- Determination of different recreational drugs in sweat by headspace solid-phase microextraction gas chromatography mass spectrometry (HS-SPME GC/MS): Application to drugged drivers. [JOURNAL ARTICLE]
- J Pharm Biomed Anal 2016 Jul 14.:282-287.
A procedure based on headspace solid-phase microextraction (HS-SPME) coupled with gas chromatography/mass spectrometry (GC/MS) has been developed for the determination of most commonly used drugs of abuse in sweat of drivers stopped during roadside controls. DrugWipe 5A sweat screening device was used to collect sweat by a specific pad rubbed gently over forehead skin surface. The procedure involved an acid hydrolysis, a HS-SPME extraction for drugs of abuse but Δ(9)-tetrahydrocannabinol, which was directly extracted in alkaline medium HS-SPME conditions, a GC separation of analytes by a capillary column and MS detection by electron impact ionisation. The method was linear from the limit of quantification (LOQ) to 50ng drug per pad (r(2)≥0.99), with an intra- and inter-assay precision and accuracy always less than 15% and an analytical recovery between 95.1% and 102.8%, depending on the considered analyte. Using the validated method, sweat from 60 apparently intoxicated drivers were found positive to one or more drugs of abuse, showing sweat patches testing as a viable economic and simple alternative to conventional (blood and/or urine) and non conventional (oral fluid) testing of drugs of abuse in drugged drivers.
- Impaired mTORC2 signaling in catecholaminergic neurons exaggerates high fat diet-induced hyperphagia. [Journal Article]
- Heliyon 2015 Sep; 1(1):e00025.
Food intake is highly regulated by central homeostatic and hedonic mechanisms in response to peripheral and environmental cues. Neutral energy balance stems from proper integration of homeostatic signals with those "sensing" the rewarding properties of food. Impairments in brain insulin signaling causes dysregulation of feeding behaviors and, as a consequence, hyperphagia. Here, we sought to determine how the mammalian target of rapamycin complex 2 (mTORC2), a complex involved in insulin signaling, influences high fat feeding.Rictor is a subunit of mTORC2, and its genetic deletion impairs mTORC2 activity. We used Cre-LoxP technology to delete Rictorin tyrosine hydroxylase (TH) expressing neurons (TH Rictor KO). We assessed food intake, body weight, body composition and DA dependent behaviors.TH Rictor KO mice display a high-fat diet specific hyperphagia, yet, when on low-fat diet, their food intake is indistinguishable from controls. Consistently, TH Rictor KO become obese only while consuming high-fat diet. This is paralleled by reduced brain DA content, and disruption of DA dependent behaviors including increased novelty-induced hyperactivity and exaggerated response to the psycho stimulant amphetamine (AMPH).Our data support a model in which mTORC2 signaling within catecholaminergic neurons constrains consumption of a high-fat diet, while disruption causes high-fat diet-specific exaggerated hyperphagia. In parallel, impaired mTORC2 signaling leads to aberrant striatal DA neurotransmission, which has been associated with obesity in human and animal models, as well as with escalating substance abuse. These data suggest that defects localized to the catecholaminergic pathways are capable of overriding homeostatic circuits, leading to obesity, metabolic impairment, and aberrant DA-dependent behaviors.
- Improved drug-use patterns at 6 months post-discharge from inpatient substance use disorder treatment: results from compulsorily and voluntarily admitted patients. [Journal Article]
- BMC Health Serv Res 2016; 16(1):291.
Treatment services to patients with substance use disorders (SUDs), including those mandated to treatment, needs to be evaluated and evidence based. The Norwegian Municipal Health Care Act calls for mandated treatment for persons with "severe and life-threatening substance use disorder" if these individuals are not otherwise willing to be voluntarily treated and consequently risk their lives over drug use. This study aims to examine substance use-related outcomes at 6 months following inpatient treatment and to analyse factors associated with improved outcomes and abstinence.This prospective study followed 202 hospitalized patients with SUD who were admitted voluntarily (VA; n = 137) or compulsorily (CA; n = 65). The European Addiction Severity Index was used at baseline and at follow-up to assess socio-demographic and substance use variables. Regression analysis was conducted to investigate factors associated with abstinence at 6 months of follow-up.The frequency of use of a preferred substance showed marked improvement for both VA and CA patients (61 and 37 %, respectively) at follow-up. Seventy-five percent of VA patients using amphetamine reported improvement compared to 53 % of CA patients. At follow-up, the CA group continued to have a higher rate of injection use. The CA group had experienced higher rates of overdose in the past 6 months and lower abstinence rates (24 % versus 50 %) at follow-up. A lower severity of drug use at intake (non-injection drug use), voluntary treatment modality, and higher treatment involvement during follow-up all were significant factors associated with abstinence at 6 months after treatment.Voluntary treatment for SUD generally yielded better outcomes; nevertheless, we also found improved outcomes for CA patients. It is important to keep in mind that in reality, the alternative to CA treatment is no treatment at all and instead a continuation of life-threatening drug use behaviours. Our observed outcomes for CA patients support the continuation of CA treatment.
