Chronic treatment with a tryptophan-rich protein hydrolysate improves emotional processing, mental energy levels and reaction time in middle-aged women.

Common pharmacological treatments of mood disorders aim to modulate serotonergic neurotransmission and enhance serotonin levels in the brain. Brain serotonin levels are dependent on the availability of its food-derived precursor essential amino acid tryptophan (Trp). We tested the hypothesis that delivery of Trp via food may serve as an alternative treatment, and examined the effects of a Trp-rich, bioavailable dietary supplement from egg protein hydrolysate on cognitive and emotional functions, mood state, and sleep quality. In a randomised, placebo-controlled, parallel trial, fifty-nine mentally and physically healthy women aged 45-65 years received placebo (n 30) or the supplement (n 29) (both as 0.5 g twice per d) for 19 d. Emotional processing was significantly changed by supplementation, exhibiting a shift in bias away from negative stimuli. The results for the Affective Go/No-Go Task exhibited a slowing of responses to negative words, suggesting reduced attention to negative emotional stimuli. The results for the Facial Emotional Expression Rating Task also supported a shift away from attention to negative emotions and a bias towards happiness. An increase in arousal-like symptoms, labelled 'high energy', shorter reaction times and a slight benefit to sustained attention were observed in the treated subjects. Finally, when the supplement was taken 60-90 min before bedtime, a feeling of happiness before going to bed was consistently reported. In summary, daily consumption of a low-dose supplement containing bioavailable Trp may have beneficial effects on emotional and cognitive functions.

Central serotonin and melanocortin pathways regulating energy homeostasis.

It is now established that the hypothalamus is essential in coordinating endocrine, autonomic, and behavioral responses to changes in energy availability. However, the interaction of key peptides, neuropeptides, and neurotransmitters systems within the hypothalamus has yet to be delineated. Recently, we investigated the mechanisms through which central serotonergic (5-hydroxytryptamine, 5-HT) systems recruit leptin-responsive hypothalamic pathways, such as the melanocortin systems, to affect energy balance. Through a combination of functional neuroanatomy, feeding, and electrophysiology studies in rodents, we found that 5-HT drugs require functional melanocortin pathways to exert their effects on food intake. Specifically, we observed that anorectic 5-HT drugs activate pro-opiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (Arc). We provide evidence that the serotonin 2C receptor (5-HT(2C)R) is expressed on POMC neurons and contributes to this effect. Finally, we found that 5-HT drug-induced hypophagia is attenuated by pharmacological or genetic blockade of downstream melanocortin 3 and 4 receptors. We review candidate brain regions expressing melanocortin 3 and 4 receptors that play a role in energy balance. A model is presented in which activation of the melanocortin system is downstream of 5-HT and is necessary to produce the complete anorectic effect of 5-HT drugs. The data reviewed in this paper incorporate the central 5-HT system to the growing list of metabolic signals that converge on melanocortin neurons in the hypothalamus.

The effect of 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') and its metabolites on neurohypophysial hormone release from the isolated rat hypothalamus.

Methylenedioxymethamphetamine (MDMA, 'ecstasy'), widely used as a recreational drug, can produce hyponatraemia. The possibility that this could result from stimulation of vasopressin by MDMA or one of its metabolites has been investigated in vitro. Release of both oxytocin and vasopressin from isolated hypothalami obtained from male Wistar rats was determined under basal conditions and following potassium (40 mM) stimulation. The results were compared with those obtained for basal and stimulated release in the presence of MDMA or metabolites in the dose range 1 microM to 100 pM (n=5 - 8) using Student's t-test with Dunnett's correction for multiple comparisons. All compounds tested affected neurohypophysial hormone release, HMMA (4-hydroxy-3-methoxymethamphetamine) and DHA (3,4-dihydroxyamphetamine) being more active than MDMA, and DHMA (3,4-dihydroxymethamphetamine) being the least active. The effect on vasopressin release was greater than that on oxytocin. In the presence of HMMA the ratio test:control for basal release increased for vasopressin from 1.1+/-0.16 to 2.7+/-0.44 (s.e.m., P<0.05) at 10 nM and for oxytocin from 1.0+/-0.05 to 1.6+/-0.12 in the same hypothalami. For MDMA the ratio increased to 1.5+/-0.27 for vasopressin and to 1.28+/-0.04 for oxytocin for 10 nM. MDMA and its metabolites can stimulate both oxytocin and vasopressin release in vitro, the response being dose dependent for each drug with HMMA being the most potent.

Docosahexaenoic and arachidonic acid prevent a decrease in dopaminergic and serotoninergic neurotransmitters in frontal cortex caused by a linoleic and alpha-linolenic acid deficient diet in formula-fed piglets.

