Pharmaco‐electroencephalographic responses in the rat differ between active and inactive locomotor states

Quantitative electroencephalography from freely moving rats is commonly used as a translational tool for predicting drug‐effects in humans. We hypothesized that drug‐effects may be expressed differently depending on whether the rat is in active locomotion or sitting still during recording sessions, and proposed automatic state‐detection as a viable tool for estimating drug‐effects free of hypo‐/hyperlocomotion‐induced effects. We aimed at developing a fully automatic and validated method for detecting two behavioural states: active and inactive, in one‐second intervals and to use the method for evaluating ketamine, DOI, d‐cycloserine, d‐amphetamine, and diazepam effects specifically within each state. The developed state‐detector attained high precision with more than 90% of the detected time correctly classified, and multiple differences between the two detected states were discovered. Ketamine‐induced delta activity was found specifically related to locomotion. Ketamine and DOI suppressed theta and beta oscillations exclusively during inactivity. Characteristic gamma and high‐frequency oscillations (HFO) enhancements of the NMDAR and 5HT_2A modulators, speculated associated with locomotion, were profound and often largest during the inactive state. State‐specific analyses, theoretically eliminating biases from altered occurrence of locomotion, revealed only few effects of d‐amphetamine and diazepam. Overall, drug‐effects were most abundant in the inactive state. In conclusion, this new validated and automatic locomotion state‐detection method enables fast and reliable state‐specific analysis facilitating discovery of state‐dependent drug‐effects and control for altered occurrence of locomotion. This may ultimately lead to better cross‐species translation of electrophysiological effects of pharmacological modulations.     

Correlates of Concurrent Khat and Tobacco Use in Yemen

Background: Habitual substance use poses public health threat. This is a growing concern in countries where one or more substances are commonly used. Many individuals in Middle Eastern and East African countries use khat (Catha edulis), a stimulant often accompanied by smoking. However, few systematic attempts have been made to characterize patterns of concurrent khat and tobacco use. Objectives: To examine correlates such as gender and patterns of khat and tobacco use in concurrent users and khat-only users. Methods: This study used a cross-sectional design with a face-to-face interview method including 151 (74 women) concurrent users of khat and tobacco and 141 (76 women) khat-only users in Yemen. Data collection was completed in 2012. Analysis of variance (ANOVA) and logistic regressions were conducted to examine gender and khat use group differences in use patterns. Results: Reported frequency and intensity of khat use were greater in men than in women. Men and women khat users used different tobacco products and beverages while using khat. Khat use was more frequent in concurrent users relative to khat-only users. Earlier age of onset of khat use was associated with greater number of cigarettes smoked during a typical khat session. Approximately 70% of concurrent users reported initiating khat use prior to tobacco use. Conclusions/Importance: The results provide support for gender differences in khat and tobacco use, differences in khat use pattern between concurrent users of khat and tobacco and khat-only users, and positive associations between khat and tobacco use.     

Mitogen‐activated protein kinase phosphatase‐2 deletion modifies ventral tegmental area function and connectivity and alters reward processing

Mitogen‐activated protein kinases (MAPKs) regulate normal brain functioning, and their dysfunction is implicated in a number of brain disorders. Thus, there is great interest in understanding the signalling systems that control MAPK functioning. One family of proteins that contribute to this process, the mitogen‐activated protein kinase phosphatases (MKPs), directly inactivate MAPKs through dephosphorylation. Recent studies have identified novel functions of MKPs in foetal development, the immune system, cancer and synaptic plasticity and memory. In the present study, we performed an unbiased investigation using MKP‐2^?/? mice to assess whether MKP‐2 plays a global role in modulating brain function. Local cerebral glucose utilization is significantly increased in the ventral tegmental area (VTA) of MKP‐2^?/? mice, with connectivity analysis revealing alterations in VTA functional connectivity, including a significant reduction in connectivity to the nucleus accumbens and hippocampus. In addition, spontaneous excitatory postsynaptic current frequency, but not amplitude, onto putative dopamine neurons in the VTA is increased in MKP‐2^?/? mice, which indicates that increased excitatory drive may account for the increased VTA glucose utilization. Consistent with modified VTA function and connectivity, in behavioural tests MKP‐2^?/? mice exhibited increased sucrose preference and impaired amphetamine‐induced hyperlocomotion. Overall, these data reveal that MKP‐2 plays a role in modulating VTA function and that its dysfunction may contribute to brain disorders in which altered reward processing is present.     

Toxicological aspects of trans fat consumption over two sequential generations of rats: Oxidative damage and preference for amphetamine

Chronic consumption of processed food causes structural changes in membrane phospholipids, affecting brain neurotransmission. Here we evaluated noxious influences of dietary fats over two generations of rats on amphetamine (AMPH)-conditioned place preference (CPP). Female rats received soybean oil (SO, rich in n-6 fatty acids (FA)), fish oil (FO, rich in n-3 FA) and hydrogenated vegetable fat (HVF, rich in trans fatty acids (TFA)) for two successive generations. Male pups from the 2nd generation were maintained on the same supplementation until 41 days of age, when they were conditioned with AMPH in CPP. While the FO group showed higher incorporation of n-3 polyunsaturated-FA (PUFA) in cortex/hippocampus, the HVF group showed TFA incorporation in these same brain areas. The SO and HVF groups showed AMPH-preference and anxiety-like symptoms during abstinence. Higher levels of protein carbonyl (PC) and lower levels of non-protein thiols (NPSH) were observed in cortex/hippocampus of the HVF group, indicating antioxidant defense system impairment. In contrast, the FO group showed no drug-preference and lower PC levels in cortex. Cortical PC was positively correlated with n-6/n-3 PUFA ratio, locomotion and anxiety-like behavior, and hippocampal PC was positively correlated with AMPH-preference, reinforcing connections between oxidative damage and AMPH-induced preference/abstinence behaviors. As brain incorporation of trans and n-6 PUFA modifies its physiological functions, it may facilitate drug addiction.     

