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- Withdrawal from chronic amphetamine reduces dopamine transmission in the rat lateral septum. [JOURNAL ARTICLE]
- J Neurosci Res 2014 Feb 19.
The lateral septum (LS) is a brain nucleus implicated in the addictive process. This study investigated whether withdrawal from chronic amphetamine (AMPH) induces alterations in dopamine (DA) transmission within the LS. Male Sprague-Dawley rats were injected with AMPH (2.5 mg/kg i.p.) or saline during 14 days and thereafter subjected to 24 hr or 14 days of withdrawal. After these withdrawal periods, we measured DA extracellular levels by in vivo microdialysis, DA tissue levels, and tyrosine hydroxylase (TH) and vesicular monoamine transporter-2 (VMAT2) expression in the LS. Our results showed a significant decrease in K(+) -induced release of DA in the LS of AMPH-treated rats, 14 days after withdrawal compared with saline-treated rats. There were no significant differences in DA tissue content and TH expression. Interestingly, there was a decrease of LS VMAT2 expression in AMPH-treated rats, 14 days after withdrawal compared with saline-treated rats. This is the first neurochemical evidence showing that withdrawal from repeated AMPH administration decreases K(+) -induced DA release in the rat LS. Our results suggest that this decrease in DA releasability could be due to a decrease in DA vesicular uptake. The possibility that these neurochemical changes are associated with AMPH abstinence syndrome should be further explored. © 2014 Wiley Periodicals, Inc.
- An N-Terminal Threonine Mutation Produces an Efflux-flavorable, Sodium-primed Conformation of the Human Dopamine Transporter. [JOURNAL ARTICLE]
- Mol Pharmacol 2014 Apr 21.
The dopamine transporter (DAT) reversibly transports dopamine (DA) through a series of conformational transitions. Alanine (T62A) or aspartate (T62D) mutagenesis of Thr 62 revealed T62D-hDAT partitions in a predominately efflux-preferring conformation. Compared to wild type (WT), T62D-hDAT exhibits reduced [(3)H]DA uptake and enhanced baseline DA efflux, while T62A-hDAT and WT-hDAT function in an influx-preferring conformation. We now interrogate the basis of the mutants' altered function with respect to membrane conductance and Na(+) sensitivity. The hDAT constructs were expressed in Xenopus oocytes to investigate if heightened membrane potential would explain the efflux characteristics of T62D-hDAT. In the absence of substrate, all constructs displayed identical resting membrane potentials. Substrate-induced inward currents were present in oocytes expressing WT- and T62A-hDAT but not T62D-hDAT suggesting bidirectional, equal ion flow through T62D-hDAT. Utilization of the fluorescent DAT substrate, ASP(+), revealed that T62D-hDAT accumulates substrate in HEK-293 cells when the substrate is not subject to efflux. Extracellular sodium (Na(+)e) replacement was used to evaluate sodium gradient requirements for DAT transport functions. The EC50 for Na(+)e stimulation of [(3)H]DA uptake was identical in all constructs expressed in HEK-293 cells. As expected, decreasing [Na(+)]e stimulated [(3)H]DA efflux in WT- and T62A-hDAT cells. Conversely, the elevated [(3)H]DA efflux in T62D-hDAT cells was independent of Na(+)e and commensurate with [(3)H]DA efflux attained in WT-hDAT cells either by removal of Na(+)e or by application of AMPH. We conclude that T62D-hDAT represents an efflux-willing, Na(+)-primed orientation-possibly representing an experimental model of the conformational impact of AMPH exposure to hDAT.
- Improvements in analytical methodology for the determination of frequently consumed illicit drugs in urban wastewater. [JOURNAL ARTICLE]
- Anal Bioanal Chem 2014 Apr 22.
Rapid and sensitive analytical methodology based on ultra high-performance liquid chromatography-tandem mass spectrometry has been developed for the determination of widely consumed drugs of abuse (amphetamines, MDMA, cocaine, opioids, cannabis and ketamine) and their major metabolites in urban wastewaters. Sample clean-up and pre-concentration was performed by a generic off-line SPE procedure using Oasis HLB. Special effort was made to incorporate amphetamine, which was found highly problematic in the wastewater samples tested, including an additional clean-up with Oasis MCX SPE and dispersive primary secondary amine. Correction for possible SPE losses or degradation during storage was made by the use of isotope-labelled internal standards (ILIS), available for all compounds, which were added to the samples as surrogates. Although ILIS were also efficient for matrix effects correction, the strong ionization suppression observed was not eliminated; therefore, a four-fold dilution prior to SPE was applied to influent wastewaters and a low injection volume was selected (3 μL), in order to reach a compromise between matrix effects, chromatographic performance and sensitivity. The method was validated at 25 and 200 ng L(-1) (effluent), and 100 and 800 ng L(-1) (influent), obtaining limits of quantification (i.e. the lowest level that the compound can be quantified and also confirmed with at least two MS/MS transitions) between 0.4-25 ng L(-1) (effluent) and 2-100 ng L(-1) (influent). The applicability of the method was demonstrated by analysis of 14 influent and 14 effluent wastewater samples collected over 2 weeks in Castellón (Spain) within a European collaborative study.