This study examined the effects of diets deficient (D) in linoleic [18:2(n-6)] and linolenic acid [18:3(n-3)] at 0.8 and 0.05% energy, respectively, or adequate (C) in 18:2(n-6) and 18:3(n-3) at 8.3 and 0.8% energy, respectively, without (-) or with (+) 0.2% energy arachidonic [20:4(n-6)] and 0.16% energy docosahexaenoic [22:6(n-3)] acid in piglets fed from birth to 18 d. Frontal cortex dopaminergic and serotoninergic neurotransmitters and phospholipid fatty acids were measured. Piglets fed the D- diet had significantly lower frontal cortex dopamine, 3,4-dihydroxyphenylacetic (DOPAC), homovanillic acid (HVA), serotonin and 5-hydroxyindoleacetic acid (5-HIAA) concentrations than did piglets fed the C- diets. Frontal cortex dopamine, norepinephrine, DOPAC, HVA, serotonin and 5-HIAA were higher in piglets fed the D+ compared to those fed the D- diet (P < 0.05) and not different between piglets fed the D+ and those fed the C- diets or the C- and C+ diets. Piglets fed the D- diet had lower frontal cortex phosphatidylcholine (PC) and phosphatidylinositol (PI) 20:4(n-6) and PC and phosphatidylethanolamine (PE) 22:6(n-3) than did piglets fed the C- diet (P < 0.05). Piglets fed the D+ diet had higher frontal cortex PC and PI 20:4(n-6) and PC, PE, PS and PI 22:6(n-3) than did piglets fed the D- diet. These studies show that dietary essential fatty acid deficiency fed for 18 d from birth affects frontal cortex neurotransmitters in rapidly growing piglets and that these changes are specifically due to 20:4(n-6) and/or 22:6(n-3).

Platelet [3H]paroxetine and [3H]lysergic acid diethylamide binding in seasonal affective disorder and the effect of bright light therapy.

BACKGROUND: Seasonal affective disorder (SAD) has been regarded as a melatonin disorder, but the pathophysiological mechanisms of SAD are to a large extent unclarified. Serotonergic mechanisms have also been studied, but they have shown inconsistent results. METHODS: We have compared [3H]paroxetine and [3H]lysergic acid diethylamide (LSD) binding in platelets from 23 SAD patients and 23 controls. Then SAD patients had 4 weeks of light therapy. On the last treatment day new blood samples were drawn. Symptoms before and after light treatment were measured by SIGH-SAD. RESULTS: Bmax for paroxetine binding before light treatment was higher in SAD patients compared to controls and also higher in responders than in nonresponders. Bmax decreased significantly during light treatment. We also found a negative correlation between the two Bmax values before but not after light treatment. There was a negative correlation between Bmax for paroxetine binding before treatment and clinical status after treatment. Patients with reduced Bmax for LSD binding after treatment had a better clinical treatment response. CONCLUSIONS: The present study indicates that serotonin receptor parameters might be suitable in the prediction of clinical response to light treatment.

The effect of N-methylation on fenfluramine's neurotoxic and pharmacologic actions.

N-Methylation separates methamphetamine's neurotoxic and pharmacologic effects. In particular, N-methylation eliminates methamphetamine's neurotoxic activity while preserving its behavioral pharmacologic activity. The purpose of the present studies was to determine whether N-methylation could also be used to separate fenfluramine's neurotoxic and pharmacologic effects. Fenfluramine-induced serotonin neurotoxicity was assessed by measuring serotonin axonal markers 2 weeks after fenfluramine administration. Pharmacologic effects of fenfluramine were assessed by measuring fenfluramine-induced anorexia and fenfluramine discrimination. Both fenfluramine and its N-methylated analog, N-methylfenfluramine, produced dose-related effects in food intake, drug-discrimination and neurotoxicity studies. Although N-methylation reduced the neurotoxic potency of fenfluramine, it also reduced its pharmacologic activity. Neurotoxic potency was reduced 4- to 8-fold (depending on brain region), while pharmacologic potency was reduced 4- to 10-fold (depending on paradigm). Notably, N-methylation did not change the efficacy of fenfluramine as a serotonin neurotoxin, anorectic agent or discrimination stimulus. These results indicate that fenfluramine's behavioral and neurotoxic effects, unlike those of methamphetamine, are not dissociated by N-methylation. Further, the present results suggest that the effectiveness of side-chain nitrogen substitution in separating the behavioral and neurotoxic effects of amphetamine derivatives is strongly influenced by ring substitutions.