Augmented acquisition of cocaine self-administration and altered brain glucose metabolism in adult female but not male rats exposed to a cannabinoid agonist during adolescence

Marijuana consumption during adolescence has been proposed to be a stepping stone for adult cocaine addiction. However, experimental evidence for this hypothesis is missing. In this work we chronically injected male and female Wistar rats with either the cannabinoid agonist CP 55,940 (CP; 0.4 mg/kg) or its corresponding vehicle. Adult acquisition (seven 30 min daily sessions) and maintenance (fourteen 2 h daily sessions) of cocaine self administration (1 mg/kg), food reinforced operant learning under conditions of normal (ad libitum access to food), and high motivation (food restriction schedule) were measured. Additionally, brain metabolic activity was analyzed by means of [18F] fluorodeoxyglucose positron emission tomography. During the acquisition phase, female CP treated rats showed a higher rate of cocaine self administration as compared to vehicle treated females and males; no differences were found between both male groups. This effect disappeared in the maintenance phase. Moreover, no differences among groups were evident in the food reinforced operant task, pointing to the cocaine specific nature of the effect seen in self administration rather than a general change in reward processing. Basal brain metabolic activity also changed in CP treated females when compared to their vehicle treated counterparts with no differences being found in the males; more specifically we observed a hyper activation of the frontal cortex and a hypo activation of the amygdalo entorhinal cortex. Our results suggest that a chronic exposure to cannabinoids during adolescence alters the susceptibility to acquire cocaine self administration, in a sex specific fashion. This increased susceptibility could be related to thechanges in brain metabolic activity induced by cannabinoids during adolescenceThis work was supported by Grants FIS G03/05 (Red de Trastornos Adictivos), BSO2001-1099, FIS 01-05-01, Plan Nacional sobre Drogas (PNSD) 2001–2003, PNSD 2004–2007, GR-SAL/0260/2004 to EA and Grants INT/2012/ 2002, CB06/01/0079, and CENIT (2006–2009) to MDPublicad

mGluR5 Antagonist-Induced Psychoactive Properties: MTEP Drug Discrimination, a Pharmacologically Selective Non-NMDA Effect with Apparent Lack of Reinforcing Properties

ABSTRACT Fenobam [N-(3-chlorophenyl)-N9-(4,5-dihydro-1-methyl-4-oxo-1H-imidazole-2-yl)urea], a potent metabotropic glutamate mGluR5 receptor antagonist, reported to have analgesic effects in animals and anxiolytic effects in humans, also caused adverse events, including psychostimulant-type effects and "derealization phenomena." Recent electrophysiologic, pharmacologic, and anatomic data show that the mGluR5 antagonists 2-methyl-6-(phenylethynyl)pyridine (MPEP) and (E)-2-methyl-6-styryl-pyridine (SIB-1893) can inhibit NMDA receptor-mediated activity and that mGluR5 receptors are highly expressed in limbic and forebrain regions. The present studies first evaluated the potential of mGluR5 receptor antagonists to cause PCP-like psychoactive effects in a rat drug discrimination procedure and, second, explored and characterized the selective mGluR5 antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) as a discriminative stimulus and compared MTEP with other drugs known to be psychoactive in humans. Additionally, the reinforcing potential of MPEP and MTEP was compared with phencyclidine (PCP) in a rat intravenous self-administration procedure. Dizocilpine [(1)-MK-801] and ketamine caused full PCP-appropriate responding. Memantine and the mGluR5 antagonists caused no or weak partial PCPappropriate responding. In MTEP-trained rats, MTEP, MPEP, and fenobam caused full and equipotent MTEP-appropriate responding. (1)-MK-801 and memantine caused MTEPappropriate responding below 70%, whereas PCP, chlordiazepoxide and LSD caused MTEP-appropriate responding below 50%. D 9 -Tetrahydrocannabinol, yohimbine, arecoline, and pentylenetetrazole all caused MTEP-appropriate responding below 20%. Rats self-administered PCP but not MPEP or MTEP, indicating a lack of reinforcing effects of the mGluR5 antagonists. These data suggest that the mGluR5 antagonists appear not to have reinforcing properties, that the discriminative effects of mGluR5 antagonists and PCP are dissimilar, and that mGluR5 antagonists may produce psychoactive effects different from NMDA-antagonists and other drugs with known psychotomimetic properties

THC alters alters morphology of neurons in medial prefrontal cortex, orbital prefrontal cortex, and nucleus accumbens and alters the ability of later experience to promote structural plasticity

