Effect of caffeine on mitochondrial biogenesis in the skeletal muscle - A narrative review.

Caffeine is one of the most widely used substances as recreational drug for performance-enhancement in sport, underpinned by a strong evidence base. Although the effects of caffeine are widely investigated within the scope of performance physiology, the molecular effects of caffeine within skeletal muscle remain unclear. Evidence from in vitro and in vivo models suggest that caffeine regulates the glucose metabolism in the skeletal muscle. Moreover, caffeine seems to stimulate CaMKII, PPARδ/ß, AMPK and PGC1α, classical markers of exercise-adaptations, including mitochondrial biogenesis and mitochondrial content. This review summarizes evidence to suggest caffeine-effects within skeletal muscle fibers, focusing on the putative role of caffeine on mitochondrial biogenesis to explore whether caffeine supplementation might be a strategy to enhance mitochondrial biogenesis.

Presence of illicit drugs and metabolites in influents and effluents of 25 sewage water treatment plants and map of drug consumption in France.

Consumption of illicit drugs is a new concern for water management that must be considered not only because of the social and public health aspects but also in an environmental context in relation with the contamination of surface waters. Indeed, sewage treatment plant (STP) effluents contain drug residues that have not been eliminated since STP treatments are not completely efficient in their removal. We developed and validated an HPLC-MS/MS analytical method to assess the concentrations of 17 illicit drugs and metabolites in raw urban wastewaters: cocaine and its metabolites, amphetamine and amphetamine-likes (methamphetamine, MDMA, MDEA, MDA), opiates and opiate substitutes (methadone and buprenorphine), and THC-COOH cannabis metabolite. This method has been applied to the analysis of influent and effluent samples from 25 STPs located in France all over the country. The results allowed evaluating the drug consumption in the areas connected to the STPs and the efficiency of the treatment technology implied. We selected STPs according to their volume capacity, their treatment technologies (biofilters, activated sludges, MBR) and their geographical location. In influents, the concentrations varied between 6 ng/L for EDDP (main metabolite of methadone) and 3050 ng/L for benzoylecgonine (cocaine metabolite). Consumption maps were drawn for cocaine, MDMA, opiates, cannabis and amphetamine-like compounds. Geographical significant differences were observed and highlighted the fact that drug consumption inside a country is not homogeneous. In parallel, comparisons between STP technology processes showed differences of efficiency. More, some compounds appear very resistant to STP processes leading to the contamination of receiving water.

Gas and liquid chromatography-mass spectrometry studies on the metabolism of the synthetic phenylacetylindole cannabimimetic JWH-250, the psychoactive component of smoking mixtures.

Prohibition of some synthetic cannabimimetics (e.g., JWH-018, JWH-073 and CP 47497) in a number of countries has led to a rise in new compounds in herbal mixtures that create marijuana-like psychotropic effects when smoked. The cannabimimetic JWH-250 (1-pentyl-3-(2-methoxyphenylacetyl)indole) was identified in May 2009 by the German Federal Criminal Police as an new ingredient in herbal smoking mixtures. The absence or low presence of the native compound in urine samples collected from persons who had consumed JWH-250 necessitates a detailed identification of their metabolites, which are excreted with urine and present in blood. Using gas and liquid chromatography-mass spectrometry (GC-MS and LC-MS/MS), we identified a series of metabolites in urine samples and serum sample from humans and urine samples from rats that were products of the following reactions: (a) mono- and dihydroxylation of aromatic and aliphatic residues of the parent compound, (b) trihydroxylation and dehydration of the N-alkyl chain, (c) N-dealkylation and (d) N-dealkylation and monohydroxylation. The prevailing urinary metabolites in humans were the monohydroxylated forms, while N-dealkylated and N-dealkyl monohydroxylated forms were found in rats. The detection of the mono- and dihydroxylated metabolites of JWH-250 in urine and serum samples by GC-MS and LC-MS/MS proved to be effective in determining consumption of this drug.

In vitro approaches to studying the metabolism of new psychoactive compounds.

In the last two decades, a large number of new drugs from several drug classes have appeared on the illicit drug market. While some of these compounds have meanwhile been scheduled as controlled substances, the majority of them are (still) sold as so-called 'legal highs', mostly via the Internet. At the time they appear on the market the metabolism of these drugs is generally unknown. Therefore, it must be studied in order to obtain data necessary for analytical method development as well as toxicological risk assessment. In vitro metabolism studies of new designer drugs can be performed for identification and structure elucidation of new designer drug metabolites or to assess the qualitative and quantitative involvement of certain enzymes in the metabolism of a particular drug. In this review, the value of the following enzyme preparations for in vitro metabolism studies of new designer drugs will be discussed: liver microsomes, recombinant cDNA-expressed enzymes, liver cytosol, S9 mix, and hepatocytes. This will cover the major metabolic enzymes: cytochrome P450 monooxygenases, flavin-monooxygenases, monoamine oxidases, UDP-glucuronyltransferases, sulfotransferases, and catechol-O-methyltransferases. Important analytical aspects such as the value of mass spectrometric techniques will also be covered.

