Effects of Acute Tryptophan Depletion on Brain Serotonin Function and Concentrations of Dopamine and Norepinephrine in C57BL/6J and BALB/cJ Mice

Acute tryptophan depletion (ATD) is a method of lowering brain serotonin (5-HT). Administration of large neutral amino acids (LNAA) limits the transport of endogenous tryptophan (TRP) across the blood brain barrier by competition with other LNAAs and subsequently decreases serotonergic neurotransmission. A recent discussion on the specificity and efficacy of the ATD paradigm for inhibition of central nervous 5-HT has arisen. Moreover, side effects such as vomiting and nausea after intake of amino acids (AA) still limit its use. ATD Moja-De is a revised mixture of AAs which is less nauseating than conventional protocols. It has been used in preliminary clinical studies but its effects on central 5-HT mechanisms and other neurotransmitter systems have not been validated in an animal model. We tested ATD Moja-De (TRP−) in two strains of mice: C57BL/6J, and BALB/cJ, which are reported to have impaired 5-HT synthesis and a more anxious phenotype relative to other strains of mice. ATD Moja-De lowered brain TRP, significantly decreased 5-HT synthesis as indexed by 5-HTP levels after decarboxlyase inhibition, and lowered 5-HT and 5-HIAA in both strains of mice, however more so in C57BL/6J than in BALB/cJ. Dopamine and its metabolites as well as norepinephrine were not affected. A balanced (TRP+) control mixture did not raise 5-HT or 5-HIAA. The present findings suggest that ATD Moja-De effectively and specifically suppresses central serotonergic function. These results also demonstrate a strain- specific effect of ATD Moja-De on anxiety-like behavior

Clinical application of stem cell therapy in Parkinson's disease

Cell replacement therapies in Parkinson's disease (PD) aim to provide long-lasting relief of patients' symptoms. Previous clinical trials using transplantation of human fetal ventral mesencephalic (hfVM) tissue in the striata of PD patients have provided proof-of-principle that such grafts can restore striatal dopaminergic (DA-ergic) function. The transplants survive, reinnervate the striatum, and generate adequate symptomatic relief in some patients for more than a decade following operation. However, the initial clinical trials lacked homogeneity of outcomes and were hindered by the development of troublesome graft-induced dyskinesias in a subgroup of patients. Although recent knowledge has provided insights for overcoming these obstacles, it is unlikely that transplantation of hfVM tissue will become routine treatment for PD owing to problems with tissue availability and standardization of the grafts. The main focus now is on producing DA-ergic neuroblasts for transplantation from stem cells (SCs). There is a range of emerging sources of SCs for generating a DA-ergic fate in vitro. However, the translation of these efforts in vivo currently lacks efficacy and sustainability. A successful, clinically competitive SC therapy in PD needs to produce long-lasting symptomatic relief without side effects while counteracting PD progression

Selective effects of partial and severe lesions of the serotonergic systems on Met-enkephalin and substance P neurons in rat basal ganglia.

International audienceThe effects of partial (80%) vs. severe (> 95%) depletion of serotonin (5-HT) on peptide expression in basal ganglia were examined using immunocytochemical and in situ hybridization histochemical approaches. Topographical analysis of the changes in Met-enkephalin (Met-enk) and substance P (SP) levels were performed on the rat striatum, globus pallidus and substantia nigra 3 weeks after injecting 3 microl (partial lesion) or 6 microl (severe lesion) 5,7-dihydroxytryptamine (6.6 microg/microl) into the anterior raphe nuclei. Both kinds of lesion led to significant increases (39-42%) in Met-enk immunoreactivity in the striatum; a corresponding increase (21%) was detected in the globus pallidus only after severe 5-HT depletion. Only the severe lesion increased the SP immunoreactivity in the striatum (32%) and substantia nigra (26%). Neither striatal preproenkephalin nor preprotachykinin levels showed significant differences with the control values. These results suggest that the neuronal accumulation of Met-enk or SP may be attributable to post-transcriptional events, such as a blockade of the peptide release, and that 5-HT may, thus, exert a facilitatory influence on the striatal output neurons. The results obtained after partial lesion indicate a preferential sensitivity of striatal Met-enk vs. SP containing terminals to the 5-HT denervation. These differences are illustrated in selective regional changes in peptide labeling. These data point to some balance exerted by the serotonergic and dopaminergic inputs on these neuronal populations