Case-control study of evening melatonin concentration in primary insomnia.
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Adult↗
Biomedical subjects
P J Cowen
Publications and source records attributed to P J Cowen.
Dieting decreases plasma tryptophan and increases the prolactin response to d-fenfluramine in women but not men.
We studied the effect of 3 weeks of moderate calorie restriction on 5-HT-mediated prolactin (PRL) release in healthy volunteers using the 5-HT-releasing agent d-fenfluramine. In women, dieting significantly lowered plasma total and free tryptophan (TRP) and increased the PRL response to d-fenfluramine. None of these measures were altered in men who dieted. These findings add to the data indicating that dieting alters brain 5-HT function in women, perhaps as a consequence of reducing the availability of plasma TRP.
Adult↗
Effect of pharmacologic treatments on the sleep of depressed patients.
Antidepressant drugs produce striking effects on sleep architecture that are best understood in terms of their interactions with the monoamine pathways controlling sleep and wakefulness. Many different antidepressant drugs, including tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), and selective 5-hydroxytryptamine (5-HT; serotonin) reuptake inhibitors (SSRIs), decrease rapid eye movement (REM) sleep. The reduction in REM sleep produced by antidepressants may be an important part of their mechanism of action; however, the ability of new antidepressant compounds, such as nefazodone and moclobemide, to increase REM sleep throws doubt on this suggestion. The effects of antidepressants on slow-wave sleep (SWS) are quite diverse; in general, antidepressants having significant 5-HT2A/2C receptor antagonist properties increase SWS, whereas other drugs, such as SSRIs or MAOIs, either lower SWS or produce no change. Sleep continuity is improved acutely following administration of antidepressants with sedating properties such as certain TCAs, trazodone, and mianserin. Some nonsedating drugs (ritanserin and nefazodone) also improve sleep continuity measures, possibly through 5-HT2A/2C receptor blockade.
Antidepressive Agents↗
Differential effects of clonidine, haloperidol, diazepam and tryptophan depletion on focused attention and attentional search.
As the catecholamines have long been implicated in attentional processes, the present investigation compared the effects of the mixed alpha 1/alpha 2 adrenoceptor agonist clonidine (CLO), the benzodiazepine diazepam (DZP), the D1/D2 antagonist haloperidol (HAL) and a low-tryptophan drink (Lo-TRP) on performance of tests of selective attention with distractors in four groups of young, healthy volunteers. Using a placebo-controlled, cross-over design, selective and dissociable effects on performance were found with each pharmacological manipulation. Specifically, CLO acted to broaden the focus of attention, HAL generally slowed reaction times during attentional search, and DZP and Lo-TRP produced differential effects on stimulus-response compatibility during attentional search. Furthermore, these results underline the usefulness of employing a single test with several neurochemical manipulations, allowing for a comprehensive analysis of the neurochemical basis of attention.
Adult↗
Effect of pindolol on the prolactin response to d-fenfluramine.
We studied the effect of the 5-HT1A receptor antagonist, pindolol, on the prolactin (PRL) response to the 5-HT releasing agent, d-fenfluramine (d-FEN), in ten healthy male volunteers. Pindolol pretreatment lowered baseline PRL levels but, when this effect was taken into account, did not significantly attenuate the PRL response to d-FEN. Within the limitations that attend the use of pindolol as a 5-HT1A receptor antagonist, the data suggest that although 5-HT1A receptors may play a role in the tonic release of PRL, they are not involved in the release of PRL produced by d-FEN. We propose that the PRL response to d-FEN may involve selective activation of postsynaptic 5-HT2 receptors.
Adult↗
Melatonin phase advances circadian rhythm.
We studied the effect of acute (1 day) and subacute (7 days) treatment with melatonin (0.5 mg) on the endogenous rhythms of melatonin secretion in 12 healthy male volunteers, using a placebo-controlled, double-blind, cross-over design. Melatonin given at 1700 h for 7 days significantly advanced the onset of endogenous melatonin secretion, while a single dose was without effect. These data are consistent with the hypothesis that melatonin plays a role in the organisation of circadian rhythms in humans and suggest that appropriately timed melatonin administration may provide a means of altering the timing of circadian cycles.
Adult↗
Biochemical and behavioural effects of acute tryptophan depletion in abstinent bulimic subjects: a pilot study.
We studied the effect of acute tryptophan (TRP) depletion in a group of eight abstinent bulimic (BN) subjects and in 12 healthy female controls. Despite being free of episodes of binge-eating and vomiting for a prolonged period, the abstinent BN subjects still appeared to practice dietary restrain as judged by their food intake in a test meal. In addition, their plasma TRP concentrations were significantly lower than those of the controls. Administration of a TRP-free amino acid load (52 g) significantly lowered plasma total and free TRP. However, compared to a balanced amino acid load, this procedure did not have significant effects on mood, appetite or food intake in either the abstinent BN subjects or the healthy controls.
Adult↗
Ondansetron and opiate craving. A novel pharmacological approach to addiction.
