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- Bath Salts in the Emergency Department: A Survey of Emergency Clinicians' Experience With Bath Salts-Intoxicated Patients. [JOURNAL ARTICLE]
- J Addict Med 2014 Dec 18.
Several novel synthetic amphetamines have been marketed worldwide as "bath salts." The use of bath salts is associated with severe medical consequences resulting in a US federal ban over the last 3 years on the more common substances found in this group. Bath salts intoxication has a relatively nonspecific presentation, and urine toxicology confirmation in emergency departments (EDs) is impractical because the turnaround time is several days. Emergency clinicians must therefore rely heavily on patients' self-reports to verify the diagnosis. We performed an online survey of emergency clinicians to determine their degree of exposure to bath salts-intoxicated patients, the clinically relevant features of such patients, and the typical emergency management.We invited 124 physicians and physician assistants in 7 Cleveland Clinic EDs to participate in an online survey.From a total of 43 of the 124 respondents, 77% did not specifically ask patients about bath salts use. Sixty percent had encountered a bath salts-intoxicated individual. Most respondents reported that the majority of patients were male, were between 19 and 29 years old, and used other drugs in addition to bath salts. Agitation, aggression/violence, and hallucinations were reported to be the most common presentations, and intravenous/intramuscular tranquilization was reported as the most often used management. Most patients were discharged home from the ED.Despite the lack of toxicology screening in EDs, about two thirds of the surveyed emergency clinicians encountered bath salts-intoxicated individuals. Our study demonstrates the need for increased screening of bath salts intoxication in EDs, especially in agitated patients.
- Changes in serotonin transporter (5-HTT) gene expression in peripheral blood cells after MDMA intake. [JOURNAL ARTICLE]
- Psychopharmacology (Berl) 2014 Dec 20.
3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is an amphetamine derivative abused worldwide. Although data report that relatively high doses of MDMA deplete serotonin (5-HT) content and decrease the availability of serotonin transporters (5-HTT), there is no available evidence as to the adaptive mechanisms taking place in 5-HTT gene expression following MDMA intake in humans.To evaluate the pharmacological effects of MDMA on 5-HTT gene expression, using peripheral mononuclear cells as a biomarker of the central nervous system, and study whether an association exists between 5-HTT gene expression and psychobiological scores.A randomized, double-blind, controlled trial was conducted in 18 (nine women) healthy recreational MDMA users. Subjects were genotyped for 5-HTT linked polymorphism region (5-HTTLPR). MDMA 75 mg or placebo was administered; Profile of Mood States (POMS) and 5-HTT gene expression measures were performed at baseline, 90, and 165 min post administration. POMS scores were correlated with changes in gene expression.The administration of 75 mg MDMA induced a significant twofold increase in 5-HTT gene expression after 165 min of drug administration. Significant associations were found between gene expression and POMS scores after MDMA administration. Results for each gender and 5-HTTLPR genotype are also reported.Preliminary results show that MDMA causes substantial regulatory changes in the expression of serotonergic markers, likely being modulated by the 5-HTTLPR polymorphism. Changes in 5-HTT gene expression may play an important role in the regulation of mood state.
- Manganese-enhanced Magnetic Resonance Imaging Reveals Differential Long-term Neuroadaptation after Methamphetamine and the Substituted Cathinone 4-Methylmethcathinone (Mephedrone). [JOURNAL ARTICLE]
- Int J Neuropsychopharmacol 2014 Dec 7.
