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- Concentrations of Cocaine and Benzoylecgonine in Femoral Blood from Cocaine-Related Deaths Compared with Venous Blood from Impaired Drivers. [JOURNAL ARTICLE]
- J Anal Toxicol 2013 Dec 9.
The concentrations of cocaine and its major metabolite benzoylecgonine (BZE) were determined in femoral blood from 132 cocaine-related deaths and compared with venous blood from 988 apprehended drivers. Cocaine and BZE were determined by solid-phase extraction and isotope dilution gas chromatography-mass spectrometry with limits of quantitation of 0.02 mg/L for both substances. Significantly more men (95-98%) than women (2-5%) abused cocaine, although their mean age was about the same (29-30 years). Mean age (±SD) of cocaine-related deaths was 29 ± 7 years, which was not significantly different from 30 ± 8 years in traffic cases (P > 0.05). The median concentration of cocaine in blood in 61 fatalities was 0.10 mg/L compared with 0.06 mg/L in traffic cases (P < 0.001). In drug intoxication deaths, the median concentration of cocaine was 0.13 mg/L (N = 25), which was not significantly different from 0.09 mg/L (N = 36) in other causes of death. Cocaine-related deaths mostly involved mixed drug intoxications including co-ingestion of heroin, cannabis, amphetamines as well as legal drugs, such as benzodiazepines and/or ethanol. The concentrations of cocaine in blood from living and deceased persons overlapped, which makes it infeasible to predict toxicity from the analytical toxicology results alone.
- Differences in the neurochemical and behavioural profiles of lisdexamfetamine methylphenidate and modafinil revealed by simultaneous dual-probe microdialysis and locomotor activity measurements in freely-moving rats. [JOURNAL ARTICLE]
- J Psychopharmacol 2013 Dec 10.
Lisdexamfetamine dimesylate is a novel prodrug approved in North America, Europe and Brazil for treating attention deficit hyperactivity disorder (ADHD). It undergoes rate-limited hydrolysis by red blood cells to yield d-amphetamine. Following our previous work comparing lisdexamfetamine with d-amphetamine, the neurochemical and behavioural profiles of lisdexamfetamine, methylphenidate and modafinil were compared by dual-probe microdialysis in the prefrontal cortex (PFC) and striatum of conscious rats with simultaneous locomotor activity measurement. We employed pharmacologically equivalent doses of all compounds and those that spanned the therapeutically relevant and psychostimulant range. Lisdexamfetamine (0.5, 1.5, 4.5 mg/kg d-amphetamine base, per os (po)), methylphenidate (3, 10, 30 mg/kg base, po) and modafinil (100, 300, 600 mg/kg base, po) increased efflux of dopamine and noradrenaline in PFC, and dopamine in striatum. Only lisdexamfetamine increased 5-hydroxytryptamine (5-HT) efflux in PFC and striatum. Lisdexamfetamine had larger and more sustained effects on catecholaminergic neurotransmission than methylphenidate or modafinil. Linear correlations were observed between striatal dopamine efflux and locomotor activity for lisdexamfetamine and methylphenidate, but not modafinil. Regression slopes revealed greater increases in extracellular dopamine could be elicited without producing locomotor activation by lisdexamfetamine than methylphenidate. These results are consistent with clinical findings showing that lisdexamfetamine is an effective ADHD medication with prolonged duration of action and good separation between its therapeutic actions and stimulant side-effects.
- Development of a method for the analysis of drugs of abuse in vitreous humor by capillary electrophoresis with diode array detection (CE-DAD). [JOURNAL ARTICLE]
- J Chromatogr B Analyt Technol Biomed Life Sci 2013 Oct 21.:84-91.
