Caenorhabditis elegans Show Preference for Stimulants and Potential as a Model Organism for Medications Screening

The nematode Caenorhabditis elegans (C. elegans) is a popular invertebrate model organism to study neurobiological disease states. This is due in part to the intricate mapping of all neurons and synapses of the entire animal, the wide availability of mutant strains, and the genetic and molecular tools that can be used to manipulate the genome and gene expression. We have shown that, C. elegans develops a conditioned preference for cues that had previously been paired with either cocaine or methamphetamine exposure that is dependent on dopamine neurotransmission, similar to findings using place conditioning with rats and mice. In the current study, we show C. elegans also display a preference for, and self-exposure to, cocaine and nicotine. This substance of abuse (SOA) preference response can be selectively blocked by pretreatment with naltrexone and is consistent with the recent discovery of an opioid receptor system in C. elegans. In addition, pre-exposure to the smoking cessation treatment varenicline also inhibits self-exposure to nicotine. Exposure to concentrations of treatments that inhibit SOA preference/self-exposure did not induce any significant inhibition of locomotor activity or affect food or benzaldehyde chemotaxis. These data provide predictive validity for the development of high-throughput C. elegans behavioral medication screens. These screens could enable fast and accurate generation of data to identify compounds that may be effective in treating human addiction. The successful development and validation of such models would introduce powerful and novel tools in the search for new pharmacological treatments for substance use disorders, and provide a platform to study the mechanisms that underlie addictions

Chronic stress produces enduring sex- and region-specific alterations in novel stress-induced c-Fos expression

Prolonged or repeated exposure to stress increases risk for a variety of psychological disorders, many of which are marked by dysfunction of corticolimbic brain regions. Notably, women are more likely than men to be diagnosed with these disorders, especially when onset of symptoms follows stressful life events. Using rodent models, investigators have recently begun to elucidate sex-specific changes in the brain and behavior that occur immediately following chronic stress. However, little is known regarding the lasting sequelae of chronic stress, as well as how potential changes may impact responsivity to future stressors. We recently demonstrated that male and female rats show different patterns of dendritic reorganization in medial prefrontal cortex in the days following chronic stress. Here, we examined the immediate and lasting effects of chronic restraint stress (CRS; 3 h/day, 10 days) on neuronal activation, across several corticolimbic brain regions, induced by novel acute stress exposure. Chronically stressed male and female rats were exposed to acute elevated platform stress (EPS) either 1 (CRS-EPS) or 7 (CRS-Rest-EPS) days after CRS. Compared to rats exposed to EPS only, significant reductions in acute stress-induced c-Fos expression were observed in the medial prefrontal cortex, hippocampus, and paraventricular nucleus of the hypothalamus (PVN) in CRS-EPS male rats, some of which persisted to 7 days post-stress. In contrast, we found little modulation of novel stress-induced c-Fos expression in CRS-EPS female rats. However, CRS-Rest-EPS female rats exhibited a significant enhancement of acute stress-induced neuronal activity in the PVN. Together, these data show that prior chronic stress produces sex- and region-specific alterations in novel stress-induced neuronal activation, which are dependent on the presence or absence of a rest period following chronic stress. These findings suggest that the post-stress rest period may give rise to sex-specific neuroadaptations to stress, which may underlie sex differences in stress susceptibility versus resilience

Empagliflozin in Patients with Chronic Kidney Disease

Background The effects of empagliflozin in patients with chronic kidney disease who are at risk for disease progression are not well understood. The EMPA-KIDNEY trial was designed to assess the effects of treatment with empagliflozin in a broad range of such patients. Methods We enrolled patients with chronic kidney disease who had an estimated glomerular filtration rate (eGFR) of at least 20 but less than 45 ml per minute per 1.73 m(2) of body-surface area, or who had an eGFR of at least 45 but less than 90 ml per minute per 1.73 m(2) with a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 200. Patients were randomly assigned to receive empagliflozin (10 mg once daily) or matching placebo. The primary outcome was a composite of progression of kidney disease (defined as end-stage kidney disease, a sustained decrease in eGFR to < 10 ml per minute per 1.73 m(2), a sustained decrease in eGFR of & GE;40% from baseline, or death from renal causes) or death from cardiovascular causes. Results A total of 6609 patients underwent randomization. During a median of 2.0 years of follow-up, progression of kidney disease or death from cardiovascular causes occurred in 432 of 3304 patients (13.1%) in the empagliflozin group and in 558 of 3305 patients (16.9%) in the placebo group (hazard ratio, 0.72; 95% confidence interval [CI], 0.64 to 0.82; P < 0.001). Results were consistent among patients with or without diabetes and across subgroups defined according to eGFR ranges. The rate of hospitalization from any cause was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.86; 95% CI, 0.78 to 0.95; P=0.003), but there were no significant between-group differences with respect to the composite outcome of hospitalization for heart failure or death from cardiovascular causes (which occurred in 4.0% in the empagliflozin group and 4.6% in the placebo group) or death from any cause (in 4.5% and 5.1%, respectively). The rates of serious adverse events were similar in the two groups. Conclusions Among a wide range of patients with chronic kidney disease who were at risk for disease progression, empagliflozin therapy led to a lower risk of progression of kidney disease or death from cardiovascular causes than placebo