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- Harm reduction history, response, and current trends in Asia. [JOURNAL ARTICLE]
- J Food Drug Anal 2013 Dec; 21(4):S113-S116.
HIV epidemics in Asia have been initially driven through injecting drug use and the use of shared needles and syringes. Molecular epidemiological work has shown that where there is heroin trafficking and use, so too is there HIV. Given the often strict enforcement of national anti-narcotic laws, harm reduction responses to HIV infections driven by injecting drug use have been historically slow. As it became clear that preventing HIV meant embracing harm reduction, many countries in the region have adopted harm reduction as part of their national AIDS strategy and increasingly as part of their national drug strategy. Initial successes have proven that harm reduction, as it pertains to HIV among IDUs, can and does work in Asia. These initial successes have led to more comprehensive scale-up of other essential components of HIV prevention among IDUs, including increased availability of opiate substitution programs. Still, multiple challenges remain as overall coverage of services in the region remains poor. Changes in the availability and patterns of use of drugs, including the exponential increase in the use of amphetamine-type stimulants, is providing ongoing challenges to both the law enforcement and public health sectors. This paper reflects on the history of harm reduction in Asia and the shifting trends forcing policy makers to adapt and expand harm reduction strategies to include an ever widening approach to criminal justice, policing, public health, and human rights.
- Underestimation of substance abuse in psychiatric patients by conventional hospital screening. [JOURNAL ARTICLE]
- J Psychiatr Res 2014 Sep 10.
Psychiatric diagnosis mainly relies on behavioral signs and symptoms. Substance abuse can mimic the clinical presentation of primary psychiatric disorders and can also complicate the management of psychiatric patients. The reliability and accuracy of urine toxicology is a vital tool in the optimal treatment of these patients. Current demographics of substance abuse suggest that in addition to the most conventional drugs of abuse (e.g. cocaine, cannabis) that are of concern to treating physicians, prescription medications and new designer drugs also should be when evaluating patients who present with symptoms of psychosis/drug addiction or altered mental status.Urine samples from 220 psychiatric inpatients admitted to either an acute drug and alcohol unit or acute psychiatric unit were analyzed for drugs by the standard hospital assay (KIMS) and by a more sensitive ELISA and GC-MS basic drug screening protocol.The standard hospital toxicology (KIMS) was inferior to the ELISA and GC-MS methods in terms of both assay sensitivity and in detecting a broader number of drugs. The KIMS tests failed to identify opiates and amphetamine/methamphetamine in 50% of the patients. The KIMS screen did not identify zolpidem, buprenorphine and a number of synthetic drugs of abuse including cathinone and tryptamines.In order to reliably identify substance abuse in patients with altered mental status in inpatient settings, analytical methodologies with adequate assay sensitivity and range to detect the vast majority of commonly abused illicit drugs and prescription medications are required for optimal clinical assessment and treatment.
- Inhibition of urokinase plasminogen activator "uPA" activity alters ethanol consumption and conditioned place preference in mice. [Journal Article]
- Drug Des Devel Ther 2014.:1391-403.
Urokinase plasminogen activator, uPA, is a serine protease implicated in addiction to drugs of abuse. Using its specific inhibitor, B428, we and others have characterized the role of uPA in the rewarding properties of psychostimulants, including cocaine and amphetamine, but none have examined the role of uPA in ethanol use disorders. Therefore, in the current study, we extended our observations to the role of uPA in ethanol consumption and ethanol-induced conditioned place preference. The general aim of the present series of experiments was to investigate the effects of the administration of the B428 on voluntary alcohol intake and ethanol conditioned reward. A two-bottle choice, unlimited-access paradigm was used to compare ethanol intake between vehicle- and 3, 10, and 30 mg/kg B428-administered mice. For this purpose, the mice were presented with an ethanol solution (2.5%-20%) and water, at each concentration for 4 days, and their consumption was measured daily. Consumption of saccharin and quinine solutions was also measured. Systemic administration of B428 dose-dependently decreased ethanol intake and preference. Additionally, B428 mice did not differ from vehicle mice in their intake of graded solutions of tastants, suggesting that the uPA inhibition did not alter taste function. Also, ethanol metabolism was not affected following B428 injection. More importantly, 1.5 g/kg ethanol-induced conditioned place preference acquisition was blocked following B428 administration. Taken together, our results are the first to implicate uPA inhibition in the regulation of ethanol consumption and preference, and suggest that uPA may be considered as a possible therapeutic drug target for alcoholism and abstinence.
- Tolcapone suppresses ethanol intake in alcohol-preferring rats performing a novel cued access protocol. [Journal Article]
- Alcohol Clin Exp Res 2014 Sep; 38(9):2468-78.