This work presents the development of an analytical method based on capillary electrophoresis with diode array detection for the analysis of drugs of abuse and biotransformation products in vitreous humor. Composition of the background electrolyte, implementation of an online pre-concentration strategy and sample preparation procedures were objects of study. The complete electrophoretic separation of 12 analytes (amphetamine, methamphetamine, 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyethylamphetamine (MDEA), ketamine, cocaine, cocaethylene, lidocaine, morphine, 6-monoacetylmorphine and heroin) and the internal standard N-methyl-1-(3,4-methylenedioxyphenyl)-2-butamine (MBDB) was obtained within 13min of run. The method was validated presenting good linearity (r(2)>0.99), recovery ≥90%, precision better than 12% RSD and acceptable accuracy in the range of 86-118% at three concentration levels (50, 100 and 500ng/mL). LODs and LOQs in the order of 1-5ng/mL and 5-10ng/mL, respectively, were obtained. After validation, the method was applied to eighty-seven vitreous humor samples and the results were compared to those obtained by a liquid chromatography tandem mass spectrometry (LC-MS/MS) screening method, routinely used by the forensic toxicology laboratory of the Sao Paulo State Police, Brazil. Cocaine was detected in 7.1%, cocaethylene in 3.6%, lidocaine in 2.4% and ketamine in 1.2% of the total number of analyzed samples.
- Neonatal Exposure to Estradiol Valerate Increases Dopamine Content in Nigrostriatal Pathway During Adulthood in the Rat. [JOURNAL ARTICLE]
- Horm Metab Res 2013 Dec 9.
Research in programming has focused in the study of stimuli that affect sensitive periods of development such as prenatal and neonatal stage. We previously showed that exposure to estradiol valerate to female rats during the first 12 h of life increased catecholamine content in ventromedial-arcuatus hypothalamus of the adult rat. However, changes in others dopaminergic circuits have not been studied. The purpose of this work was to determine the neurotransmitters changes induced by neonatal estradiol valerate (0.1 mg/50 μl s. c. per rat) administration on nigrostriatal pathway of adult female rats. Sesame oil (50 μl s. c. per rat) was administered in a control parallel group. EV-1 adult rats presented effective markers of long-term estrogenization as decreased serum levels of progesterone and a reduction in the size of estrogen-sensitive organs. In the brain, neonatal estradiol valerate administration led to a significant increase in dopamine content in striatum, substantia nigra and ventral tegmental area. With respect to the contents of dopamine metabolites, only 3-methoxytyramine content increased in substantia nigra and ventral tegmental area. In addition, the content of noradrenaline increased only in striatum. Interestingly, estrogenized rats lacked locomotor activity induced by acute dose of amphetamine (1 mg/kg i. p.). Altogether, these results show that neonatal exposure to estradiol valerate permanently modified the content of monoamine neurotransmitters in nigrostriatal pathway and amphetamine-induced locomotor activity of adult female rats. This might imply that estrogenized rats could have changes in the expression of key proteins in dopaminergic regulation, as tyrosine hydroxylase and dopamine transporter.
- Modulation of behavioral networks by selective interneuronal inactivation. [JOURNAL ARTICLE]
- Mol Psychiatry 2013 Dec 10.
Gamma-aminobutyric acid (GABA)-ergic disturbances are hallmark features of schizophrenia and other neuropsychiatric disorders and encompass multiple interneuronal cell types. Using bacterial artificial chromosome-driven, miRNA silencing technology we generated transgenic mouse lines that suppress glutamic acid decarboxylase 1 (GAD1) in either cholecystokinin (CCK)- or neuropeptide Y (NPY)-expressing interneurons. In situ lipidomic and proteomic analyses on brain tissue sections revealed distinct, brain region-specific profiles in each transgenic line. Behavioral analyses revealed that suppression of GAD1 in CCK+ interneurons resulted in locomotor and olfactory sensory changes, whereas suppression in NPY+ interneurons affected anxiety-related behaviors and social interaction. Both transgenic mouse lines had altered sensitivity to amphetamine albeit in opposite directions. Together, these data argue that reduced GAD1 expression leads to altered molecular and behavioral profiles in a cell type-dependent manner, and that these subpopulations of interneurons are strong and opposing modulators of dopamine system function. Furthermore, our findings also support the hypothesis that neuronal networks are differentially controlled by diverse inhibitory subnetworks.Molecular Psychiatry advance online publication, 10 December 2013; doi:10.1038/mp.2013.167.
