We show here that the transcription factor Npas4 is an important regulator of medium spiny neuron spine density and electrophysiological parameters and that it determines the magnitude of cocaine‐induced hyperlocomotion in mice. Npas4 is induced by synaptic stimuli that cause calcium influx, but not dopaminergic or PKA‐stimulating input, in mouse medium spiny neurons and human iPSC‐derived forebrain organoids. This induction is independent of ubiquitous kinase pathways such as PKA and MAPK cascades, and instead depends on calcineurin and nuclear calcium signalling. Npas4 controls a large regulon containing transcripts for synaptic molecules, such as NMDA receptors and VDCC subunits, and determines in vivo MSN spine density, firing rate, I/O gain function and paired‐pulse facilitation. These functions at the molecular and cellular levels control the locomotor response to drugs of abuse, as Npas4 knockdown in the nucleus accumbens decreases hyperlocomotion in response to cocaine in male mice while leaving basal locomotor behaviour unchanged.

D2R-NMDAR receptor heteromers are potential therapeutic targets in drug addiction.

No abstract

Drug addiction is defined as a compulsive pattern of drug-seeking- and taking- behavior, with recurrent episodes of abstinence and relapse, and a loss of control despite negative consequences. Addictive drugs promote reinforcement by increasing dopamine in the mesocorticolimbic system, which alters excitatory glutamate transmission within the reward circuitry, thereby hijacking reward processing. Within the reward circuitry, the striatum is a key target structure of drugs of abuse since it is at the crossroad of converging glutamate inputs from limbic, thalamic and cortical regions, encoding components of drug-associated stimuli and environment, and dopamine that mediates reward prediction error and incentive values. These signals are integrated by medium-sized spiny neurons (MSN), which receive glutamate and dopamine axons converging onto their dendritic spines. MSN primarily form two mostly distinct populations based on the expression of either DA-D1 (D1R) or DA-D2 (D2R) receptors. While a classical view is that the two MSN populations act in parallel, playing antagonistic functional roles, the picture seems much more complex. Herein, we review recent studies, based on the use of cell-type-specific manipulations, demonstrating that dopamine differentially modulates dendritic spine density and synapse formation, as well as glutamate transmission, at specific inputs projecting onto D1R-MSN and D2R-MSN to shape persistent pathological behavioral in response to drugs of abuse. We also discuss the identification of distinct molecular events underlying the detrimental interplay between dopamine and glutamate signaling in D1R-MSN and D2R-MSN and highlight the relevance of such cell-type-specific molecular studies for the development of innovative strategies with potential therapeutic value for addiction. Because drug addiction is highly prevalent in patients with other psychiatric disorders when compared to the general population, we last discuss the hypothesis that shared cellular and molecular adaptations within common circuits could explain the co-occurrence of addiction and depression. We will therefore conclude this review by examining how the nucleus accumbens (NAc) could constitute a key interface between addiction and depression.

Background In the context of the Covid-19 pandemic and following the increasing number of suspicious Covid-19 cases in Madagascar, Malagasy laboratories are overflowed mainly due to lack of human resource and available material restriction. The development and validation of rapid and easy-to-perform diagnostic methods are worth of interest and high priority. The aim of this prospective study was to evaluate the performances of a rapid immunochromatographic test for the detection of SARS-CoV-2 antigen, in comparison to Reverse transcription polymerase chain reaction (RT-PCR). Methods The fluorescence immunochromatographic SARS-CoV-2 antigen test StandardTM Q COVID-19 Ag Test (SD Biosensor Republic Korea) was evaluated in samples derived from patients who were examined for disease categories. Diagnostic accuracy was determined in comparison to SARS-CoV-2 RT-PCR considered as gold standard. Results A total of 200 samples were included; 94 were RT-PCR positive. Median patients’ age was 38.36 years, 63.5 % were male. Overall sensitivity and specificity of the Standard TM Q COVID-19 Ag (SD Biosensor® Republic Korea) were 62.66% and 100%, the sensitivity was significantly higher (100%) in samples with high viral loads (Ct<29). Conclusions This antigen-based immunofluorescence RDT could be the potential to become an important tool for the early diagnosis of SARS-CoV-2 particularly in situations with limited access to molecular methods particularly in rural area of Madagascar.

