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- Amphetamine in Adolescence Disrupts the Development of Medial Prefrontal Cortex Dopamine Connectivity in a dcc-Dependent Manner. [JOURNAL ARTICLE]
- Neuropsychopharmacology 2014 Oct 22.
Initiation of drug use during adolescence is a strong predictor of both the incidence and severity of addiction throughout the lifetime. Intriguingly, adolescence is a period of dynamic refinement in the organization of neuronal connectivity, in particular medial prefrontal cortex (mPFC) dopamine circuitry. The guidance cue receptor, DCC (deleted in colorectal cancer), is highly expressed by dopamine neurons and orchestrates their innervation to the mPFC during adolescence. Furthermore, we have shown that amphetamine in adolescence regulates DCC expression in dopamine neurons. Drugs in adolescence may therefore induce their enduring behavioral effects via DCC-mediated disruption in mPFC dopamine development. In this study we investigated the impact of repeated exposure to amphetamine during adolescence on both the development of mPFC dopamine connectivity and on salience attribution to drug context in adulthood. We compare these effects to those induced by adult exposure to an identical amphetamine regimen. Finally, we determine whether DCC signaling within dopamine neurons is necessary for these events. Exposure to amphetamine in adolescence, but not in adulthood, leads to an increase in the span of dopamine innervation to the mPFC, but a reduction of presynaptic sites present on these axons. Amphetamine treatment in adolescence, but not in adulthood, also produces an increase in salience attribution to a previously drug-paired context in adulthood. Remarkably, DCC signaling within dopamine neurons is required for both of these effects. Drugs of abuse in adolescence may therefore induce their detrimental behavioral consequences by disrupting mesocortical dopamine development through alterations in the DCC signaling cascade.Neuropsychopharmacology accepted article preview online, 22 October 2014. doi:10.1038/npp.2014.287.
- The rare DAT coding variant Val559 perturbs DA neuron function, changes behavior, and alters in vivo responses to psychostimulants. [JOURNAL ARTICLE]
- Proc Natl Acad Sci U S A 2014 Oct 20.
Despite the critical role of the presynaptic dopamine (DA) transporter (DAT, SLC6A3) in DA clearance and psychostimulant responses, evidence that DAT dysfunction supports risk for mental illness is indirect. Recently, we identified a rare, nonsynonymous Slc6a3 variant that produces the DAT substitution Ala559Val in two male siblings who share a diagnosis of attention-deficit hyperactivity disorder (ADHD), with other studies identifying the variant in subjects with bipolar disorder (BPD) and autism spectrum disorder (ASD). Previously, using transfected cell studies, we observed that although DAT Val559 displays normal total and surface DAT protein levels, and normal DA recognition and uptake, the variant transporter exhibits anomalous DA efflux (ADE) and lacks capacity for amphetamine (AMPH)-stimulated DA release. To pursue the significance of these findings in vivo, we engineered DAT Val559 knock-in mice, and here we demonstrate in this model the presence of elevated extracellular DA levels, altered somatodendritic and presynaptic D2 DA receptor (D2R) function, a blunted ability of DA terminals to support depolarization and AMPH-evoked DA release, and disruptions in basal and psychostimulant-evoked locomotor behavior. Together, our studies demonstrate an in vivo functional impact of the DAT Val559 variant, providing support for the ability of DAT dysfunction to impact risk for mental illness.
- D4 Dopamine Receptor-Specific Antagonist Improves Reversal Learning Impairment in Amphetamine-Treated Male Rats. [JOURNAL ARTICLE]
- Exp Clin Psychopharmacol 2014 Oct 20.
The Attentional Set-Shifting Task (ASST) is a rodent analog of the Wisconsin Card Sorting Task, which measures executive functioning. The ASST tests for reversal of stimulus-response learning and the formation and maintenance of attentional sets. Depletion of dopamine has been shown to improve performance on attentional shifts. The study presented here questioned whether a D4-specific antagonist, L-745,870, could have a similar effect on animals, even after being treated with repeated doses of amphetamine. Three groups of male rats were given either 10 saline injections (n = 12), 10 amphetamine injections (2 mg/kg; n = 8), or 10 amphetamine injections plus 1 pretreatment injection of L-745,870 (0.1 mg/kg; n = 8) 20 min prior to testing. One-way ANOVA results showed that amphetamine-only rats were impaired on all 3 reversals (Ms = 19, 16.4, and 17.1) compared with L-745,870-treated rats (Ms = 9.8, 10.9, and 9.6) and controls (Ms = 8.6, 9.6, 9.3; all ps < .01). L-745,870-treated rats also displayed reduced latencies to respond compared with both saline controls and amphetamine rats. It is thought that D4 receptors play a role in cue salience, and that by blocking these receptors, animals display less attachment to previously rewarded cues. The results presented support this idea and imply that blocking of D4 receptors can reverse the impairment in reversals caused by amphetamine. (PsycINFO Database Record (c) 2014 APA, all rights reserved).
- Treatment Receipt and Outcomes from a Clinic Employing the Attention-Deficit/Hyperactivity Disorder Treatment Guideline of the Children's Medication Algorithm Project. [JOURNAL ARTICLE]
- J Child Adolesc Psychopharmacol 2014 Oct 20.