- In vivo evidence for greater amphetamine-induced dopamine release in pathological gambling: a positron emission tomography study with [(11)C]-(+)-PHNO. [JOURNAL ARTICLE]
- Mol Psychiatry 2013 Dec 10.
Drug addiction has been associated with deficits in mesostriatal dopamine (DA) function, but whether this state extends to behavioral addictions such as pathological gambling (PG) is unclear. Here we used positron emission tomography and the D3 receptor-preferring radioligand [(11)C]-(+)-PHNO during a dual-scan protocol to investigate DA release in response to oral amphetamine in pathological gamblers (n=12) and healthy controls (n=11). In contrast with human neuroimaging findings in drug addiction, we report the first evidence that PG is associated with greater DA release in dorsal striatum (54-63% greater [(11)C]-(+)-PHNO displacement) than controls. Importantly, dopaminergic response to amphetamine in gamblers was positively predicted by D3 receptor levels (measured in substantia nigra), and related to gambling severity, allowing for construction of a mechanistic model that could help explain DA contributions to PG. Our results are consistent with a hyperdopaminergic state in PG, and support the hypothesis that dopaminergic sensitization involving D3-related mechanisms might contribute to the pathophysiology of behavioral addictions.Molecular Psychiatry advance online publication, 10 December 2013; doi:10.1038/mp.2013.163.
- Analysis of drugs of abuse in wastewater from two Canadian cities. [JOURNAL ARTICLE]
- Sci Total Environ 2013 Dec 6.
Several drugs of abuse, including amphetamines, cocaine and its metabolite, benzoylecgonine and several opioid prescription drugs were detected in wastewater from two Canadian cities, a small community (75,000 population) and a large urban center (1.6million population). The objective of this study was to evaluate community use of these drugs in two cities with large differences in population size and demographics. In addition, we evaluated the use of the Polar Organic Chemical Integrative Sampler (POCIS) as a monitoring tool for drugs of abuse. Heroin was not detected at either location, probably because this illicit drug is metabolized to morphine prior to excretion. Acetylcodeine and acetylmorphine were also not detected. Estimates of community consumption from wastewater analysis indicated that the most widely used drug was cocaine at a median level of consumption in the larger city of approximately 38 doses per day per 1000 people. Consumption of the substituted amphetamine, ephedrine, as well as methamphetamine was also higher in the larger city, at 21 and 1.8 doses per day per 1000 people, respectively. Use of amphetamine, MDMA and tramadol were similar in both centers, but use of oxycodone was greater in the smaller city. Use of MDMA (ecstasy) peaked on weekends. Ketamine was detected in wastewater from the larger city; the first report of abuse of this veterinary anesthetic in a North American city. POCIS sampling rates were determined for the first time for 7 of the target compounds. Comparing the time weighted average concentrations estimated from POCIS data to the concentrations obtained from 24-h composite samples, the data were generally comparable, except for some compounds which were not detected in POCIS deployed in the untreated wastewater, probably because of biofouling or accumulation of debris on the cages containing the POCIS. This study indicates that the size and demographics of population centers can influence the patterns of abuse of drugs.
- Effect of amphetamine on corrected-QT interval change during methadone maintenance treatment in Taiwan: A prospective cohort study. [JOURNAL ARTICLE]
- Drug Alcohol Rev 2013 Dec 10.
Previous studies have suggested that methadone is associated with prolonged corrected-QT (QTc) interval, but published prospective research studies in this area are relatively scarce. This study investigates QTc interval change among methadone maintenance patients and possible associated risk factors. One of the aims is to explore the effect of amphetamines.This prospective cohort study with six-month follow up assesses the effect of methadone on QTc interval among a sample (n = 170) of heroin users in a methadone maintenance treatment program in Taiwan. Demographic data, substance use history, medical history and laboratory studies were collected at study enrollment. Twelve-lead electrocardiograms were performed for all participants both at study enrollment and six months later.The median daily methadone dose was 41 mg. A mean increase of QTc interval (17.1 ms, SD = 50.0, P < 0.001) was found at six-month follow up. QTc interval prolongation in the sample at baseline was 2.9%, and at six months was 12.4%. A positive correlation was found between comorbid amphetamine use frequency in the past month and QTc interval change. Methadone dose was not associated with QTc change.An increase of mean QTc interval was found among methadone maintenance patients at six-month follow up. Electrocardiogram monitoring should be performed among patients who are at risk of frequently using amphetamines during methadone maintenance treatment.
