Rapid Dopaminergic Modulation of the Fish Hypothalamic Transcriptome and Proteome

Background - Dopamine (DA) is a major neurotransmitter playing an important role in the regulation of vertebrate reproduction. We developed a novel method for the comparison of transcriptomic and proteomic data obtained from in vivo experiments designed to study the neuroendocrine actions of DA. // Methods and Findings - Female goldfish were injected (i.p.) with DA agonists (D1-specific; SKF 38393, or D2-specific; LY 171555) and sacrificed after 5 h. Serum LH levels were reduced by 57% and 75% by SKF 38393 and LY 171555, respectively, indicating that the treatments produced physiologically relevant responses in vivo. Bioinformatic strategies and a ray-finned fish database were established for microarray and iTRAQ proteomic analysis of the hypothalamus, revealing a total of 3088 mRNAs and 42 proteins as being differentially regulated by the treatments. Twenty one proteins and mRNAs corresponding to these proteins appeared on both lists. Many of the mRNAs and proteins affected by the treatments were grouped into the Gene Ontology categorizations of protein complex, signal transduction, response to stimulus, and regulation of cellular processes. There was a 57% and 14% directional agreement between the differentially-regulated mRNAs and proteins for SKF 38393 and LY 171555, respectively. // Conclusions - The results demonstrate the applicability of advanced high-throughput genomic and proteomic analyses in an amendable well-studied teleost model species whose genome has yet to be sequenced. We demonstrate that DA rapidly regulates multiple hypothalamic pathways and processes that are also known to be involved in pathologies of the central nervous system

DMTs and Covid-19 severity in MS: a pooled analysis from Italy and France

We evaluated the effect of DMTs on Covid-19 severity in patients with MS, with a pooled-analysis of two large cohorts from Italy and France. The association of baseline characteristics and DMTs with Covid-19 severity was assessed by multivariate ordinal-logistic models and pooled by a fixed-effect meta-analysis. 1066 patients with MS from Italy and 721 from France were included. In the multivariate model, anti-CD20 therapies were significantly associated (OR = 2.05, 95%CI = 1.39–3.02, p < 0.001) with Covid-19 severity, whereas interferon indicated a decreased risk (OR = 0.42, 95%CI = 0.18–0.99, p = 0.047). This pooled-analysis confirms an increased risk of severe Covid-19 in patients on anti-CD20 therapies and supports the protective role of interferon

CB1-independent inhibition of dopamine transporter activity by cannabinoids in mouse dorsal striatum

The original publication may be found at www.blackwell-synergy.comCannabinoid drugs are known to affect dopaminergic neurotransmission in the basal ganglia circuitry. In this study, we used in vitro and in vivo techniques to investigate whether cannabinoid agonists and antagonist could affect dopaminergic transmission in the striatum by acting at the dopamine transporter. Incubation of striatal synaptosomes with the cannabinoid agonists WIN55,212-2 or methanandamide decreased dopamine uptake (IC50 = 2.0 μmol/L and 3.1 μmol/L, respectively). A similar inhibitory effect was observed after application of the inactive WIN55,212-2 isomer, S(−)WIN55,212-3. The CB1 antagonist AM251 did not reverse WIN55,212-2 effect but rather mimicked it. WIN55,212-2 and AM251 partially displaced the binding of the cocaine analog [3H]WIN35,428, thus acting as dopamine transporter pseudo-substrates in the high micromolar range. High-speed chronoamperometry measurements showed that WIN55,212-2 (4 mg/kg, i.p.) caused significant release of endogenous dopamine via activation of CB1 receptors, followed by a reduction of dopamine clearance. This reduction was CB1-independent, as it was mimicked by S(−)WIN55,212-3. Administration of AM251 (1 and 4 mg/kg, i.p.) increased the signal amplitude and reduced the clearance of dopamine pressure ejected into the striatum. These results indicate that both cannabinoid agonists and antagonists inhibit dopamine transporter activity via molecular targets other than CB1 receptors.Price, David A., Owens, William A., Gould, Georgianna G., Frazer, Alan, Roberts, James L., Daws, Lynette C., Giuffrida, Andre

Differences in the metabolism of the aromatic amino acid hydroxylase cofactor, tetrahydrobiopterin, in mutant mice with neurological and immunological defects.

Tetrahydrobiopterin (BH4) levels and GTP cyclohydrolase activity (GTP-CH) were measured in tissues from mutants and controls of 24 different mouse strains to identify mutants that might be suitable models for diseases which are characterized by a deficiency of the biopterin cofactor, such as parkinsonism and atypical phenylketonuria. BH4 levels and GTP-CH activity were determined in brain, liver, and spleen obtained from 24 mutants with neurological or immunological defects. BH4 levels in brain were slightly but significantly decreased in only two mutants, spastic (spa) and jittery (ji), while GTP-CH activity in brain was not significantly lower than controls in any of the strains examined. GTP-CH levels in liver were significantly decreased in four mutant strains (jittery, ji; leaner, tgla; reeler, rl; and anorexia, anx); however, BH4 levels were significantly lower only in the mutant anorexia (anx). The most significant and widespread changes in both BH4 levels and GTP-CH activity were observed in spleen. In those mutants which were most affected, BH4 levels and GTP-CH activity were decreased 85-90%