Abstract Objective: Little is known about the pattern of service receipt and outcomes from clinics implementing best practice guidelines in child mental health. This study aimed to determine these variables for a clinic that implemented an attention-deficit/hyperactivity disorder (ADHD) treatment guideline proposed by the Children's Medication Algorithm Project (CMAP). Methods: Secondary analyses of medical record extracts were conducted for children who received treatment from 2007 to 2012 in a specialty clinic linked to a public children's hospital in Canada. Patterns of medication selection and dosing were compared with CMAP guidelines. Outcomes were based on parent and teacher ratings on the ADHD portion of the Multimodal Treatment Study for ADHD (MTA)- Swanson, Nolan, and Pelham, Version IV (SNAP-IV). Results: Data were available for 132 children (ages 5-14), 81.8% of whom had no previous ADHD medication exposure, and 97.0% of whom had started at least one medication. Methylphenidate was used first for 59.8% of children, whereas 33.3% started with an amphetamine product. Of the 47.0% of children who progressed to a second medication trial, 88.7% tried a stimulant from a second class. In total, 19.7% tried atomoxetine, which was typically used as a third stage choice (i.e., after two different stimulant exposures). Stage four to six medications were rarely used, rather stimulants were retried after atomoxetine and/or medication combinations were tried. Symptomatic remission at the end of treatment was achieved by 70.4% and 82.4%, according to parents and teachers respectively, for those with outcome data and who completed treatment. Outcomes for those further along the treatment algorithm were similar to discharges at the beginning of the algorithm. Conclusions: The high rates of symptomatic remission observed within this clinical service may be a function of adherence to CMAP recommendations. However, the lack of a comparison group or experimental design prevents determination of causality. Additional investigations of the impacts of implementing evidence-based guidelines are critically needed, with proposed benchmarks to inform outcome evaluations.
- Synthetic cathinones and their rewarding and reinforcing effects in rodents. [JOURNAL ARTICLE]
- Adv Neurosci (Hindawi) 2014 Jun 4.:209875.
Synthetic cathinones, colloquially referred to as "bath salts", are derivatives of the psychoactive alkaloid cathinone found in Catha edulis (Khat). Since the mid-to-late 2000's, these amphetamine-like psychostimulants have gained popularity amongst drug users due to their potency, low cost, ease of procurement, and constantly evolving chemical structures. Concomitant with their increased use is the emergence of a growing collection of case reports of bizarre and dangerous behaviors, toxicity to numerous organ systems, and death. However, scientific information regarding the abuse liability of these drugs has been relatively slower to materialize. Recently we have published several studies demonstrating that laboratory rodents will readily self-administer the "first generation" synthetic cathinones methylenedioxypyrovalerone (MDPV) and methylone via the intravenous route, in patterns similar to those of methamphetamine. Under progressive ratio schedules of reinforcement, the rank order of reinforcing efficacy of these compounds are MDPV ≥ methamphetamine > methylone. MDPV and methylone, as well as the "second generation" synthetic cathinones α-pyrrolidinovalerophenone (α-PVP) and 4-methylethcathinone (4-MEC), also dose-dependently increase brain reward function. Collectively, these findings indicate that synthetic cathinones have a high abuse and addiction potential and underscore the need for future assessment of the extent and duration of neurotoxicity induced by these emerging drugs of abuse.
- Impact of a Restrictive Drug Access Program on the risk of Cardiovascular Encounters in Children Exposed to ADHD Medications. [Journal Article]
- J Popul Ther Clin Pharmacol 2014; 21(3):e357-69.
BackgroundADHD medications increase clinical encounters for cardiovascular symptoms. Uncertain are the roles of differences in ADHD medications and restrictive practices by drug programs. MethodsWe conducted two nested case-control studies. The first was nested within a cohort of children de novo users of methylphenidate, amphetamines or atomoxetine and the second case-control study was nested within a subcohort of de novo amphetamine or atomoxetine users with no cardiovascular events prior to the first dispensing of either drug. The outcome for both studies was the composite of physician visits, emergency room visits or hospitalizations for cardiovascular reasons. Cases were matched on sex, age and date of entry within the cohorts, with up to 10 controls. Patients with an active dispensation of ADHD medications at the index date (and up to 90 days previously) were considered exposed. Conditional logistic regression was used to calculate odd ratios (OR). ResultsThe full cohort comprised 38,495 patients. Among these patients, 3595 (9.3%) had no prior cardiovascular events (the subcohort). In the full cohort, an association was demonstrated with exposure to amphetamine and atomoxetine (but not methylphenidate) and the cardiovascular encounter outcomes. When the sub-cohort was analyzed the associations with amphetamine or atomoxetine were no longer evident. ConclusionReimbursement policies need to be considered when conducting observational studies. Had the analysis been conducted without consideration of these policies the results would have incorrectly identified amphetamine and atomoxetine as important risk factors for cardiovascular encounters.
- Self-reported cannabis products and other illicit drugs consumption in older school-age children in Northern Lithuania: A comparison between 2006 and 2012. [Journal Article]
- Medicina (Kaunas) 2014; 50(3):162-8.