In recent years there has been a large increase in the use of substituted cathinones such as mephedrone (4-methylmethcathinone, 4-MMC), a psychostimulant drug that shows a strong resemblance to methamphetamine (METH). Unlike METH, which can produce clear long-term effects, the effects of 4-MMC have so far remained elusive. We employ manganese-enhanced magnetic resonance imaging (MEMRI), a highly sensitive method for detecting changes in NEURONAL ACTIVATION: , to investigate the effects of METH and 4-MMC on the brain.we performed a MEMRI scan 2 weeks after binge treatments (twice daily for 4 consecutive days) of METH (5 mg/kg) or 4-MMC (30 mg/kg). Furthermore, locomotor activity measurements and novel object recognition tests were performed.METH produced a widespread pattern of decreased BILATERAL: activity in several regions including the nucleus accumbens, caudate putamen, globus pallidus, thalamus, hippocampus as well as several other cortical and subcortical areas. Conversely, 4-MMC produced increased BILATERAL: activity, anatomically limited to the hypothalamus and hippocampus. Drug treatments did not affect the development of locomotor sensitization or novel object recognition performance. CONCLUSIONS: THE PATTERN OF DECREASED BRAIN ACTIVITY SEEN AFTER METH CORRESPONDS CLOSELY TO REGIONS KNOWN TO BE AFFECTED BY THIS DRUG AND CONFIRMS THE VALIDITY OF MEMRI FOR DETECTING NEUROADAPTATION TWO WEEKS AFTER AMPHETAMINE BINGE-TREATMENT: . 4-MMC, unlike METH, produced increased activity in a limited number of different brain regions. This highlights an important difference in the long-term effects of these drugs on neural function and shows precisely the anatomical localization of 4-MMC induced neuroadaptation.
- Amphetamine Decreases α2C-Adrenoceptor Binding of [11C]ORM-13070 - A PET Study in the Primate Brain. [JOURNAL ARTICLE]
- Int J Neuropsychopharmacol 2014 Dec 13.
The neurotransmitter norepinephrine has been implicated in psychiatric and neurodegenerative disorders. Examination of synaptic norepinephrine concentrations in the living brain may be possible with positron emission tomography (PET), but has been hampered by the lack of suitable radioligands. We explored the use of the novel α2C-adrenoceptor antagonist PET tracer [(11)C]ORM-13070 for measurement of amphetamine-induced changes in synaptic norepinephrine. The effect of amphetamine on [(11)C]ORM-13070 binding was evaluated ex vivo in rat brain sections and in vivo with PET imaging in monkeys. Microdialysis experiments confirmed amphetamine-induced elevations in rat striatal norepinephrine and dopamine concentrations. Regional [(11)C]ORM-13070 receptor binding was high in the striatum and low in the cerebellum. After injection of [(11)C]ORM-13070 in rats, mean striatal specific binding ratios, determined using cerebellum as a reference region, were 1.4 ± 0.3 after vehicle pretreatment and 1.2 ± 0.2 after amphetamine administration (0.3 mg/kg, s.c.). Injection of [(11)C]ORM-13070 in nonhuman primates resulted in mean striatal binding potential (BPND) estimates of 0.65 ± 0.12 at baseline. Intravenous administration of amphetamine (0.5 and 1.0 mg/kg, i.v.) reduced BPND values by 31-50 %. Amphetamine (0.3 mg/kg, s.c.) increased extracellular norepinephrine (by 400 %) and dopamine (by 270 %) in rat striatum. Together, these results indicate that [(11)C]ORM-13070 may be a useful tool for evaluation of synaptic norepinephrine concentrations in vivo. Future studies are required to further understand a potential contribution of dopamine to the amphetamine-induced effect.
- Effects of pubertal cannabinoid administration on attentional set-shifting and dopaminergic hyper-responsivity in a developmental disruption model of schizophrenia. [JOURNAL ARTICLE]
- Int J Neuropsychopharmacol 2014 Dec 13.