Dopamine (DA) has been shown to play a central role in regulating motivated behavior and encoding reward. Chronic drug abuse elicits a state of hypodopaminergia in the mesocorticolimbic (MCL) system in both humans and preclinical rodent models of addiction, including those modeling alcohol use disorders (AUD).Working under the hypothesis that reductions in the bioavailability of DA play an integral role in the expression of the excessive drinking phenotype, the catechol-O-methyltransferase (COMT) inhibitor tolcapone was used as a means to amplify cortical DA concentration and drinking behaviors were then assessed. Sucrose and ethanol (EtOH) consumption were measured in P and Wistar rats in both a free choice drinking protocol and a novel cued access protocol.Tolcapone attenuated the consumption of EtOH, and to a lesser extent sucrose, in P rats in the cued access protocol, while no effect was observed in the free choice drinking protocol. Tolcapone also decreased EtOH consumption in high drinking Wistar rats. A follow-up experiment using the indirect DA agonist d-amphetamine showed no change in EtOH consumption.Collectively, these data suggest that COMT inhibitors may be capable of alleviating the extremely motivating or salient nature of stimuli associated with alcohol. The hypothesis is put forth that the relative specificity of tolcapone for cortical DA systems may mediate the suppression of the high seeking/drinking phenotype.
- Microinjection of cocaine- and amphetamine-regulated transcript 55-102 peptide into the nucleus accumbens could modulate anxiety-related behavior in rats. [JOURNAL ARTICLE]
- Neuropeptides 2014 Sep 10.
Cocaine- and amphetamine-regulated transcript (CART) peptide is abundantly expressed in the nucleus accumbens (NAcc) and is involved in stress, anxiety and reward responses. To examine the role of CART peptide in anxiety-related behavior, naïve rats were bilaterally injected with CART 55-102 peptide (0.5, 1.0 or 2.5 µg/0.5 µl/side) or vehicle into the NAcc. Following this, their anxiety-related behavior was assessed using the elevated plus maze and the open field tests with a one-week interval between the tests. There was no difference in the time spent in open arms, or number of entries into open arms on the elevated plus maze in the CART-treated animals at any dose, when compared with the vehicle-treated group. However, there was a significant increase in the time spent in the center of the open field with administration of the low dose of CART peptide (0.5 µg/0.5 µl/side), although this effect disappeared at the high dose (2.5 µg/0.5 µl/side). None of the doses of CART peptide altered total locomotion in these tests. To further determine the possible anxiety-modulating effect of CART peptide at low dosages, the light and dark test was performed. Additional groups of rats given doses of 0.01 µg/0.5 µl/side or 0.5 µg/0.5 µl/side of CART peptide showed increased exploration time in the light side. These results suggest that accumbal-CART peptide reduces anxiety-like behavior in a dose-dependent manner.
- Stereochemistry of mephedrone neuropharmacology: enantiomer-specific behavioral and neurochemical effects in rats. [JOURNAL ARTICLE]
- Br J Pharmacol 2014 Sep 26.
Synthetic cathinones, commonly referred to as "bath salts", are a group of amphetamine-like drugs gaining popularity worldwide. 4-Methylmethcathinone (mephedrone, MEPH) is the most commonly abused synthetic cathinone in the United Kingdom, and exerts its effects by acting as a substrate-type releaser at monoamine transporters. Similar to other cathinone-related compounds, MEPH has a chiral center and exists stably as two enantiomers, R-mephedrone (R-MEPH) and S-mephedrone (S-MEPH).Here, we provide the first investigation into the neurochemical and behavioral effects of R- and S-MEPH. We analyzed both enantiomers in rat brain synaptosome neurotransmitter release assays, as well as investigated effects on locomotor activity (eg. ambulatory activity and repetitive movements), behavioral sensitization, and reward.Both enantiomers displayed similar potency as substrates (i.e., releasers) at dopamine transporters, but R-MEPH was much less potent than S-MEPH as a substrate at serotonin transporters. Locomotor activity was evaluated in acute and repeated administration paradigms, with R-MEPH producing greater repetitive movements than S-MEPH across multiple doses. After repeated drug exposure, only R-MEPH produced sensitization of repetitive movements. R-MEPH produced a conditioned place preference whereas S-MEPH did not. Lastly, R-MEPH and S-MEPH produced biphasic profiles in an assay of intracranial self-stimulation (ICSS), but R-MEPH produced greater ICSS facilitation than S-MEPH.Our data are the first to demonstrate stereospecific effects of MEPH enantiomers and suggest that predominant dopaminergic actions of R-MEPH (i.e., the lack of serotonergic actions) render this stereoisomer more stimulant-like when compared to S-MEPH. This hypothesis warrants further study.
- Relationships Between Computer-Based Testing and Behavioral Ratings in the Assessment of Attention and Activity in a Pediatric ADHD Stimulant Crossover Trial. [JOURNAL ARTICLE]
- Clin Neuropsychol 2014 Sep 24.:1-16.