Cannabis use is widespread among young people in Europe. The aim of this study was to analyze and to compare the associations between the self-reported consumption of cannabis products and other illicit drugs among older schoolchildren in 2006 and in 2012.Two cross-sectional surveys were conducted in 2006 and 2012 in Northern Lithuania. In total 3447 young people aged 17-19 years were investigated (1585 male and 1862 female). For this survey, the ESPAD questionnaire was used.In Northern Lithuania, the schoolchildren aged 17-19 years self-reported that 16.7% in 2006 and 23.9% in 2012 of them tried cannabis products. The consumption of cannabis products in the age group of 17 years increased from 14.9% in 2006 to 21.5% in 2012. The consumption of cannabis together with alcohol increased from 7.6% to 14.3%. Cannabis consumers more often tried amphetamines, heroin, LSD, cocaine, crack, ecstasy, hallucinogenic mushrooms, and injective drugs. In 2012, cannabis consumers girls less than boys used only crack and injective drugs; all other illicit drugs they used the same often as boys.The cannabis products consumption in schoolchildren has increased by 7%. Nearly twofold increase was observed in the consumption of cannabis together with alcohol. Young people who used cannabis products more often tried other illicit drugs. There were no differences by gender in the consumption of illicit drugs among cannabis consumers.
- Application of direct-infusion ESI-MS/MS for toxicological screening. [Journal Article]
- Bioanalysis 2014 Aug; 6(15):2043-55.
Direct-infusion ESI-MS/MS is a powerful approach for the identification of substances in complex mixtures. The aim of this work was to investigate its applicability to the toxicological screening of blood samples. A simple protein precipitation was used, followed by a 15 min infusion of the extract in the mass spectrometer.The application of the procedure to commercial quality controls and authentic post-mortem blood samples demonstrated that the direct-infusion ESI-MS/MS approach enables the simultaneous identification of substances that require different chromatographic conditions. However, poor sensitivity was observed for benzodiazepine, amphetamines and opiate compounds.Considering the facile implementation and positive performance of direct-infusion ESI-MS/MS, this approach may to be a valuable complementary technique for systematic toxicological analysis procedures.
- Physical and Mental Health Issues among Homeless Youth in British Columbia, Canada: Are they Different from Older Homeless Adults? [Journal Article]
- J Can Acad Child Adolesc Psychiatry 2014 Sep; 23(3):200-6.
Youth homelessness is on the rise in North America, yet this vulnerable population is rarely studied and compared with adults. This paper aimed to study the homeless youth and identify specific vulnerabilities, which rendered them different from the adult homeless population. It also aimed to describe the youth homeless population and their significant co-morbidities.DATA WAS DERIVED FROM THE BC HEALTH OF THE HOMELESS STUDY (BCHOHS), CARRIED OUT IN THREE CITIES IN BRITISH COLUMBIA, CANADA: the large urban centre Vancouver (n=250); the mid-sized city and capital of the province Victoria (n=150). Measures included socio-demographic information, the Maudsley Addiction Profile (MAP), the Childhood Trauma Questionnaire (CTQ) and the Mini International Neuropsychiatric Interview (MINI) Plus.Youth constituted 16.5% (n=82) of the homeless population. Compared to the adult homeless, the homeless youth were more often female (55%), were Aboriginal (47.6%), had greater substance abuse of alcohol (70.7%), amphetamines (8.5%) and cannabis (75.6%). A lower prevalence of sexually transmitted diseases (0.2%) and psychotic disorders (13.4%) was also observed. The prevalence of traumatic experiences, other psychiatric disorders and physical illnesses were similar between the adult and homeless youth.Homeless youth have high rates of physical and psychiatric comorbidity, similar to the adult homeless, despite being 20 years younger. An urgent need for interventions that go beyond the standardized ones being offered to homeless populations as a whole, and to derive specific strategies that target this vulnerable population is required.
- Deficient Wnt signalling triggers striatal synaptic degeneration and impaired motor behaviour in adult mice. [Journal Article]
- Nat Commun 2014.:4992.
Synapse degeneration is an early and invariant feature of neurodegenerative diseases. Indeed, synapse loss occurs prior to neuronal degeneration and correlates with the symptom severity of these diseases. However, the molecular mechanisms that trigger synaptic loss remain poorly understood. Here we demonstrate that deficient Wnt signalling elicits synaptic degeneration in the adult striatum. Inducible expression of the secreted Wnt antagonist Dickkopf1 (Dkk1) in adult mice (iDkk1) decreases the number of cortico-striatal glutamatergic synapses and of D1 and D2 dopamine receptor clusters. Synapse loss occurs in the absence of axon retraction or cell death. The remaining excitatory terminals contain fewer synaptic vesicles and have a reduced probability of evoked transmitter release. IDkk1 mice show impaired motor coordination and are irresponsive to amphetamine. These studies identify Wnts as key endogenous regulators of synaptic maintenance and suggest that dysfunction in Wnt signalling contributes to synaptic degeneration at early stages in neurodegenerative diseases.