- Stimulant drug effects on touchscreen automated paired-associates learning (PAL) in rats. [Journal Article]
- Learn Mem 2016 Aug; 23(8):422-6.
Here we tested in rats effects of the procognitive drugs modafinil and methylphenidate on post-acquisition performance in an object-location paired-associates learning (PAL) task. Modafinil (32; 64 mg/kg) was without effect, while higher (9 mg/kg) but not lower (4.5 mg/kg) doses of methylphenidate impaired PAL performance. Likewise, higher but not lower doses of amphetamine (0.4; 0.8 mg/kg) and MK-801 (0.08; 0.12 mg/kg) decreased PAL performance. Impaired PAL performance induced by methylphenidate, amphetamine, and MK801 most likely reflects compromised cognitive function, e.g., retrieval of learned paired associates. Our data suggest that stimulant drugs such as methylphenidate and modafinil might not facilitate performance in hippocampus-related cognitive tasks.
- Cocaine- and amphetamine-regulated transcript: a novel regulator of energy homeostasis expressed in a subpopulation of pancreatic islet cells. [EDITORIAL]
- Diabetologia 2016 Jul 15.
Type 2 diabetes is characterised by chronic hyperglycaemia and its incidence is highly increased by exaggerated food consumption. It results from a lack of insulin action/production, but growing evidence suggests that it might also involve hyperglucagonaemia and impaired control of glucose homeostasis by the brain. In recent years, the cocaine and amphetamine-regulated transcript (CART) peptides have generated a lot of interest in the battle against obesity because, via the brain, they exert anorexic effects and they increase energy expenditure. They are also localised, outside the brain, in discrete regions of the body and play a hormonal role in controlling various functions. In this issue of Diabetologia, the Wierup group (doi: 10.1007/s00125-016-4020-6 ) shows that CART peptides are expressed heterogeneously in islet cells of various species, including humans, and that their expression is upregulated in diabetes. The authors also shine a spotlight on some interesting effects of CART peptides on islet function, including stimulation of insulin secretion and inhibition of glucagon release. CART peptides would thus be at the centre of a cooperation between the brain and the endocrine pancreas to control glucose homeostasis. Although the mechanisms of action of CART peptides remain enigmatic because no specific receptor for these peptides has so far been discovered, their potential therapeutic use is evident and represents a new challenge for future research.
- Metabolomics of Methylphenidate and Ethylphenidate: Implications in Pharmacological and Toxicological Effects. [JOURNAL ARTICLE]
- Eur J Drug Metab Pharmacokinet 2016 Jul 20.
Methylphenidate (MPH) is primarily indicated for attention-deficit hyperactivity disorder and narcolepsy therapy. A marked individual variability in the dose-response has been observed, and therefore dosage must be titrated for optimal therapeutic effect with minimal toxicity. This variability has been claimed to be predominantly pharmacokinetic. Moreover, due to its similar pharmacodynamics to amphetamine, MPH has been abused and fatalities have been reported. This review aims to discuss metabolomics of MPH, namely by presenting all major and minor metabolites. Ritalinic acid is the main metabolite. In addition, minor pathways involving aromatic hydroxylation, microsomal oxidation and conjugation have also been reported to form the p-hydroxy-, oxo- and conjugated metabolites, respectively. MPH may undergo transesterification with ethanol producing ethylphenidate, which is also pharmacologically active. It is expected that knowing the metabolomics of MPH may provide further insights regarding individual contribution for MPH pharmacodynamics and toxicological effects, namely if ethanol is co-consumed.
- HIV and Syphilis Prevalence Among Transgender Women in Ho Chi Minh City, Vietnam. [JOURNAL ARTICLE]
- AIDS Behav 2016 Jul 19.
Globally, transgender women have higher risk for HIV than the general population and men who have sex with men, but there is little data on this population in Vietnam. In 2015 we conducted a biological and behavioral survey of 205 transgender women in Ho Chi Minh City, Vietnam. Factors associated with HIV and syphilis infection were assessed through multivariable logistic regression models. Median age was 25 years (range 18-64). Overall prevalence was 18.0 % for HIV and 17.6 % for syphilis. Factors independently associated with HIV infection included risky alcohol use [adjusted Odds Ratio (aOR) 3.55, 95 % confidence interval (CI) 1.53-8.21], amphetamine stimulant use (aOR 2.90, 95 % CI 1.27-6.61), sex with male sex workers (aOR 4.73, 95 % CI 1.72-13.0), and history of sex with an adult before the age of 18 years (aOR 2.97, 95 % CI 1.06-8.34). Two factors associated with syphilis infection were HIV infection (aOR 2.37, 95 % CI 1.03-5.45) and condomless anal sex with casual partners (aOR 2.27, 95 % CI 1.03-5.00). In order to address the HIV and syphilis epidemics in Vietnamese transgender women, interventions are needed to make HIV and sexually transmitted infection screening and treatment more accessible.
