Impact of Substance Use Disorder Pharmacotherapy on Executive Function: A Narrative Review

Substance use disorders are chronic, relapsing, and harmful conditions characterized by executive dysfunction. While there are currently no approved pharmacotherapy options for stimulant and cannabis use disorders, there are several evidence-based options available to help reduce symptoms during detoxification and aid long-term cessation for those with tobacco, alcohol and opioid use disorders. While these medication options have shown clinical efficacy, less is known regarding their potential to enhance executive function. This narrative review aims to provide a brief overview of research that has investigated whether commonly used pharmacotherapies for these substance use disorders (nicotine, bupropion, varenicline, disulfiram, acamprosate, nalmefene, naltrexone, methadone, buprenorphine, and lofexidine) effect three core executive function components (working memory, inhibitory control and cognitive flexibility). While pharmacotherapy-induced enhancement of executive function may improve cessation outcomes in dependent populations, there are limited and inconsistent findings regarding the effects of these medications on executive function. We discuss possible reasons for the mixed findings and suggest some future avenues of work that may enhance the understanding of addiction pharmacotherapy and cognitive training interventions and lead to improved patient outcomes

Transcriptomic Characterization of the Human Habenula Highlights Drug Metabolism and the Neuroimmune System

Due to size and accessibility, most information about the habenula is derived from rodent studies. To better understand the molecular signature of the habenula we characterized the genes that have high expression in the habenula. We compared anatomical expression profiles of three normal adult human brains and four fetal brains. We used gene set enrichment analyses to determine if genes annotated to specific molecular functions, cellular components, and biological processes are enriched in the habenula. We also tested gene sets related to depression and addiction to determine if they uniquely involve the habenula. As expected, we observed high habenular expression of GPR151, nicotinic cholinergic receptors, and cilia-associated genes (medial division). Genes identified in genetic studies of smoking and associated with nicotine response were enriched in the habenula. Genes associated with major depressive disorder did not have enriched expression in the habenula but genes negatively correlated with hedonic well-being were, providing a link to anhedonia. We observed enrichment of genes associated with diseases that are comorbid with addictions (hematopoiesis, thrombosis, liver cirrhosis, pneumonia, and pulmonary fibrosis) and depression (rheumatoid arthritis, multiple sclerosis, and kidney disease). These inflammatory diseases mark a neuroimmune signature that is supported by genes associated with mast cells, acute inflammatory response, and leukocyte migration. We also found enrichment of cytochrome p450 genes suggesting the habenula is uniquely sensitive to endogenous and xenobiotic compounds. Our results suggest the habenula receives negative reward signals from immune and drug processing molecules. This is consistent with the habenular role in the “anti-reward” system and suggests it may be a key bridge between autoimmune disorders, drug use, and psychiatric diseases

Consequences of cell-to-cell P-glycoprotein transfer on acquired multidrug resistance in breast cancer: a cell population dynamics model

Cancer is a proliferation disease affecting a genetically unstable cell population, in which molecular alterations can be somatically inherited by genetic, epigenetic or extragenetic transmission processes, leading to a cooperation of neoplastic cells within tumoral tissue. The efflux protein P-glycoprotein (P gp) is overexpressed in many cancer cells and has known capacity to confer multidrug resistance to cytotoxic therapies. Recently, cell-to-cell P-gp transfers have been shown. Herein, we combine experimental evidence and a mathematical model to examine the consequences of an intercellular P-gp trafficking in the extragenetic transfer of multidrug resistance from resistant to sensitive cell subpopulations. We report cell-to-cell transfers of functional P-gp in co-cultures of a P-gp overexpressing human breast cancer MCF-7 cell variant, selected for its resistance towards doxorubicin, with the parental sensitive cell line. We found that P-gp as well as efflux activity distribution are progressively reorganized over time in co-cultures analyzed by flow cytometry. A mathematical model based on a Boltzmann type integro-partial differential equation structured by a continuum variable corresponding to P-gp activity describes the cell populations in co-culture. The mathematical model elucidates the population elements in the experimental data, specifically, the initial proportions, the proliferative growth rates, and the transfer rates of P-gp in the sensitive and resistant subpopulations. We confirmed cell-to-cell transfer of functional P-gp. The transfer process depends on the gradient of P-gp expression in the donor-recipient cell interactions, as they evolve over time. Extragenetically acquired drug resistance is an additional aptitude of neoplastic cells which has implications in the diagnostic value of P-gp expression and in the design of chemotherapy regimensComment: 13 pages, 8 figures, 1 tabl

Amylin and leptin interaction: role during pregnancy, lactation and neonatal development

Amylin is co-secreted with insulin by pancreatic β-cells in response to a meal and produced by neurons in discrete hypothalamic brain areas. Leptin is proportionally secreted by the adipose tissue. Both hormones control food intake and energy homeostasis post-weaning in rodents. While amylin's main site of action is located in the area postrema (AP) and leptin's is located in the mediobasal hypothalamus, both hormones can also influence the other's signaling pathway; amylin has been shown enhance hypothalamic leptin signaling, and amylin signaling in the AP may rely on functional leptin receptors to modulate its effects. These two hormones also play major roles during other life periods. During pregnancy, leptin levels rise as a result of an increase in fat depot resulting in gestational leptin-resistance to prepare the maternal body for the metabolic needs during fetal development. The role of amylin is far less studied during pregnancy and lactation, though amylin levels seem to be elevated during pregnancy relative to insulin. Whether amylin and leptin interact during pregnancy and lactation remains to be assessed. Lastly, during brain development, amylin and leptin are major regulators of cell birth during embryogenesis and act as neurotrophic factors in the neonatal period. This review will highlight the role of amylin and leptin, and their possible interaction, during these dynamic time periods of pregnancy, lactation, and early development

Jonathan Frankel, Crisis, Revolution, and Russian Jews

Il s’agit de la dernière contribution de Jonathan Frankel à l’histoire des juifs de Russie. Publié peu après sa mort en mai 2008, ce recueil d’essais fut cependant préparé par ses soins. Il regroupe onze de ses principaux articles, écrits à différentes périodes de sa carrière, et permet de mesurer la portée du travail de l’un des plus grands historiens des juifs russes. Né à Londres en 1935 de parents immigrés d’Europe centrale, Jonathan Frankel découvrit l’histoire russe à Cambridge et consa..