BACKGROUND: Pharmacological approaches to opiate addiction have for the most part been limited to a role in detoxification. A high percentage of patients who complete detoxification programmes relapse. METHOD: In the present study, we used a simple laboratory method to investigate suggestions from preclinical studies that 5-(hydroxytryptamine) HT3 receptor antagonists have a role in the treatment of addiction. RESULTS: We showed that addicts stably maintained on methadone experienced significant craving, dysphoria, and withdrawal-like symptoms when exposed to a video containing drug-related cues. The craving was not lessened by treatment with the 5-HT3 receptor antagonist, ondansetron (4 mg orally). CONCLUSION: Our current findings do not support a role for 5-HT3 receptor agonists in the reduction of craving in opiate addicts.
Female↗
Effect of valine on 5-HT-mediated prolactin release in healthy volunteers, and on mood in remitted depressed patients.
BACKGROUND: Animal experimental studies suggest that the amino acid valine may decrease brain serotonin (5-HT) function by inhibiting the transport of the 5-HT precursor, L-tryptophan, across the blood barrier. The aim of the present study was to assess whether valine could decrease brain 5-HT function in healthy subjects and provoke symptomatic relapse in recently remitted depressed patients taking antidepressant drug treatment. METHOD: We studied the effect of valine (30 g) on the prolactin (PRL) response to the 5-HT releasing agent, D-fenfluramine, in healthy male subjects and on the mood of 12 remitted depressed patients taking either selective serotonin re-uptake inhibitors (n = 10) or lithium and amitriptyline (n = 2). RESULTS: Valine significantly lowered the PRL response to D-fenfluramine in healthy subjects. In the remitted depressives, valine caused a mild but detectable lowering of mood on a number of measures but only one patient experienced a significant relapse in mood. CONCLUSIONS: Valine administration may decrease brain 5-HT neurotransmission in humans. This effect could explain the mild increase in depressive symptoms in patients taking 5-HT-potentiating drugs.
Adult↗
The 5-HT3 antagonist, BRL 46470 does not attenuate m-chlorophenylpiperazine (mCPP)-induced changes in human volunteers.
Results from animal studies have suggested that serotonin (5-HT) antagonists acting on the 5-HT3 receptor may have anxiolytic properties. We have assessed whether pretreatment with the 5-HT3 receptor antagonist BRL 46470 (1 mg orally) attenuates the increase in anxiety induced in healthy volunteers by intravenous infusion of m-chlorophenylpiperazine (mCPP: 0.08 mg/kg over 2 min). In this double-blind placebo-controlled crossover study in 12 healthy men who were volunteers, infusion of mCPP caused significant increases in self-ratings for the psychological and physical symptoms of anxiety, for the symptoms of panic attack, and in the plasma levels of cortisol and prolactin, with four subjects (33%) experiencing an mCPP-induced "panic attack." Pretreatment with BRL 46470 did not attenuate any of these mCPP-induced changes. These results do not support suggestions from animal studies that 5-HT3 receptor antagonists can attenuate mCPP-induced anxiety, although it is conceivable that a different dose of BRL 46470 may have been effective.
Administration, Oral↗
m-Chlorophenylpiperazine decreases food intake in a test meal.
We studied the effect of the 5-HT receptor agonist, m-chlorophenylpiperazine (mCPP) (0.4 mg/kg), on food intake in 12 healthy female volunteers, in a double-blind placebo controlled design. Compared to placebo, mCPP significantly lowered food intake in a test meal. Treatment with mCPP also caused significant increases in ratings of nausea and light-headedness, though these effects had remitted by the time of the test meal. The results suggest that activation of brain 5-HT2C receptors may lower food intake in humans; it is also possible, however, that the hypophagic effect of mCPP in the present study could be a consequence of its adverse subjective side effects.
Adult↗
Neuroendocrine effects of sumatriptan.
The neuroendocrine effects of the 5-HT receptor agonist, sumatriptan (6 mg subcutaneously), were studied in 11 healthy male subjects using a placebo-controlled, cross-over design. Compared to placebo, sumatriptan significantly lowered levels of plasma prolactin but increased those of plasma growth hormone. There was no effect on plasma cortisol concentrations. The neuroendocrine effects of sumatriptan differ from those of previously described 5-HT-receptor agonists, and may be a consequence of selective activation of 5-HT1D or 5-HT1B receptors. However, the present data cannot exclude the possibility that the neuroendocrine changes reflect nonspecific stress responses or changes in pituitary blood flow.
Adult↗
p-Chloroamphetamine (PCA), 3,4-methylenedioxy-methamphetamine (MDMA) and d-fenfluramine pretreatment attenuates d-fenfluramine-evoked release of 5-HT in vivo.