This study investigated the relationships between computer-based testing and behavioral ratings in the assessment of stimulant-induced changes in attention and activity in a pediatric ADHD crossover trial with methylphenidate, dextroamphetamine, and a placebo. Here 36 children between 9 and 14 years old were randomly and evenly assigned to each of six counterbalanced drug orders. A computer-based continuous performance test combined with a motion-tracking system (cb-CPT-MTS) and an ADHD questionnaire rated by teachers constituted the outcome measures. All outcome measures responded to stimulants in a comparable way at the group level, as shown by significant treatment effects of similar size for the two stimulants compared with a placebo. Computer-based and rating-based measures were unrelated in the assessment of stimulant-induced changes in attention and activity in individual children; no significant correlations between these measures in the assessment of change from placebo to stimulant conditions across the sample were detected. Results suggest that computer-based testing and behavioral ratings cannot be considered equivalent in the assessment of stimulant-induced changes in attention and activity among ADHD children.
- Evidence That Formulations of the Selective MAO-B Inhibitor, Selegiline, Which Bypass First-Pass Metabolism, Also Inhibit MAO-A in the Human Brain. [JOURNAL ARTICLE]
- Neuropsychopharmacology 2014 Sep 24.
Selegiline is a selective, irreversible inhibitor of monoamine oxidase B (MAO-B) at the conventional dose (10 mg/day oral) that is used in the treatment of Parkinson's disease. However, controlled studies have demonstrated antidepressant activity for high doses of oral selegiline and for transdermal selegiline suggesting that when plasma levels of selegiline are elevated, brain MAO-A might also be inhibited. Zydis selegiline (Zelapar®) is an orally disintegrating formulation of selegiline, which is absorbed through the buccal mucosa producing higher plasma levels of selegiline and reduced amphetamine metabolites compared to equal doses of conventional selegiline. Although there is indirect evidence that Zydis selegiline at high doses loses its selectivity for MAO-B, there is no direct evidence that it also inhibits brain MAO-A in humans. We measured brain MAO-A in 18 healthy men after a 28-day treatment with Zydis selegiline (2.5, 5.0 or 10 mg/day) and in 3 subjects receiving the selegiline transdermal system (Emsam patch, 6 mg/day) using PET and the MAO-A radiotracer [(11)C]clorgyline. We also measured dopamine transporter (DAT) availability in three subjects from the 10 mg group. The 10 mg Zydis selegiline dose significantly inhibited MAO-A (36.9±19.7%, range 11-70%, p<0.007)) but not DAT; and while Emsam also inhibited MAO-A (33.2±28.9 (range 9-68%) the difference did not reach significance (p=0.10) presumably because of the small sample size. Our results provide the first direct evidence of brain MAO-A inhibition in humans by formulations of selegiline, which are currently postulated but not verified to target brain MAO-A in addition to MAO-B.Neuropsychopharmacology accepted article preview online, 24 September 2014. doi:10.1038/npp.2014.214.
- Identification and quantitation of 4-bromo-2,5-dimethoxyamphetamine in seized blotters. [JOURNAL ARTICLE]
- Leg Med (Tokyo) 2014 Sep 11.
Blotters are usually impregnated with hallucinogens such as lysergic acid diethylamide (LSD); only rarely other psychoactive substances are detected. In this work we identified 4-bromo-2,5-dimethoxyamphetamine (DOB) and 2,5-dimethoxyamphetamine (DMA) in illicit blotters seized in Italy. This report describes a rapid method for the simultaneous identification and quantitation of DOB and its precursor (DMA) by liquid chromatography tandem mass spectrometry (LC-MS-MS), using 2,3-dimethoxyphenethylamine-d3 as internal standard. Regression equations were linear over the tested concentration range with good correlation coefficients. The achieved levels of sensitivity may be suitable to confirm the possible presence of DOB and DMA also in low concentration or in traces in seized material for forensic analysis. The developed method showed good reproducibility and sensitivity, and could be used for similar routine analysis. To our knowledge, this is the first report describing the detection of DOB and DMA from blotters.
- Repeated amphetamine treatment alters spinal magnetic resonance signals and pain sensitivity in mice. [JOURNAL ARTICLE]
- Neurosci Lett 2014 Sep 22.
Manganese-enhanced magnetic resonance imaging (MEMRI) has been extensively used in studying the structural and functional features of the central nervous system (CNS). Divalent manganese ion (Mn(2+)) not only enhances MRI contrast, but also enters cells via voltage-gated calcium channels or ionotropic glutamate receptors, which represents an index of neural activities. In the current mouse model, following repeated amphetamine (Amph) treatment, a reduction of reactivity to thermal pain stimulus was noticed. Since the spinal dorsal horn is the first relay station for pain transmission in the CNS, we examined the changes of neural activity in the dorsal spinal cord, particularly the superficial dorsal horn, by analyzing manganese-enhanced T1-weighted MR images (T1WIs). Our data revealed a temporal correlation between reduced pain sensitivity and increased MEMR signals in the spinal dorsal horn subsequent to repeated Amph treatments.