Adolescent exposure to cannabinoids in vulnerable individuals is proposed to be a risk factor for psychiatric conditions later in life, particularly schizophrenia. Evidence from studies in animals has indicated that a combination of repeated pubertal cannabinoid administration with either neonatal prefrontocortical lesion, isolation rearing or chronic NMDA receptor antagonism administration induces enhanced schizophrenia-like behavioral disruptions. The effects of adolescent exposure to CB1 receptor agonists, however, have not been tested in a developmental disruption model of schizophrenia. This was tested in the methylazoxymethanol (MAM) model, in which repeated treatment with the synthetic cannabinoid agonist WIN 55,212-2 (WIN; 1.2 mg/kg) was extended over 25 days throughout puberty (PD40-PD65) in control and MAM rats. The rats received 20 injections which were delivered irregularly to mimic the human condition. Adult rats were tested for attentional set-shifting task and locomotor response to amphetamine, which was compared with in vivo recording from ventral tegmental area (VTA) dopamine (DA) neurons. MAM-treated rats showed impairment in the attentional set-shifting task, augmented locomotor response to amphetamine administration and increased number of spontaneously active DA neurons in the VTA. Interestingly, pubertal WIN treatment in normal animals induced similar changes at adulthood as those observed in MAM-treated rats, supporting the notion that adolescence exposure to cannabinoids may represent a risk factor for developing schizophrenia-like signs at adulthood. However, contrary to expectations, pubertal WIN administration did not exacerbate the behavioral and electrophysiological changes in MAM-treated rats beyond that observed in WIN-treated saline rats. Indeed, WIN treatment actually attenuated the locomotor response to amphetamine in MAM rats without impacting DA neuron activity states. Taken together, the present results indicate that the impact of cannabinoids during puberty/adolescence on schizophrenia models is more complex than may be predicted.
- Stimulant use disorders in people with psychosis: A meta-analysis of rate and factors affecting variation. [REVIEW]
- Aust N Z J Psychiatry 2014 Dec 17.
Stimulant abuse and dependence often complicate the care of people with psychotic disorders. This study systematically reviews the prevalence estimates reported for stimulant abuse and dependence in people with psychotic disorders, and examines personal, clinical, regional and methodological factors which explain variation in these rates.PsychINFO, EMBASE and MEDLINE (1946-2013) were searched systematically for studies reporting on stimulant drug use disorders in representative samples of people with psychotic disorders. Random effects models estimated the pooled rate of a stimulant use disorder, defined to include stimulant abuse and stimulant dependence. Study characteristics associated with heterogeneity in rates of stimulant use disorder were examined by subgroup analyses for categorical variables, by meta-regression for continuous independent variables and by multiple meta-regression.Sixty-four studies provided 68 estimates of lifetime or recent stimulant use disorders in 22,500 people with psychosis. The pooled rate of stimulant use disorder was 8.9% (95% CI 7.4%, 10.5%). Higher rates of stimulant use disorders were reported in studies of affective psychosis, studies from inpatient settings, studies from the USA and Australia, and studies with higher rates of cannabis disorder; in multiple meta-regression analysis these factors explained 68% of between-study variance. Rates of stimulant use disorder were stable over time, and unrelated to age, sex, stage of psychosis, type of stimulant drug or study methodology factors.Reported rates of stimulant use disorder in people with psychosis are much higher than in the general population but vary widely and are associated with regional, service setting and clinical differences between studies. It is likely that stimulants contribute to the overall burden of psychosis, and that social and environmental factors combine with drug and illness-related factors to influence stimulant use in psychosis.
- Serotonin/Dopamine Interactions in a Hyperactive Mouse: Reduced Serotonin Receptor 1B Activity Reverses Effects of Dopamine Transporter Knockout. [JOURNAL ARTICLE]
- PLoS One 2014; 9(12):e115009.
Knockout (KO) mice that lack the dopamine transporter (SL6A3; DAT) display increased locomotion that can be attenuated, under some circumstances, by administration of drugs that normally produce psychostimulant-like effects, such as amphetamine and methylphenidate. These results have led to suggestions that DAT KO mice may model features of attention deficit hyperactivity disorder (ADHD) and that these drugs may act upon serotonin (5-HT) systems to produce these unusual locomotor decreasing effects. Evidence from patterns of brain expression and initial pharmacologic studies led us to use genetic and pharmacologic approaches to examine the influence of altered 5-HT1B receptor activity on hyperactivity in DAT KO mice. Heterozygous 5-HT1B KO and pharmacologic 5-HT1B antagonism both attenuated locomotor hyperactivity in DAT KO mice. Furthermore, DAT KO mice with reduced, but not eliminated, 5-HT1B receptor expression regained cocaine-stimulated locomotion, which was absent in DAT KO mice with normal levels of 5-HT1B receptor expression. Further experiments demonstrated that the degree of habituation to the testing apparatus determined whether cocaine had no effect on locomotion in DAT KO or reduced locomotion, helping to resolve differences among prior reports. These findings of complementation of the locomotor effects of DAT KO by reducing 5-HT1B receptor activity underscore roles for interactions between specific 5-HT receptors and dopamine (DA) systems in basal and cocaine-stimulated locomotion and support evaluation of 5-HT1B antagonists as potential, non-stimulant ADHD therapeutics.
