Effects of acute tryptophan depletion on raphé functional connectivity in depression.

Depression remains a great societal burden and a major treatment challenge. Most antidepressant medications target serotonergic raphé nuclei. Acute tryptophan depletion (ATD) modulates serotonin function. To better understand the raphé's role in mood networks, we studied raphé functional connectivity in depression. Fifteen depressed patients were treated with sertraline for 12 weeks and scanned during ATD and sham conditions. Based on our previous findings in a separate cohort, resting state MRI functional connectivity between raphé and other depression-related regions (ROIs) was analyzed in narrow frequency bands. ATD decreased raphé functional connectivity with the bilateral thalamus within 0.025-0.05 Hz, and also decreased raphé functional connectivity with the right pregenual anterior cingulate cortex within 0.05-0.1 Hz. Using the control broadband filter 0.01-0.1 Hz, no significant differences in raphé-ROI functional connectivity were observed. Post-hoc analysis by remission status suggested increased raphé functional connectivity with left pregenual anterior cingulate cortex in remitters (n=10) and decreased raphé functional connectivity with left thalamus in non-remitters (n=5), both within 0.025-0.05 Hz. Reducing serotonin function appears to alter coordination of these mood-related networks in specific, low frequency ranges. For examination of effects of reduced serotonin function on mood-related networks, specific low frequency BOLD fMRI signals can identify regions implicated in neural circuitry and may enable clinically-relevant interpretation of functional connectivity measures. The biological significance of these low frequency signals detected in the raphé merits further study.

Chronic Effect of Aspartame on Ionic Homeostasis and Monoamine Neurotransmitters in the Rat Brain.

Aspartame is one of the most widely used artificial sweeteners globally. Data concerning acute neurotoxicity of aspartame is controversial, and knowledge on its chronic effect is limited. In the current study, we investigated the chronic effects of aspartame on ionic homeostasis and regional monoamine neurotransmitter concentrations in the brain. Our results showed that aspartame at high dose caused a disturbance in ionic homeostasis and induced apoptosis in the brain. We also investigated the effects of aspartame on brain regional monoamine synthesis, and the results revealed that there was a significant decrease of dopamine in corpus striatum and cerebral cortex and of serotonin in corpus striatum. Moreover, aspartame treatment significantly alters the tyrosine hydroxylase activity and amino acids levels in the brain. Our data suggest that chronic use of aspartame may affect electrolyte homeostasis and monoamine neurotransmitter synthesis dose dependently, and this might have a possible effect on cognitive functions.

Chronic tryptophan deprivation attenuates gating deficits induced by 5-HT(1A), but not 5-HT2 receptor activation.

The neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) exerts a multifaceted function in the modulation of information processing, through the activation of multiple receptor families. In particular, stimulation of 5-HT(1A) and 5-HT(2A) receptors leads to sensorimotor gating impairments and perceptual perturbations. Previous evidence has shown that chronic deprivation of L-tryptophan (TRP), the precursor of 5-HT, results in marked reductions of 5-HT brain levels, as well as neuroplastic alterations in 5-HT(1A) and 5-HT(2A) expression and/or signaling. Building on these premises, in the present study we tested whether a prolonged TRP deprivation may differentially impact the roles of these receptors in the regulation of the prepulse inhibition (PPI) of the acoustic startle reflex, a dependable index of gating. Male Sprague-Dawley rats were fed for 14 days with either a regimen with negligible TRP content (TR-) or the same diet supplemented of TRP (TR+). At the end of this schedule, rats were treated with the prototypical 5-HT(1A) receptor agonist 8-OH-DPAT (62.5-250 µg/kg, subcutaneous, s.c.) or the 5-HT2 receptor agonist DOI (0.25-1 mg/kg, s.c.). Notably, the PPI deficits induced by 8-OH-DPAT in TR- rats were significantly milder than those observed in their TR+ counterparts; these effects were fully prevented by the 5-HT(1A) antagonist WAY-100135 (10 mg/kg, intraperitoneal). Conversely, TRP deprivation did not affect the PPI-disrupting properties of DOI. These findings suggest that prolonged 5-HT depletion attenuates the influence of 5-HT(1A), but not 5-HT2 receptors on sensorimotor gating, confirming the distinct mechanisms of these two targets in PPI regulation.

Effects of high-dose large neutral amino acid supplementation on exercise, motor skill, and mental performance in Australian Rules Football players.

This study investigated the effects of high-dose large neutral amino acid (LNAA) supplementation on attenuating fatigue-induced decrements in exercise and motor skill performance in Australian Rules Football (ARF) players. Fifteen subelite ARF players participated in 3 testing sessions separated by 7 days. Players completed an initial control trial involving a reactive motor skills test (RMST) and a reactive agility test (RAT) carried out before and after fatiguing exercise. In the subsequent experimental trials, players ingested a serotonin-depleting or protein control (PC) LNAA mixture 3 h before testing, allocated in a double-blind randomized cross-over design. Blood samples were taken at presupplementation and pre- and postexercise for analysis of plasma amino acid, insulin, and metabolite concentrations. The effect of the LNAA was established as the difference in the change in the mean RMST and RAT test scores among the depleting, PC, and baseline (BL) trials. Mean overall repetition time of the RAT was moderately improved by -5.2% ± 3.4% (mean ± 90% confidence limits; effect size -0.45 ± 0.28) after ingestion of the serotonin-depleting mixture compared with the BL trial. Serotonin-depleting and PC supplements had a divergent effect on mean repetition time after fatiguing exercise in RMST: depleting serotonin elicited a small improvement (-3.0% ± 2.7%) in motor skill performance in contrast to a small decrement (2.4% ± 2.7%) after ingestion of the PC mixture, when compared to the BL. High-dose serotonin-"depleting" LNAA supplementation given 3 h prior to intermittent high-intensity exercise improved reactive motor skill and agility performance in ARF players.

[Pathogenetic and therapeutic aspects of secondary anorexia]. / Aspetti patogenetici e terapeutici dell'anoressia secondaria.

Anorexia is an often underrated symptom in the clinical management of patients suffering from chronic diseases. Moreover, the anorexia accompanying chronic diseases (secondary anorexia) is often confused with anorexia nervosa, a typically neuropsychiatric disorder involving completely different pathogenic mechanisms and therapeutic strategies. Secondary anorexia is one of the main factors responsible for the development of malnutrition, which in turn negatively affects patient morbidity and mortality. Different mechanisms have been proposed to explain the pathogenesis of secondary anorexia. However, consistent experimental and clinical evidence seems to point to hypothalamic serotonergic system hyperactivity as a preeminent cause; this hyperactivity appears to be triggered by enhanced brain availability of tryptophan, the aminoacid precursor of serotonin. The hyperactive hypothalamic serotonergic system might also represent the final effector where different regulatory and modulating pathways, including cytokines, converge. The involvement of tryptophan and the hypothalamic serotonergic system is further supported by the effectiveness of a therapeutic strategy, based on the inhibition of tryptophan entry into the brain, in increasing the food intake of anorectic patients. Although these results represent an encouraging approach to the treatment of secondary anorexia, with possible beneficial effects on the nutritional status of patients, they need to be validated in larger trials.