Neuroendocrine evidence for dopaminergic actions of hypericum extract (LI 160) in healthy volunteers.

BACKGROUND: We studied the effect of a single dose of a formulation of a methanolic extract of Hypericum perforatum (HP), also known as St. John's wort, on plasma concentrations of growth hormone (GH), prolactin (PRL), and cortisol (CORT) in 12 healthy male volunteers. METHODS: Subjects received 9 tablets of the finished product Jarsin 300 and placebo in a double-blind, balanced-order, cross-over design. RESULTS: Following HP relative to placebo, there was a significant increase in plasma GH and a significant decrease in plasma PRL. Plasma CORT levels were unchanged. CONCLUSIONS: Taken together with data from animal experimental studies, the findings suggest that this dose of HP may increase some aspects of brain dopamine function in humans.

Effect of a long-term low tryptophan diet on the prolactin responses to the 5-HT1A and 5-HT2C agonists, 8-OH-DPAT and mCPP in the male rat.

The study was undertaken to assess the long term effects of tryptophan (TRP) depletion through diet on the prolactin (PRL) responses to the serotonin (5-hydroxytryptophan, 5-HT) agonists m-chlorophenyl-piperazine (mCPP) and 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) in the male rat. The low TRP diet caused significant reductions in both plasma total TRP and brain cortical 5-HT content together with a significant increase in the PRL responses to mCPP. In contrast the PRL responses to 8-OH-DPAT in animals on the low TRP diet for 1 week and 6 weeks were similar to control rats. However, a small but significant increase in PRL was observed at 2 min after dosing in the 1-week group. At the same time the 3H-8-OH-DPAT binding parameters, Kd and Bmax, were similar in both control and TRP depleted animals. The results confirm that long-term TRP depletion causes a deficiency of brain TRP and a subsequent reduction of brain 5-HT. This is associated with an enhanced PRL response to mCPP probably resulting from a functional up-regulation of post-synaptic 5-HT2C receptors. The small or transient changes brought about by long-term TRP depletion on post-synaptic 5-HT1A receptors, suggests that these receptors may be less susceptible to 5-HT depleting effects than the 5-HT2C subtype.

Sleep disorders and their relationship to psychological disturbance in children with epilepsy.

By means of parental questionnaires, sleep disturbances were assessed in 79 schoolchildren with epilepsy (mean age 10.12, range 5-16 years) for comparisons with 73 healthy control children matched for gender and to within a maximum of 6 months of age. The daytime behaviour of the children with epilepsy was also assessed by questionnaire. The children with epilepsy were considered representative of such children under general paediatric care. Sleep disturbance was classified into five basic types (poor quality sleep, anxieties about sleep, disturbances during sleep, symptoms of disordered breathing during sleep and short duration sleep) and the behaviour questionnaire provided scores on five factors (conduct problems, hyperactivity, attention problems, anxiety and physical complaints). Compared with normal controls children with epilepsy showed much higher rates of sleep disorders, particularly poor quality sleep and anxieties about sleep. In children aged 5-11 years associations were found between disturbed daytime behaviour and sleep problems, particularly poor quality sleep. There was also a significant association between seizure frequency and anxieties about sleeping. This study highlights the potentially serious psychological and other developmental implications of persistent sleep disturbance to children with epilepsy, and the need for further research on specific types of epilepsy with careful identification of the nature of both sleep disturbance and related psychological dysfunction.

Effect of venlafaxine on pineal melatonin and noradrenaline in the male rat.

Studies in vitro indicate that the antidepressant drug, venlafaxine (VEN), inhibits the reuptake of both serotonin (5-hydroxytryptamine, 5-HT) and noradrenaline (NA) but has little activity on other neurotransmitter receptors. There are, however, few studies on the effects of VEN on monoamine neurotransmission in vivo. In the present study we examined the effect of VEN treatment on the melatonin content of the rat pineal gland because the synthesis of melatonin is regulated by the release of NA onto pinealocyte beta-adrenoceptors. Acute treatment with higher doses (15 mg/kg) of VEN significantly increased pineal melatonin and NA but this effect was attenuated by subchronic treatment. These data are consistent with in vitro data suggesting that VEN increases NA neurotransmission at higher doses and that repeated treatment can desensitize pinealocyte beta-adrenoceptors.