- Khat and synthetic cathinones: a review. [JOURNAL ARTICLE]
- Arch Toxicol 2013 Dec 8.
For centuries, 'khat sessions' have played a key role in the social and cultural traditions among several communities around Saudi Arabia and most East African countries. The identification of cathinone as the main psychoactive compound of khat leaves, exhibiting amphetamine-like pharmacological properties, resulted in the synthesis of several derivatives structurally similar to this so-called natural amphetamine. Synthetic cathinones were primarily developed for therapeutic purposes, but promptly started being misused and extensively abused for their euphoric effects. In the mid-2000's, synthetic cathinones emerged in the recreational drug markets as legal alternatives ('legal highs') to amphetamine, 'ecstasy', or cocaine. Currently, they are sold as 'bath salts' or 'plant food', under ambiguous labels lacking information about their true contents. Cathinone derivatives are conveniently available online or at 'smartshops' and are much more affordable than the traditional illicit drugs. Despite the scarcity of scientific data on these 'legal highs', synthetic cathinones use became an increasingly popular practice worldwide. Additionally, criminalization of these derivatives is often useless since for each specific substance that gets legally controlled, one or more structurally modified analogs are introduced into the legal market. Chemically, these substances are structurally related to amphetamine. For this reason, cathinone derivatives share with this drug both central nervous system stimulating and sympathomimetic features. Reports of intoxication and deaths related to the use of 'bath salts' have been frequently described over the last years, and several attempts to apply a legislative control on synthetic cathinones have been made. However, further research on their pharmacological and toxicological properties is fully required in order to access the actual potential harm of synthetic cathinones to general public health. The present work provides a review on khat and synthetic cathinones, concerning their historical background, prevalence, patterns of use, legal status, chemistry, pharmacokinetics, pharmacodynamics, and their physiological and toxicological effects on animals and humans.
- Acute total sleep deprivation potentiates amphetamine-induced locomotor-stimulant effects and behavioral sensitization in mice. [JOURNAL ARTICLE]
- Pharmacol Biochem Behav 2013 Dec 4.
It has been demonstrated that a prolonged period (48h) of paradoxical sleep deprivation (PSD) potentiates amphetamine (AMP)-induced behavioral sensitization, an animal model of addiction-related neuroadaptations. In the present study, we examined the effects of an acute short-term deprivation of total sleep (TSD) (6h) on AMP-induced behavioral sensitization in mice and compared them to the effects of short-term PSD (6h). Three-month-old male C57BL/6J mice underwent TSD (experiment 1-gentle handling method) or PSD (experiment 2-multiple platforms method) for 6h. Immediately after the sleep deprivation period, mice were tested in the open field for 10min under the effects of saline or 2.0mg/kg AMP. Seven days later, to assess behavioral sensitization, all of the mice received a challenge injection of 2.0mg/kg AMP and were tested in the open field for 10min. Total, peripheral, and central locomotion, and grooming duration were measured. TSD, but not PSD, potentiated the hyperlocomotion induced by an acute injection of AMP and this effect was due to an increased locomotion in the central squares of the apparatus. Similarly, TSD facilitated the development of AMP-induced sensitization, but only in the central locomotion parameter. The data indicate that an acute period of TSD may exacerbate the behavioral effects of AMP in mice. Because sleep architecture is composed of paradoxical and slow wave sleep, and 6-h PSD had no effects on AMP-induced hyperlocomotion or sensitization, our data suggest that the deprivation of slow wave sleep plays a critical role in the mechanisms that underlie the potentiating effects of TSD on both the acute and sensitized addiction-related responses to AMP.