- Effects of immune activation during early or late gestation on schizophrenia-related behaviour in adult rat offspring. [JOURNAL ARTICLE]
- Brain Behav Immun 2016 Jul 13.
Maternal exposure to infectious agents during gestation has been identified as a significant risk factor for schizophrenia. Using a mouse model, past work has demonstrated that the gestational timing of the immune-activating event can impact the behavioural phenotype and expression of dopaminergic and glutamatergic neurotransmission markers in the offspring. In order to determine the inter-species generality of this effect to rats, another commonly used model species, the current study investigated the impact of a viral mimetic Poly (I:C) at either an early (gestational day 10) or late (gestational day 19) time-point on schizophrenia-related behaviour and neurotransmitter receptor expression in rat offspring. Exposure to Poly (I:C) in late, but not early, gestation resulted in transient impairments in working memory. In addition, male rats exposed to maternal immune activation (MIA) in either early or late gestation exhibited sensorimotor gating deficits. Conversely, neither early nor late MIA exposure altered locomotor responses to MK-801 or amphetamine. In addition, increased dopamine 1 receptor mRNA levels were found in the nucleus accumbens of male rats exposed to early gestational MIA. The findings from this study diverge somewhat from previous findings in mice with MIA exposure, which were often found to exhibit a more comprehensive spectrum of schizophrenia-like phenotypes in both males and females, indicating potential differences in the neurodevelopmental vulnerability to MIA exposure in the rat with regards to schizophrenia related changes.
- Mesocortical Dopamine Phenotypes in Mice Lacking the Sonic Hedgehog Receptor Cdon. [Journal Article]
- eNeuro 2016 May-Jun; 3(3)
Motivated behaviors and many psychopathologies typically involve changes in dopamine release from the projections of the ventral tegmental area (VTA) and/or the substantia nigra pars compacta (SNc). The morphogen Sonic Hedgehog (Shh) specifies fates of midbrain dopamine neurons, but VTA-specific effects of Shh signaling are also being uncovered. In this study, we assessed the role of the Shh receptor Cdon in the development of VTA and SNc dopamine neurons. We find that Cdon is expressed in the proliferating progenitor zone of the embryonic ventral midbrain and that the number of proliferating cells in this region is increased in mouse Cdon(-/-) embryos. Consistent with a role of Shh in the regulation of neuronal proliferation in this region, we find that the number of tyrosine hydroxylase (TH)-positive neurons is increased in the VTA of Cdon(-/-) mice at birth and that this effect endures into adulthood. In contrast, the number of TH-positive neurons in the SNc is not altered in Cdon(-/-) mice at either age. Moreover, adult Cdon(-/-) mice have a greater number of medial prefrontal cortex (mPFC) dopamine presynaptic sites, and increased baseline concentrations of dopamine and dopamine metabolites selectively in this region. Finally, consistent with increased dopamine function in the mPFC, we find that adult Cdon(-/-) mice fail to exhibit behavioral plasticity upon repeated amphetamine treatment. Based on these data, we suggest that Cdon plays an important role encoding the diversity of dopamine neurons in the midbrain, influencing both the development of the mesocortical dopamine pathway and behavioral outputs that involve this neural circuitry.
- Reinforcer magnitude affects delay discounting and influences effects of d-amphetamine in rats. [JOURNAL ARTICLE]
- Behav Processes 2016 Jul 11.:39-45.
Impulsive choice in humans can be altered by changing reinforcer magnitude; however, this effect has not been found in rats. Current levels of impulsive choice can also influence effects of d-amphetamine. This study used a within-subject assessment to determine if impulsive choice is sensitive to changes in reinforcer magnitude, and whether effects of d-amphetamine are related to current levels of impulsive choice. A discounting procedure in which choice was for a smaller reinforcer available immediately or a larger reinforcer available after a delay that increased within session was used. Reinforcer magnitude was manipulated between conditions and impulsive choice was quantified using area under the curve (AUC). In the Smaller-Magnitude (SM) Condition, choice was between one food pellet and three food pellets. In the Larger-Magnitude (LM) Condition, choice was between two food pellets and six food pellets. Impulsive choice was greater in the SM Condition compared to the LM Condition. Further, effects of d-amphetamine (0.1-1.8mg/kg) were related to differences in impulsive choice. d-Amphetamine increased impulsive choice in the LM Condition, but had no effect on impulsive choice in the SM Condition. Overall, these results show that impulsive choice in rats is sensitive to changes in reinforcer magnitude, and that effects of d-amphetamine are influenced by current levels of impulsive choice.