Sumatriptan decreases food intake and increases plasma growth hormone in healthy women.

We studied the effect of the 5-HT1B/ID receptor agonist sumatriptan (6 mg s.c.) on plasma growth hormone and prolactin and food intake in 15 healthy female subjects using a double-blind, placebo-controlled, cross-over design. Sumatriptan significantly elevated plasma growth hormone but did not alter plasma prolactin. Sumatriptan also significantly lowered total food intake in a buffet meal, particularly decreasing the intake of fat. Our results indicate that 5-HT1B/ID receptors may be involved in the regulation of food intake in humans. In addition, while activation of 5-HT1B/ID receptors stimulates growth hormone release in both men and women, sumatriptan lowers plasma prolactin only in men, suggesting sex differences in the 5-HT regulation of prolactin release.

Paroxetine treatment and the prolactin response to sumatriptan.

We studied the effect of the selective serotonin re-uptake inhibitor (SSRI), paroxetine (20 mg daily for 16 days) on the neuroendocrine, cardiovascular, thermic and subjective responses to the 5-HT1D receptor agonist, sumatriptan (6 mg, SC). Compared to placebo injection, sumatriptan lowered plasma prolactin and oral temperature and increased diastolic blood pressure. While paroxetine increased baseline prolactin concentration, it had no effect on any of the responses to sumatriptan. In addition, paroxetine did not alter concentrations of sumatriptan in plasma. No adverse reactions resulted from the combination of sumatriptan and paroxetine. Our findings suggest that combined treatment with sumatriptan and paroxetine in the doses used in this study is not necessarily contra-indicated. In addition, short-term SSRI treatment may not desensitise 5-HT1D autoreceptors in humans.

Use of a dietary manipulation to deplete plasma tyrosine and phenylalanine in healthy subjects.

The aim of the present study was to lower plasma concentrations of tyrosine, the amino acid precursor of noradrenaline and to determine whether this manipulation impaired noradrenergic function as measured by the evening rise in concentrations of plasma melatonin. Eight healthy volunteers received three drinks: (i) an essential amino acid load with tyrosine, (ii) the same load without tyrosine and its precursor, phenylalanine and (iii) tap water. The tyrosine- and phenylalanine-deficient drink lowered plasma tyrosine by approximately 50% over 5 h. However, this did not alter the evening plasma melatonin levels compared to the other two drinks. The results suggest that amino acid loading produces a modest decline in plasma tyrosine levels but this does not lower noradrenergic neurotransmission in the pineal gland.

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.

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.

Effect of lofepramine on 5-HT function and sleep.

We studied the effect of the tricyclic antidepressant lofepramine (140-210 mg daily for 16 days) on 5-hydroxytryptamine 1A (5-HT1A) receptor sensitivity in healthy volunteers, using a buspirone neuroendocrine challenge paradigm (30 mg orally). We also studied the effect of lofepramine on platelet 5-HT content and sleep architecture. Lofepramine treatment did not alter the hypothermic, endocrine or amnesic effects of buspirone but significantly lowered platelet 5-HT content and decreased rapid eye movement sleep. Our findings suggest that at clinically used doses, lofepramine inhibits the uptake of 5-HT and produces changes in sleep architecture characteristic of tricyclic antidepressants. However, lofepramine does not appear to alter the sensitivity of 5-HT1A receptors.

Attenuation of some alcohol-induced mood changes and the desire to drink by 5-HT3 receptor blockade: a preliminary study in healthy male volunteers.

We studied the effect of the 5-HT3 receptor antagonist ondansetron (4 mg orally) on some of the psychological effects of a small dose of alcohol (580 ml of 3.6% alcohol content by volume of lager) in 16 healthy male volunteers using a double-blind placebo controlled, Latin Square cross-over design. Pretreatment with ondansetron significantly attenuated several of the subjective pleasurable effects of alcohol, and also decreased the subjective desire to drink. These findings are consistent with preclinical studies suggesting that the reinforcing properties of alcohol may be attenuated by 5-HT3 receptor blockade.