- Amphetamine-induced release of dopamine in primate prefrontal cortex and striatum: striking differences in magnitude and timecourse. [JOURNAL ARTICLE]
- J Neurochem 2014 Apr 21.
The psychostimulant amphetamine (AMPH) is frequently used to increase catecholamine levels in attention disorders and Positron Emission Tomography (PET) imaging studies. Despite the fact that most radiotracers for PET studies are characterized in non-human primates (NHPs), data on regional differences in the effect of AMPH in NHPs are very limited. The present study examined the impact of AMPH on extracellular dopamine (DA) levels in the medial prefrontal cortex and the caudate of NHPs using microdialysis. In addition to differences in magnitude, we observed striking differences in the temporal profile of extracellular DA levels between these regions that can likely be attributed to differences in the regulation of dopamine uptake and biosynthesis. The present data suggest that cortical DA levels may remain elevated longer than in the caudate which may contribute to the clinical profile of the actions of AMPH. This article is protected by copyright. All rights reserved.
- Nanoencapsulation of olanzapine increases its efficacy in antipsychotic treatment and reduces adverse effects. [Journal Article]
- J Biomed Nanotechnol 2014 Jun; 10(6):1137-45.
Olanzapine is an atypical antipsychotic drug, whose chronic use has been associated with the development of potential adverse effects such as weight gain and cardio-metabolic disorders like hypercholesterolemia and diabetes. To circumvent these side effects, the controlled release of olanzapine is a promising approach to improve adhesion of schizophrenic patients to the treatment. An innovative strategy to prolong drug release consists of loading the drug into biodegradable polymeric lipid-core nanocapsules. In this study, particle size, polydispersity, pH, zeta potential and drug loading of olanzapine-loaded lipid-core nanocapsules were analyzed. Weight gain, biochemical parameters and antipsychotic activity were evaluated in male Wistar rats. The lipid-core nanocapsules had a mean diameter of 156 +/- 13 nm, a polydispersity index lower than 0.1, a pH value of 6.12 +/- 0.14, zeta potential of -17 +/- 2.40 mV and encapsulation efficiency close to 100%. The animals treated with olanzapine-loaded lipid-core nanocapsules showed significantly lower weight gain (63.4 +/- 19.6 g) and total cholesterol levels (66.2 +/- 3.5 g x dl(-1)), compared to those administered with free olanzapine (112.6 +/- 10.3 g and 90.4 +/- 2.4 g x dl(-1)), respectively. Additionally, a more prolonged antipsychotic action was observed in the stereotyped behavior animal model induced by D,L-amphetamine, which affords to conclude that nanoencapsulation is a promising alternative to treat schizophrenic patients.
- Efficacy of stimulants for cognitive enhancement in non-attention deficit hyperactivity disorder youth: a systematic review. [Journal Article]
- Addiction 2014 Apr; 109(4):547-57.
Increasing prescription stimulant abuse among youth without diagnoses of attention deficit hyperactivity disorder (ADHD) is of concern. The most frequently cited motive for abuse is improved academic achievement via neurocognitive enhancement. Our aim in reviewing the literature was to identify neurocognitive effects of prescription stimulants in non-ADHD youth.A systematic review was conducted for youth aged 12–25 years using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Fourteen papers were included.Modafinil appears to improve reaction time (P ≤ 0.04), logical reasoning (P ≤ 0.05) and problem-solving. Methylphenidate appears to improve performance in novel tasks and attention-based tasks (P ≤ 0.05), and reduces planning latency in more complex tasks (P ≤ 0.05). Amphetamine has been shown to improve consolidation of information (0.02 ≥ P ≤ 0.05), leading to improved recall. Across all three types of prescription stimulants, research shows improved attention with lack of consensus on whether these improvements are limited to simple versus complex tasks in varying youth populations.The heterogeneity of the non-attention deficit hyperactivity disorder youth population, the variation in cognitive task characteristics and lack of replication of studies makes assessing the potential global neurocognitive benefits of stimulants among non-attention deficit hyperactivity disorder youth difficult; however, some youth may derive benefit in specific cognitive domains.
- Safety of medicines used for ADHD in children: a review of published prospective clinical trials. [JOURNAL ARTICLE]
- Arch Dis Child 2014 Apr 19.
