHRH that was not affected by FF, thus supporting the hypothesis that the serotoninergic control on GH release is impaired.

Effect of fenfluramine on prolactin and thyroid-stimulating-hormone response to thyrotropin-releasing-hormone in obese and normal women

In order to demonstrate the suggested failure of the serotoninergic system in human obesity and to evaluate the role of central serotoninergic activity in prolactin (PRL) and thyroid stimulating hormone (TSH) release in this condition, 13 euthyroid obese and 9 healthy women of normal weight were studied. A TRH test (200 micrograms i.v.) was performed before and after administration of fenfluramine (FF) 60 mg b.d. for 14 days. In the controls, FF did not modify the expected significant increase in PRL induced by TRH. In obese patients, however, the PRL levels was significantly increased after TRH, but the increase was less than in the controls. After FF, the PRL response to TRH was larger than in the pretreatment phase, with values similar to those observed in normal subjects. In neither group FF did change the TSH-stimulating effect of TRH, but the hormonal response in obese patients was greater than in the controls. The restoration of the responsiveness of PRL to TRH after central serotoninergic stimulation confirms the hypothesis that a failure of the serotoninergic system may occur in human obesity. Since FF does not interfere with the secretory pattern of basal and stimulated TSH in normal or obese subjects, the serotoninergic system does not seem to play a major role in the control of TSH secretion.

Central Serotoninergic Stimulation by Fenfluramine Challenge Does Not Affect Plasma Thyrotropin-Stimulating Hormone Levels in Man

Thyrotropin-stimulating hormone (TSH) and prolactin (PRL) responses to an acute oral challenge of fenfluramine (60 mg), a central serotoninergic (5-hydroxytryptamine) releasing/uptake inhibiting agent, were examined in 8 healthy males in order to assess the role of central serotoninergic stimulation in the release of TSH. Plasma PRL, but not TSH, was significantly elevated by fenfluramine. These data suggest that central serotoninergic activity does not play an important role in the physiologic release of plasma TSH in man. Further, thyrotropin-releasing hormone is unlikely to be the PRL-releasing factor involved in the fenfluramine-induced stimulation of PRL.

5-Hydroxyindoleacetic acid in cerebrospinal fluid in alcoholic patients under different clinical conditions

Levels of 5-hydroxyindoleacetic acid, 5-HIAA, the main serotoninergic metabolite in the central nervous system, were investigated in the cerebrospinal fluid, CSF, of male alcoholics and healthy controls. During intoxication, 5-HIAA correlated positively to blood ethanol concentration and levels gradually decreased by length of abstinence. In patients investigated after three months of alcohol abstinence, subnormal levels were noted. Assuming that the level of 5-HIAA in the CSF reflects central serotoninergic activity, the results support the assumption of subnormal activity in abstinent alcoholics and an activation during abuse.

Monophenolic octahydrobenzo[f]quinolines: central dopamine- and serotonin-receptor stimulating activity.

Eight monophenolic cis- and trans-4-n-propyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolines have been synthesized and tested for central dopamine- and serotonin-receptor stimulating activity, using biochemical and behavioral tests in rats. The trans-7-, -8-, and -9-hydroxy isomers all elicited central pre- and postsynaptic dopaminergic receptor stimulation, while the trans-10-hydroxy isomer was devoid of dopaminergic activity but instead showed central serotoninergic activity. In all four isomeric pairs, the trans isomers were consistently much more potent than their corresponding cis analogues. The apparent presynaptic selectivity of the dopaminergic cis isomer cis-9-hydroxy-4-n-propyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinoline could not be confirmed due to the toxic properties of this compound. Central dopamine receptors (autoreceptors and postsynaptic receptors) can accept dopaminergic compounds with one of possibly two N-substituents being larger than n-propyl, if this substituent is properly oriented in relation to the rest of the molecule.

Evidence for a receptor supersensitivity following impairment of central serotoninergic activity in the rabbit

In order to investigate whether a chronic impairment of neuronal serotoninergic transmission in the CNS could result in a receptor supersensitivity, rabbits were pretreated either with 5,6-dihydroxytryptamine (5,6-DHT) or p-chlorophenylalanine (PCPA) and then tested for their hyperthermic response to serotoninergic agonists. A previous (10 days before) intracerebroventricular injection of 5,6-DHT (75 microgram into each cerebral ventricle) significantly potentiated the increase in body temperature induced either by quipazine (1 mg/kg i.v.) or by 5-hydroxytryptophan (5-HTP 2 mg/kg i.v.) in combination with a MAO inhibitor (phenylethylhydrazine 10 mg/kg i.v. 16 h before). Pretreatment with PCPA (100 mg/kg s.c. four times on alternate days, the last dose 48 h before the experiment) also enhanced the hyperthermic effect of quipazine, whereas it inhibited the hyperthermic response to 5-HTP plus MAO inhibitor. These results suggest the existence of a receptor supersensitivity following prolonged blockade of serotoninergic neuronal transmission in the CNS.