Chemistry, pharmacology, and metabolism of emerging drugs of abuse.

In recent years, besides the classic designer drugs of the amphetamine type, a series of new drug classes appeared on the illicit drugs market. The chemistry, pharmacology, toxicology, metabolism, and toxicokinetics is discussed of 2,5-dimethoxy amphetamines, 2,5-dimethoxy phenethylamines, beta-keto-amphetamines, phencyclidine derivatives as well as of herbal drugs, ie, Kratom. They have gained popularity and notoriety as rave drugs. The metabolic pathways, the involvement of cytochrome P450 isoenzymes in the main pathways, and their roles in hepatic clearance are also summarized.

PTEN-5-HT2C coupling: a new target for treating drug addiction.

It is well known that the ventral tegmental area (VTA) is a brain region in which virtually all abused drugs exert rewarding effects by activating its dopamine neurons. We recently found that the tumour suppressor enzyme phosphatase and tensin homologue deleted on chromosome 10 (PTEN) directly interacts to a region in the third intracellular loop (3L4F) of serotonin 5-HT2C receptors (5-HT2cR) in the rat VTA. PTEN limits agonist-induced 5-HT2cR phosphorylation via its protein phosphatase activity. Systemic or intra-amygdaloid application of the interfering peptide Tat-3L4F is able to disrupt PTEN coupling with 5-HT2cR in the rat VTA, resulting both in a suppression of the increased firing rate of VTA dopaminergic neurons induced by Delta 9-tetrahydrocannabinol (THC), the psychoactive ingredient of marijuana, and in a blockade of the conditioned place preference induced by THC and nicotine [Ji, S.P. et al. (2006). Nat. Med., 12: 324-329]. Because the blockade effects of Tat-3L4F peptide on the conditioned preference could be achieved by the suppression of Tat-3L4F peptide on the rewarding and/or learning/memory mechanisms associated with conditioned place preference, we recently explored whether Tat-3L4F can affect learning and memory. We observed that Tat-3L4F did not produce significant effects on spatial learning and memory in a Morris water maze test, thus indicating that Tat-3L4F can effectively suppress the rewarding effects induced by drugs of abuse.

In situ hybridization analysis of RGS mRNA regulation and behavioral phenotyping of RGS mutant mice.

To elucidate the functional role of regulators of G-protein signaling (RGS) in vivo, it will be critical to (i) determine how RGS activity is altered in response to a variety of manipulations and (ii) observe how the system is changed when RGS protein function is altered genetically. To facilitate studies of dynamic regulation of RGS protein activity, this article describes detailed methods for radioisotopic in situ hybridization for semiquantitative analyses of RGS mRNA abundances. Toward characterizing the functional differences in mice with genetically altered RGS activities, this article describes a subset of behavioral tests suitable for assaying sensitivities to drugs of abuse. These protocols should provide valuable guidance for investigators to establish these methodologies independently in their own laboratories and, over time, increase our understanding of RGS function in vivo.

The pre-clinical behavioural pharmacology of 3,4-methylenedioxymethamphetamine (MDMA).

3,4-Methylenedioxymethamphetamine (MDMA) is a relatively novel drug of abuse and as such little is currently known of its behavioural pharmacology. This review aims to examine whether MDMA represents a novel class of abused drug. MDMA is known as a selective serotonergic neurotoxin in a variety of animal species but acutely it is a potent releaser and/or reuptake inhibitor of presynaptic serotonin, dopamine, noradrenaline, and acetylcholine. Interaction of these effects contributes to its behavioural pharmacology, in particular its effects on body temperature. Drug discrimination studies indicate that MDMA and related drugs produce unique interoceptive effects which have led to their classification as entactogens. This is supported by results from other behavioural paradigms although there is evidence for dose dependency of MDMA-specific effects. MDMA also produces conditioned place preference but is not a potent reinforcer in self-administration studies. These unique behavioural effects probably underlie its current popularity. MDMA is found in the street drug ecstasy but it may not be appropriate to equate the two as other drugs are routinely found in ecstasy tablets