Psychoactive drugs have the ability to alter the morphology of neuronal dendrites and spines and to influence later experience‐dependent structural plasticity. If rats are given repeated injections of psychomotor stimulants (amphetamine, cocaine, nicotine) prior to being placed in complex environments, the drug experience interferes with the ability of the environment to increase dendritic arborization and spine density. Repeated exposure to Delta 9‐Tetrahydrocannabinol (THC) changes the morphology of dendrites in medial prefrontal cortex (mPFC) and nucleus accumbens (NAcc). To determine if drugs other than psychomotor stimulants will also interfere with later experience‐dependent structural plasticity we gave Long‐Evans rats THC (0.5 mg/kg) or saline for 11 days before placing them in complex environments or standard laboratory caging for 90 days. Brains were subsequently processed for Golgi‐Cox staining and analysis of dendritic morphology and spine density mPFC, orbital frontal cortex (OFC), and NAcc. THC altered both dendritic arborization and spine density in all three regions, and, like psychomotor stimulants, THC influenced the effect of later experience in complex environments to shape the structure of neurons in these three regions. We conclude that THC may therefore contribute to persistent behavioral and cognitive deficits associated with prolonged use of the drug.Both repeated exposure to Delta 9‐THC and housing in complex environments changes the morphology of dendrites in mPFC, OFC, and NAcc. Prior exposure to THC influenced the effect of later experience in complex environments to shape the structure of neurons in these three regions.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141383/1/syn22020.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141383/2/syn22020_am.pd

Simulation of Avalanche breakthroughin Si and SiC

This paper describes a Monte Carlo simulation of avalanche breakthrough in Si and SiC, which is intended as a teaching aid in introductory courses on semiconductor devices. The model used approximates the charge carriers as hard balls bouncing o each other and transferring kinetic energy between themselves, with ionizations being recorded when EKin > Eg. The simulated results are close to their expected values for Si, and signicantly higher than expected for SiC. It is suggested that this indicates the existence of an hitherto unknown to the author material parameter in SiC that would suppress the carrier velocities, since the bandgap energy itself is too low to counteract the high critical eld that has been measured in SiC.Denna uppsats beskriver en Monte Carlo-simulering av avalanchegenombrott i kisel och kiselkarbid, med tanked att denna ska användas som ett hjälpmedel i undervisningen i introduktionskurser i halvledarkomponenter. Modellen som används approximerar laddningsbärarna som hårda klot som studsar på varandra och på så sätt överför kinetisk energi sinsemellan. Jonisationer registreras vid kollisioner där EKin > Eg. De simulerade resultaten stämmer väl överens med verkligheten för kisel, men är bedydligt högre än väntat för kiselkarbid. Det föreslås att detta pekar på en för författaren okänd materialparameter som sänker elektronhastigheten i kiselkarbid, då bandgapsenergin i sig är för låg för att förklara det höga kritiska fält som uppmätts i kiselkarbid

Analysis of vortex movement in an YBCO thin film : Models of the vortex solid-to-liquid transition compared to a sensitive resistive measurement of a strongly pinned YBCO thin film

When a high-temperature superconductor transitions in the presence of a magnetic field, the resistance does not immediately go to zero. Instead, the transition is smoothed by the resistive effects of moving vortices so that perfect conductivity isn't reached until several K below Tc, where the vortices have frozen into a glass state. The properties of this glass depend mainly on the amount and correlation between impurities in the superconductor. This report describes a study of the glass transition in an YBCO thin film rich in uncorrelated impurities. The aim was to use sensitive resistive measurements to determine which of two models of this transition, the vortex glass model and the vortex molasses model, is more accurate. After evaluation, both models are found lacking and a third model is put forth. This model, which resembles the normal distribution, excellently describes the YBCO thin film case. When the new model is tested against data from similar measurements, an YBCO single crystal and a TlBaCaCuO thin film, the results are mixed. Further study is suggested to determine the model's range of validity

How the elderly are effected by digital training efforts : An investigation regarding how digital exclusion can be prevented seen from a long-term perspective

Dagens digitala samhälle håller på att utvecklas i en oerhört snabb takt, vilket inte alltid gör det lätt för personer att anpassa sig till förändringarna. Speciellt inte om man som individ redan tillhör socialt utsatta grupper, vilket är fallet för många av den äldre generationen. Dessa grupper hamnar enkelt i digitala utanförskap, där de inte har samma möjligheter till att använda sig av samhällets digitaliserade tjänster på samma sätt som resten av befolkningen. Denna fallstudie har då till syfte att försöka mäta effektiviteten av ett specifikt utbildningstillfälle som genomfördes i Torsby kommun. Målet med detta utbildningstillfälle var att utbilda dess äldre deltagare om digital användning och med hjälp av en mer praktiskt inlärning förhoppningsvis även motverka deras digitala utanförskap. Hur effektiv var denna insats sett ur ett kortsiktigt kontra långsiktigt perspektiv? För att ta reda på detta genomfördes det kvalitativa telefonintervjuer med ett antal tidigare deltagare. Denna återkoppling genomfördes ungefär två och en halv månader efter utbildningstillfället för att se hur väl de tidigare deltagarna hade kommit ihåg sin utbildning. Resultatet och analyseringen av intervjuerna visar på att de flesta deltagare inte hade förändrat sina vanor särskilt mycket efter utbildningstillfället. Orsaken bakom detta verkar huvudsakligen vara fortsatt osäkerhet gällande ämnet, där flera av deltagarna svarade med att de inte kunde komma ihåg vad som hade lärts ut under utbildningstillfället. Även om i stort sett alla uppringda svarade med att de tyckte om tillfället verkar det som att det heller inte var tillräckligt för att effektivt motverka deltagarnas digitala utanförskap, vilket skulle kunna vara en potentiell förbättringspunkt för uppkommande insatser