- Amphetamine activates/potentiates a ligand-gated ion channel. [Comment, Journal Article]
- Channels (Austin) 2014; 8(4):294-5.
- Electrochemical simulation of cocaine metabolism-a step toward predictive toxicology for drugs of abuse. [Journal Article, Research Support, Non-U.S. Gov't]
- Eur J Mass Spectrom (Chichester, Eng) 2014; 20(4):279-85.
Knowledge of the metabolic pathways and biotransformation of the most popular drugs, such as cocaine, amphetamine, morphine and others, is crucial for the elucidation of their possible toxicity and mechanism of action in the human body. In vitro studies on metabolism are mainly based on the incubation of drugs with liver celL homogenate and utilizing Living animals. These methods need to be followed by isolation and detection of metabolic products, which makes these techniques time-consuming and technically demanding. We show here that the oxidative metabolism that occurs in the liver cells and is mainly caused by cytochrome P450 can be successfully mimicked with the electrochemical system [EC] connected on-line with electrospray ionization mass spectrometry. Cocaine was chosen as a model drug for these studies and was analyzed with a previously described system under various conditions using the boron-doped diamond working electrode. The results were compared with the number of metabolites generated by a standard procedure based on the reaction with the rat Liver microsomes. Two electrochemical products of cocaine oxidation were created, of which one was a natural metabolite of cocaine in the human body-norcocaine. The EC provides a promising platform for the screening of the addictive drug phase I metabolism. The metabolites can be directly analyzed by mass spectrometry or collected and separated by Liquid chromatog- raphy. No Liver cell homogenate or microsome is necessary to generate these metabolites, which simplifies separation of the mixtures and reduces time and costs of all experiments.
- PDE10A inhibitors stimulate or suppress motor behavior dependent on the relative activation state of the direct and indirect striatal output pathways. [Journal Article]
- Pharmacol Res Perspect 2014 Aug; 2(4):e00057.
The enzyme phosphodiesterase 10A (PDE10A) regulates the activity of striatal, medium spiny neurons (MSNs), which are divided into a behaviorally stimulating, Gs-coupled D1 receptor-expressing "direct" pathway and a behaviorally suppressant, Gi-coupled D2 receptor-expressing "indirect" pathway. Activating both pathways, PDE10A inhibitors (PDE10AIs) combine functional characteristics of D2 antagonists and D1 agonists. While the effects of PDE10AIs on spontaneous and stimulated behavior have been extensively reported, the present study investigates their effects on suppressed behavior under various conditions of reduced dopaminergic neurotransmission: blockade of D1 receptors with SCH-23390, blockade of D2 receptors with haloperidol, or depletion of dopamine with RO-4-1284 or reserpine. In rats, PDE10AIs displayed relatively low cataleptic activity per se. After blocking D1 receptors, however, they induced pronounced catalepsy at low doses close to those required for inhibition of apomorphine-induced behavior; slightly higher doses resulted in behavioral stimulant effects, counteracting the catalepsy. PDE10AIs also counteracted catalepsy and related behaviors induced by D2 receptor blockade or dopamine depletion; catalepsy was replaced by behavioral stimulant effects under the latter but not the former condition. Similar interactions were observed at the level of locomotion in mice. At doses close to those inhibiting d-amphetamine-induced hyperlocomotion, PDE10AIs reversed hypolocomotion induced by D1 receptor blockade or dopamine depletion but not hypolocomotion induced by D2 receptor blockade. It is concluded that PDE10AIs stimulate or inhibit motor behavior dependent on the relative activation state of the direct and indirect striatal output pathways.