To assess the long-term safety of drugs for attention deficit hyperactivity disorder (ADHD).A bibliographic search was performed in the MEDLINE, EMBASE and PsycINFO databases for prospective studies evaluating the incidence of adverse events (AEs) in children and adolescents treated for ADHD.A total of six prospective studies that monitored drug safety during therapy for at least 12 weeks were retrieved. The drugs studied were atomoxetine (two studies, 802 patients), osmotic-controlled released oral methylphenidate formulation (two studies, 512 patients), extended release formulation of mixed amphetamine salts (one study, 568 patients) and transdermal methylphenidate (one study, 326 patients). Heterogeneity was found in the duration of follow-up (ranging between 1 and 4 years) and in the way data were reported.The rate of treatment-related AEs ranged from 58% to 78%, and the rate of discontinuation due to AEs ranged from 8% to 25% of the children.Decreased appetite, insomnia, headache and abdominal pain were the most common AEs observed.Most AEs and cases of discontinuation occurred during the first few months of treatment.Few studies evaluated the long-term safety of drugs for ADHD. Heterogeneity in follow-up duration and in data reporting made comparing different studies and drugs difficult. A systematic monitoring of long-term safety is needed.
- Effect of Desipramine and Citalopram Treatment on Forced Swimming Test-Induced Changes in Cocaine- and Amphetamine-Regulated Transcript (CART) Immunoreactivity in Mice. [JOURNAL ARTICLE]
- Neurochem Res 2014 Apr 20.
Recent study demonstrates antidepressant-like effect of cocaine- and amphetamine-regulated transcript (CART) in the forced swimming test (FST), but less is known about whether antidepressant treatments alter levels of CART immunoreactivity (CART-IR) in the FST. To explore this possibility, we assessed the treatment effects of desipramine and citalopram, which inhibit the reuptake of norepinephrine and serotonin into the presynaptic terminals, respectively, on changes in levels of CART-IR before and after the test swim in mouse brain. Levels of CART-IR in the nucleus accumbens shell (AcbSh), dorsal bed nucleus of the stria terminalis (dBNST), and hypothalamic paraventricular nucleus (PVN) were significantly increased before the test swim by desipramine and citalopram treatments. This increase in CART-IR in the AcbSh, dBNST, and PVN before the test swim remained elevated by desipramine treatment after the test swim, but this increase in these brain areas returned to near control levels after test swim by citalopram treatment. Citalopram, but not desipramine, treatment increased levels of CART-IR in the central nucleus of the amygdala (CeA) and the locus ceruleus (LC) before the test swim, and this increase was returned to control levels after the test swim in the CeA, but not in the LC. These results suggest common and distinct regulation of CART by desipramine and citalopram treatments in the FST and raise the possibility that CART in the AcbSh, dBNST, and CeA may be involved in antidepressant-like effect in the FST.
- Contrasting changes in extracellular dopamine and glutamate along the rostrocaudal axis of the anterior cingulate cortex of the rat following an acute d-amphetamine or dopamine challenge. [JOURNAL ARTICLE]
- Neuropharmacology 2014 Apr 17.
There is evidence for functional specificity of subregions along the rostrocaudal axis of the anterior cingulate cortex (ACC). The subregion-specific distribution of dopaminergic afferents and glutamatergic efferents along the ACC make these obvious candidates for coding such regional responses. We investigated this possibility using microdialysis in freely-moving rats to compare changes in extracellular dopamine and glutamate in the rostral ('rACC: Cg1 and Cg3 (prelimbic area)) and caudal ('cACC': Cg1 and Cg2) ACC induced by systemic or local administration of d-amphetamine. Systemic administration of d-amphetamine (3 mg/kg, i.p.) caused a transient increase in extracellular dopamine in the rACC, but an apparent increase in the cACC of the same animals was less clearly defined. Local infusion of d-amphetamine increased dopamine efflux in the rACC, only. Glutamate efflux in the rACC was increased by local infusion of dopamine (5 - 50 μM), which had negligible effect in the cACC, but only systemic administration of d-amphetamine into the cACC increased glutamate efflux. The asymmetry in the neurochemical responses within the rACC and cACC, to the same experimental challenges, could help explain why different subregions are recruited in the response to specific environmental and somatosensory stimuli and should be taken into account when studying the regulation of neurotransmission in the ACC.
- Acute influence of alcohol, THC or central stimulants on violent suicide: A Swedish population study. [Journal Article, Research Support, Non-U.S. Gov't]
- J Forensic Sci 2014 Mar; 59(2):436-40.
Alcohol and substance abuse in general is a risk factor for suicide, but very little is known about the acute effect in relation to suicide method. Based on information from 18,894 medico-legal death investigations, including toxicological findings and manner of death, did the present study investigate whether acute influence of alcohol, tetrahydrocannabinol (THC), or central stimulants (amphetamine and cocaine) was related to the use of a violent suicide method, in comparison with the nonviolent method self-poisoning and alcohol-/illicit drug-negative suicide decedents. Multivariate analysis was conducted, and the results revealed that acute influence of THC was related to using the violent suicide method–– jumping from a height (RR 1.62; 95% CI 1.01–2.41). Alcohol intoxication was not related to any violent method, while the central stimulant-positive suicide decedent had a higher, albeit not significant, risk of several violent methods. The study contributes with elucidating suicide methods in relation to acute intoxication.