Utforskande av Framväxande Entiteter och Disambiguering av Entiteter i Nyhetsartiklar

Publicly editable knowledge bases such as Wikipedia and Wikidata have over the years grown tremendously in size. Despite the quick growth, they can never be fully complete due to the continuous stream of events happening in the world. In the task of Entity Linking, it is attempted to link mentions of objects in a document to its respective corresponding entries in a knowledge base. However, due to the incompleteness of knowledge bases, new or emerging entities cannot be linked. Attempts to solve this issue have created the field referred to as Emerging Entities. Recent state-of-the-art work has addressed the issue with promising results in English. In this thesis, the previous work is examined by evaluating its method in the context of a much smaller language; Swedish. The results reveal an expected drop in overall performance although remaining relative competitiveness. This indicates that the method is a feasible approach to the problem of Emerging Entities even for much less used languages. Due to limitations in the scope of the related work, this thesis also suggests a method for evaluating the accuracy of how the Emerging Entities are modeled in a knowledge base. The study also provides a comprehensive look into the landscape of Emerging Entities and suggests further improvements

Cannabis och hjärnans belöningssystem

Allt sedan amerikanen Olds av en ren slump upptäckte belöningssystemet på 1950-talet har forskningen om hur droger påverkar hjärnan intensifierats. Senare års forskning har visat att cannabis påverkar specifika receptorer (mottagarmolekyler) i hjärnan och därmed aktiverar hjärnans belöningssystem, i likhet med alkohol, nikotin, heroin, amfetamin och kokain. Kunskapssökandet har nu kommit så långt att vi även börjar få en del svar på hur den psykoaktiva substansen delta-9-tetrahydrocannabinol (THC) mer specifikt påverkar belöningssystemet. Delta-9-tetrahydrocannabinol (THC; the main psychoactive substance in cannabis) acts on specific receptors in the brain and thereby activates the reward system, a feature common to all addictive drugs. Extensive research has started to provide specific information on how THC acts on the reward system and an overview of this knowledge is presented here. Keywords: delta-9-tetrahydrocannabinol, cannabinoid receptor, reward, nucleus accumbens, revie

Neurobiological effects of early life cannabis exposure in relation to the gateway hypothesis

The use of Cannabis sativa preparations, such as hashish and marijuana, is wide-spread among young people, including pregnant women. Despite this concern, the consequences of cannabis exposure on the brain during periods of active brain development, such as the prenatal phase and adolescence, is not well known. Several epidemiological studies support the cannabis gateway hypothesis, where early cannabis use is suggested to increase the risk of initiating use of other illicit drugs, e.g., amphetamine or heroin. However, the nature of such direct links are unclear. Therefore, the aim of this thesis was to test experimentally the cannabis gateway hypothesis, i.e., to determine whether cannabis exposure during periods of active brain development alters reward-related behavior and neurobiology for psychostimulant and opioid drugs by the use of animal models. In the first study, we examined the effects of early adolescent exposure (postnatal day; PND; 28-32, one injection per day) with the synthetic cannabinoid CB1 receptor agonist WIN55,212-2 and the main psychoactive substance in C. sativa, Δ9-tetrahydrocannabinol (THC) on amphetamine-induced motor behavior and dopamine release in the nucleus accumbens during adolescence. No alterations were evident in the cannabinoid exposed rats, results which did not support the cannabis gateway hypothesis in relation to subsequent psychostimulant abuse. Next, we investigated the effects of adolescent exposure on subsequent opioid reward-related behavior and the neurobiology of opioid and cannabinoid systems during adulthood. We studied THC exposure across the full adolescent period (PND 28-49), and administered the drug once every third day in order to better mimic the pattern of intermittent use seen in teenagers. The results revealed discrete opioid-related alterations within brain regions highly implicated in reward and hedonic processing (e.g., increased proenkephalin gene expression in the nucleus accumbens and increased mu opioid receptors in the ventral tegmental area). This was coupled to increased heroin intake in a self-administration paradigm and increased morphine conditioned place preference, indicating altered sensitivity to the reinforcing properties of opioids. Furthermore, in evaluating the adolescent ontogeny of the opioid and cannabinoid systems within limbic-related brain areas, we found that active endocannabinoid- and opioid- related neurodevelopment takes place to a very high extent during this period. Most pronounced were the alterations in endocannabinoid levels in cognitive brain areas, even though alterations were also apparent in reward-related regions. Finally, we investigated the effects of prenatal cannabis exposure (gestational day 5- PND 2) on subsequent opioid reward-related behavior and neurobiology of the opioid and cannabinoid systems in adulthood. Similar to adolescent cannabis exposure, prenatal exposure induced discrete opioid-related alterations within brain regions highly implicated in reward and hedonic processing. Moreover, elevated heroin-seeking observed during extinction and after food deprivation was evident in the THC exposed rats, suggesting an increased motivation for drug use under conditions of stress. Taken together, this thesis presents neurobiological support for the cannabis gateway hypothesis in terms of adult opiate, but not amphetamine, abuse, with underlying long-term disturbances of discrete opioid-related systems within limbic brain regions