The persistent and experience-dependent nature of drug addiction may result in part from epigenetic alterations, including non-coding micro-RNAs (miRNAs), which are both critical for neuronal function and modulated by cocaine in the striatum. Two major striatal cell populations, the striato-nigral and striato-pallidal projection neurons, express, respectively, the D1 (D1-SPNs) and D2 (D2-SPNs) dopamine receptor, and display distinct but complementary functions in drug-evoked responses. However, a cell-type-specific role for miRNAs action has yet to be clarified. Here, we evaluated the expression of a subset of miRNAs proposed to modulate cocaine effects in the nucleus accumbens (NAc) and dorsal striatum (DS) upon sustained cocaine exposure in mice and showed that these selected miRNAs were preferentially upregulated in the NAc. We focused on miR-1 considering the important role of some of its predicted mRNA targets, Fosb and Npas4, in the effects of cocaine. We validated these targets in vitro and in vivo. We explored the potential of miR-1 to regulate cocaine-induced behavior by overexpressing it in specific striatal cell populations. In DS D1-SPNs miR-1 overexpression downregulated Fosb and Npas4 and reduced cocaine-induced CPP reinstatement, but increased cue-induced cocaine seeking. In DS D2-SPNs miR-1 overexpression reduced the motivation to self-administer cocaine. Our results indicate a role of miR1 and its target genes, Fosb and Npas4, in these behaviors and highlight a precise cell-type- and region-specific modulatory role of miR-1, illustrating the importance of cell-specific investigations.

Introduction: On contact of antibiotics, S. aureus has gradually acquired multiple antibiotic resistances, including the methicillin (MRSA) and without lose its virulence. The aim of the present study was to report the evolution of resistance of S. aureus to different common antibiotics and to determine the antibiotics active against MRSA. Materials and methods: This is a retrospective and descriptive study for 10 years from January 2005 to December 2014 at the Laboratory of Microbiology of the HU-JRA Antananarivo, the biggest academic hospital located in the capital of Madagascar. All demands for standard bacteriological examination were registered in the laboratory for various bacteriological exams or from samples taken from hospitalized patients and we included all positive cultures for S. aureus. The variables selected and used for the study were community or nosocomial sources of patients and results of susceptibility testing. Results: A total of 906 results from 282 (31.12%) community-acquired and 624 (68.88%) nosocomial infections were studied an average of 100±25strains by year of study. Overall, the prevalence of MRSA was 13.83% (39 of 282 isolates)for community-acquired strains, and 15.70% (98 of 624) for nosocomial infections (p> 0.05)with a total of 29.53%. Resistance rate to trimethoprim-sulfamethoxazole was significantly higher in nosocomial infection than in community-acquired. No significant difference was observed in other antibiotics. Of the 137 MRSA, except vancomycin, fusidic acid is the antibiotic that worked the most in 114 cases (83.21%) followed by gentamicin in 96 cases (70.07%). Apart from ciprofloxacin and tetracycline that we have noticed an increase in resistance rates in 2012 and 2013, almost all antibiotics tested have a stable rate of resistance. Conclusion: The antibiotics tested showed extremely high rates of resistance and that the problem of antibiotic resistance in S. aureus is effective in our center.

Pseudomonas aeruginosa has the ability to resist almost all available antibiotics by rapidly accumulating multiple resistance mechanisms and thus lead to a therapeutic impasse and higher mortality in infected patients. The objective of this study was to assess the phenotypic variation in resistance to tobramycin and ofloxacin from Pseudomonas aeruginosa by repeated exhibition after determination of the minimum inhibitory concentration. This is a prospective and descriptive study carried out in the Laboratory of Microbiology of Fundamental and Applied Biochemistry (Faculty of Sciences, Antananarivo) during the month of January 2020. The strains studied were the virulent wild strain of Pseudomonas aeruginosa PAO1 supplied by the Laboratory and two clinical strains of Pseudomonas aeruginosa from the Microbiology Laboratory of the Joseph Ravoahangy Andrianavalona University Hospital Center, Antananarivo. The strains of P. aeruginosa were cultured in the liquid culture medium (which is Luria Bertani, added with a buffer system of 3- (N-morpholino) propanesulfonic acid (LB-MOPS) which will stabilize the pH and a solid culture medium which is Columbia agar. Repeated exhibition to Tobramycin and Ofloxacin from these strains have been made. The MIC is determined by a visual evaluation of the turbidity of the various wells of the microplate. The MIC value of Pseudomonas aeruginosa with tobramycin and ofloxacin is very variable for the initial MIC until the 5th generation after repeated exhibition. More Pseudomonas aeruginosa is exposed to an antibiotic many times, the more it develops resistance to this antibiotic, even being sensitive at the start. That is to say, clinically, the dose prescribed for the antibiotic has been greatly exceeded if Pseudomonas aeruginosa is repeatedly exposed to the same antibiotic.