Cocaine addiction is a major health problem that affects millions of people. Cocaine acts by inhibiting dopamine, noradrenaline and serotonin [5-hydroxytryptamine(5-HT)] reuptake. The dopaminergic system is generally assumed to be involved in the reinforcing aspects of the drug, but the role of 5-HT in the addictive potential of cocaine is unclear. In light of pharmacological manipulations and cocaine use-related disease states affecting brain 5-HT levels, we review studies on the effect of cocaine on central 5-HT function. In addition, the contribution of 5-HT to the rewarding, aversive, discriminative and subjective, as well as the motivational and reinforcing effects of cocaine is discussed. We specifically focus on net changes in the extracellular 5-HT levels that occur as a consequence of acute and chronic cocaine exposure and how these influence cocaine abuse-related behaviour. Overall, the data indicate that 5-HT plays a major role in the psychomotor stimulant, rewarding and discriminative stimulant effects of cocaine, but also affects the motivational and reinforcing effects of the drug. In addition, 5-HT mediates, to some extent, the aversive effects of cocaine. Difficulties with data interpretation are discussed.

Metabolic challenge tests may be a valuable tool to magnify the effects of diet on health. The use of transcriptomics enables a more extensive characterization of the effects of diet. The question remains whether transcriptome time‐course analyses during challenge tests will deliver more information on the effect of diet than a static fasting measurement. A dietary intervention known to improve health is energy restriction (ER). Seventy‐two healthy, overweight men and women aged 50–65 were subjected to an oral glucose tolerance test (OGTT) and a mixed‐meal test (MMT) before and after 12 wk of a 20% ER diet or control diet. Whole‐genome gene expression of peripheral blood mononuclear cells was performed before and after the intervention. This was done during fasting, during the OGTT at 30, 60, and 120 min, and during the MMT at 60, 120, 240, and 360 min. Upon ER, the OGTT resulted in a faster and more pronounced down‐regulation in gene expression of oxidative phosphorylation, cell adhesion, and DNA replication compared with the control. The MMT showed less‐consistent effects. The OGTT combined with transcriptomics can be used to measure dynamic cellular adaptation upon an intervention that cannot be determined with a static fasting measurement.—Van Bussel, I. P. G., Fazelzadeh, P., Frost, G. S., Rundle, M., Afman, L. A. Measuring phenotypic flexibility by transcriptome time‐course analyses during challenge tests before and after energy restriction. FASEB J. 33, 10280–10290 (2019). http://www.fasebj.org

BackgroundCaloric restriction (CR) is considered to increase lifespan and to prevent various age-related diseases in different nonhuman organisms. Only a limited number of CR studies have been performed on humans, and results put CR as a beneficial tool to decrease risk factors in several age-related diseases. The question remains at what age CR should be implemented to be most effective with respect to healthy aging. The aim of our study was to elucidate the role of age in the transcriptional response to a completely controlled 30 % CR diet on immune cells, as immune response is affected during aging. Ten healthy young men, aged 20–28, and nine healthy old men, aged 64–85, were subjected to a 2-week weight maintenance diet, followed by 3 weeks of 30 % CR. Before and after 30 % CR, the whole genome gene expression in peripheral blood mononuclear cells (PBMCs) was assessed.ResultsExpression of 554 genes showed a different response between young and old men upon CR. Gene set enrichment analysis revealed a downregulation of gene sets involved in the immune response in young but not in old men. At baseline, immune response-related genes were higher expressed in old compared to young men. Upstream regulator analyses revealed that most potential regulators were controlling the immune response.ConclusionsBased on the gene expression data, we theorise that a short period of CR is not effective in old men regarding immune-related pathways while it is effective in young men.Trial registrationClinicalTrials.gov, NCT00561145Electronic supplementary materialThe online version of this article (doi:10.1186/s12263-016-0528-0) contains supplementary material, which is available to authorized users.

Based on gene expression changes, we concluded that consumption of normal protein quantity compared with high-protein quantity during ER has a more beneficial effect on inflammation-related gene expression in WAT.

Chapter 1 | General introduction Energy restrictionEnergy restriction (ER) is a dietary intervention that reduces energy intake without malnutrition and is used as a dietary strategy to lose weight. Next to ER as a weight loss strategy, it has been implemented as a tool to extend life span, as was shown in Caenorhabditis elegans [1], Saccharomyces cerevisiae [2], and rodents [3]. In this context it is mostly referred to as caloric restriction (CR). Within this thesis I will use the following nomenclature (1) ER as a reduction in energy intake aimed at inducing weight loss in overweight or obese subjects; and (2) CR as a reduction in energy intake aimed at improving health and life span in non-obese subjects. CR is not directly aimed at weight loss. Nevertheless reduction of calorie intake often leads to weight loss.Of ER and CR, ER is mostly applied in humans, since it is the most effective strategy to lose bodyweight in overweight and obese people. The resulting loss in bodyweight has many beneficial health effects, including a reduction in blood pressure, low-density lipoprotein cholesterol, triglycerides, fasting plasma glucose, and haemoglobin A1c [4], resulting in a reduced risk of developing cardiovascular disease (CVD), and diabetes type II [5].