Neuroendocrine and temperature effects of nefazodone in healthy volunteers.

The effects of a novel antidepressant, nefazodone (50 mg, 100 mg, and 200 mg orally) on neuroendocrine function and temperature were assessed using a single-blind, crossover design in eight healthy male volunteers. Nefazodone significantly increased plasma levels of prolactin (PRL) and raised oral temperature. There was also a trend towards an increase in plasma cortisol. These results are consistent with an acute facilitatory effect of some aspects of 5-HT neurotransmission, perhaps mediated through nefazodone's metabolism to its major metabolite, m-chlorophenylpiperazine (mCPP).

Alpha-2-adrenoceptor control of cortisol and ACTH in normal volunteers: preliminary open trial of the effects of acute and chronic idazoxan.

To examine the role of alpha 2-adrenoceptors in the control of cortisol and ACTH, hormone responses to the selective alpha 2-antagonist idazoxan were studied in 12 normal volunteers. Plasma cortisol and ACTH were measured from 0930h-1230h on three occasions: before, on the 1st day, and on the 22nd day of an open treatment trial with idazoxan 40 mg administered three times per day. Compared with pretreatment cortisol levels, acute but not chronic idazoxan treatment attenuated the normal diurnal fall in plasma cortisol. Plasma ACTH concentrations were not altered by either dose of idazoxan. The attenuation of the diurnal fall in cortisol after acute idazoxan may be mediated through increased central availability of norepinephrine, and is similar to responses after high doses of the less selective alpha 2-antagonist yohimbine. Activity of central noradrenergic neurons appears to be reduced or normalized by chronic idazoxan, indicated by restoration of the normal diurnal fall in cortisol.

Does metergoline selectively attenuate 5-HT mediated prolactin release?

Administration of the non-selective 5-HT receptor antagonist metergoline (0.5 mg/kg) to male rats attenuated the prolactin response to the 5-HT releasing agent d-fenfluramine (7.5 mg/kg) but not to the dopamine receptor antagonist haloperidol (1.5 mg/kg). In contrast, in healthy male volunteers, pretreatment with metergoline (4 mg orally) abolished the prolactin response to intravenous haloperidol (5 micrograms/kg). The findings suggest that in humans blockade of a prolactin response by a conventional oral dose of metergoline cannot be taken as evidence of involvement of 5-HT-mediated mechanisms.

Acute and chronic idazoxan in normal volunteers: biochemical, physiological and psychological effects.

The acute and chronic effects of the selective a(2)-antagonist idazoxan were studied in 12 normal volunteers. Plasma 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), blood pressure and psychological responses to oral challenge doses of idazoxan 40 mg were measured twice, on the first and 22nd day of treatment with idazoxan 40 mg t.d.s. Changes in nocturnal melatonin output were studied on six occasions, before, during and after idazoxan treatment. Although baseline MHPG levels were significantly reduced after chronic treatment with idazoxan, idazoxan challenge did not alter MHPG concentrations on either test day. A small rise in systolic blood pressure occurred after acute but not chronic idazoxan challenge tests. Systolic blood pressure values were significantly lower during the chronic compared with the acute test. Diastolic blood pressure and heart rate were not affected by acute or chronic treatment. Subjects reported increases in self- ratings of arousal and reductions in sedation and anxiety of similar magnitude after acute and chronic idazoxan. Nocturnal plasma melatonin secretion was not altered by drug administration or withdrawal, although urinary 6-sulphatoxymelatonin excretion was significantly reduced on acute withdrawal. The increase in systolic blood pressure and arousal self-ratings after acute idazoxan are in accordance with the reported effects of other a(2)-antagonists, although we did not find increased anxiety or elevated plasma MHPG levels. Chronic idazoxan appears to reduce or normalize activity of noradrenergic systems, indicated by reduced baseline systolic blood pressure and MHPG, and loss of the pressor response to idazoxan. Withdrawal of idazoxan leads to an abrupt fall in noradrenergic activity, as demonstrated by the fall in urinary 6-sulphatoxymelatonin.