Dexamphetamine substitute‐prescribing in pregnancy: a 10‐year retrospective audit

Background: In the UK dexamphetamine has been used widely as a treatment for amphetamine users. We sought to study the effects of illicit amphetamine use on pregnancy, and to evaluate the safety and effectiveness of prescribing to pregnant users.

Method: The ante‐natal care and birth outcomes of 47 amphetamine‐using women who were prescribed dexamphetamine and 41 who were not, were compared with each other, and with local population norms. Analyses by dose of dexamphetamine were performed. Data was also collected for two equivalent samples of heroin users.

Results: The prescribed amphetamine and heroin users received adequate antenatal care. Despite this there was a high rate of low birth weight in both groups. It is doubtful that prescribed dexamphetamine contributed substantially to these adverse outcomes in the amphetamine users, as they were very similar in those not prescribed to. Also, there was no association demonstrated with duration of prescribing or maximum dose. ‘On‐top’ use was the best predictor of adverse birth outcomes.

Conclusions: Dexamphetamine substitution delivered alongside a specialist midwifery service is successful at ensuring clients receive adequate antenatal care, but should be initiated with caution and used as a last‐line treatment. Clients should be informed of possible risks, including those relating to continued use of street‐drugs.     

Gastrointestinal Decontamination: Maybe We'Re Both Right (Commentary)

Context. Naphyrone (naphthylpyrovalerone) is a cathinone derivative and recreational drug related to mephedrone. Case. We report a 31-year-old man who ingested a dose of naphyrone (100 mg), which produced acute sympathomimetic toxicity with restlessness, insomnia, anxiety, and hallucinations lasting for 2 days. Naphyrone was detected in the patient's plasma by gas chromatography with mass spectrometry at concentrations of 0.03 and 0.02 mg/L, 40 and 60 h after drug intake, respectively. Discussion. Based on the present case report and user web-reports, as well as on the chemical structure and pharmacological characteristics, naphyrone produces stimulant-like psychotropic effects and sympathomimetic toxicity.     

Effect of Food on Early Drug Exposure from Extended-Release Stimulants: Results from the Concerta®, Adderall XR™ Food Evaluation (CAFÉ) Study

Summary

Stimulant therapy is the mainstay of treatment for children, adolescents and adults with attention-deficit/hyperactivity disorder (ADHD). Once-daily, extended-release oral formulations offer long acting control of symptoms by modifying drug delivery and absorption. In particular, consistency in early drug exposure is important for symptom control during school or work hours. Because these once-daily formulations are usually taken in the morning, the timing of the doses with breakfast is important. This study compared the effect of a high-fat breakfast on early drug exposure from a morning dose of two extended-release stimulant formulations: the osmotic-controlled OROS® tablet of methylphenidate HCl (Concerta®) and the capsule containing extended-release beads of mixed amphetamine salts (Adderall XR?). The study had a single-dose, open-label, randomised, four-treatment, crossover design in which healthy subjects received either 36?mg Concerta® or 20?mg Adderall XR? in the morning after an overnight fast or a high-fat breakfast. Serial blood samples were collected over 28?h to determine plasma concentrations of methylphenidate and amphetamine. The food effect on early drug exposure and the pharmacokinetic profiles up to 8?h after dosing of the two extended-release stimulants were directly compared using partial area (AUCp4h, AUCp6h and AUCp8h) fed/fasted ratios. Amphetamine concentrations were markedly lower when the subjects had eaten breakfast, resulting in lower early drug exposures (p?<?0.0001). By contrast, methylphenidate concentrations over the same 8?h were unaffected by breakfast, providing consistent levels of early drug exposure. Therefore, as a child's or adult's eating pattern varies, methylphenidate exposure over the first 8?h would be expected to have less day-to-day variation compared with amphetamine exposure. The osmotic-controlled OROS® tablet provides a reliable and consistent delivery of methylphenidate HCl, independent of food, for patients with ADHD.     

A clinician’s guide to ADHD treatment options

Attention deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental condition of children and adolescents that often persists into adulthood. Primary care physicians are commonly the first to diagnosis ADHD and initiate a treatment plan with the patient. Guidelines recommend psychostimulant treatment as a first-line therapy in the management plan because it has a substantial impact on alleviating the core symptoms of ADHD. The recent development of a variety of methylphenidate and amphetamine formulations provides many options to meet individual patient lifestyle needs. Liquid, chewable, sprinkled capsule, wearable patch, and orally disintegrating tablet formulations are currently available for patients who may be noncompliant with or have difficulty swallowing traditional pills. This review provides a resource for physicians to identify the stimulant delivery formulation that best suits the patient. Formulations in development are also discussed.