Previous work has suggested that repeated treatment with substituted amphetamines including PCA, MDMA and d-fenfluramine produces a persistent neurodegeneration which is relatively selective for the fine serotoninergic terminals arising from the dorsal raphe nucleus. The aim of the present study was to investigate whether the acute releasing effect of d-fenfluramine might also be sensitive to lesions produced by PCA, MDMA and d-fenfluramine itself. Basal and 5-HT release evoked by d-fenfluramine or 100 mM KCl was measured by microdialysis in frontal or parietal cortex of rats 2 weeks after they had been treated with a neurodegenerative regime of PCA, MDMA, d-fenfluramine, or vehicle. In frontal cortex of vehicle controls, d-fenfluramine (10 mg/kg IP) and KCl (100 mM via microdialysis probe) evoked an increase in 5-HT of 1740% and 779% of basal, respectively. PCA pretreatment reduced d-fenfluramine-evoked 5-HT release by 90.9% while potassium-evoked release was reduced by only 66.8%. Similar results were obtained in parietal cortex. MDMA (20 mg/kg x 8) and d-fenfluramine (1.25 mg/kg x 8) pretreatment reduced d-fenfluramine-evoked release of 5-HT in frontal cortex by 45.2% and 72.0%, respectively. Overall, the present data are consistent with the hypothesis that the acute release of 5-HT evoked by d-fenfluramine occurs via those terminals destroyed by pretreatment with PCA, MDMA and d-fenfluramine, while KCl evokes release from both PCA-sensitive and PCA-insensitive terminals. The significance of these results for the interpretation of neuroendocrine data from d-fenfluramine challenge tests is discussed.
Amphetamines↗
Neuroendocrine responses to intravenous L-tryptophan in obsessive compulsive disorder.
We studied the neuroendocrine responses produced by intravenous L-tryptophan (TRP) in 16 untreated patients with obsessive compulsive disorder (OCD) and 16 matched healthy controls. The increase in plasma growth hormone seen following TRP was significantly greater in the OCD patients, while TRP-induced prolactin release did not differ from controls. Taken in conjunction with findings from other neuroendocrine studies the data suggest that some aspects of 5-HT1A neurotransmission may be increased in OCD. This increase may represent a compensatory change which promotes adaptation to stress in non-depressed OCD patients.
Adolescent↗
Effects of hydrocortisone on brain 5-HT function and sleep.
The effects of hydrocortisone administration (20 mg, orally, twice daily) on the sensitivity of brain 5-HT1A receptors in healthy volunteers were studied using a buspirone challenge paradigm. The effects of hydrocortisone administration on sleep architecture were also studied. Hydrocortisone treatment significantly attenuated the hypothermic and cortisol responses to buspirone; however, the prolactin and growth hormone responses were unchanged. Hydrocortisone also decreased the amount of rapid eye movement sleep (REM). The ability of hydrocortisone to attenuate 5-HT1A receptor mediated hypothermia and decrease REM sleep is shared by certain antidepressant treatments and may be related to the effects of corticosteroids on mood.
Administration, Oral↗
The effects of administration of mCPP on psychological, cognitive, cardiovascular, hormonal and MHPG measurements in human volunteers.
m-Chlorophenylpiperazine (mCPP) is a metabolite of the antidepressant trazodone which has been widely used in psychopharmacology research as a probe of serotonin (5-hydroxytryptamine; 5-HT) function. However, in addition to binding at 5-HT receptors it also binds strongly to alpha 2-adrenoceptors, and it is conceivable that some of the physical and psychological symptoms previously reported following mCPP infusion are due to effects upon central noradrenergic neurotransmitter function. In this double-blind placebo-controlled balanced-crossover study in 12 healthy male volunteers we have examined the effects of infusion of mCPP (0.08 mg/kg over 2 min) on symptoms of anxiety, cognitive performance, pulse and blood pressure, and plasma concentrations of adrenocorticotrophic hormone (ACTH), cortisol, prolactin, growth hormone, and the noradrenaline metabolite 3-methoxy-4-hydroxyphenyl glycerol (MHPG). The results confirm previous findings that in humans mCPP causes significant increases in the symptoms of anxiety, and in the plasma concentrations of cortisol, prolactin and growth hormone. In addition, our results demonstrate that mCPP causes no significant changes in cognitive performance, in pulse or systolic blood pressure, or in the plasma concentration of MHPG. Since pulse, systolic blood pressure and MHPG plasma concentrations all to some degree reflect central noradrenergic activity, we believe it unlikely that the psychological and hormonal effects of mCPP are due primarily to effects on noradrenergic neurotransmission. Further studies to address this specific issue are needed, however, before firm conclusions can be reached.
Adrenocorticotropic Hormone↗
5-HT1A receptor sensitivity in major depression. A neuroendocrine study with buspirone.
The hypothermic, growth hormone and corticotrophin (ACTH) responses to the 5-HT1A receptor agonist buspirone (30 mg orally) were measured in 20 unmedicated patients with major depression and 20 healthy controls. Compared with the controls, the hypothermic responses of the depressed patients to buspirone were significantly attenuated, particularly in patients with melancholic depression. In contrast, the responses of growth hormone and ACTH to buspirone were unchanged. The data suggest that major depression may be associated with impaired sensitivity of 5-HT1A autoreceptors but that the function of the post-synaptic 5-HT1A receptors that mediate growth hormone and ACTH release is unaltered. Within the limitations that attend the use of buspirone as a 5-HT1A probe, our data suggest that the decrement in serotonin neurotransmission at post-synaptic 5-HT1A receptors in depression is due to decreased serotonin release rather than impaired responsivity of post-synaptic 5-HT1A receptors.
Adolescent↗