Rapport de recherche bibliographique (DESS Ingénierie documentaire) : Ecole nationale supérieure des sciences de l'information et des bibliothèques, Université Claude Bernard Lyon 1 : Villeurbanne (France) : 2001. / Notes bibliogr.

Australian and international literature provides strong evidence that intravenous use of psychostimulants increases the harms experienced by users, including heightening the risk of blood-borne virus (BBV) infection. The few Australian studies that include women who inject psychostimulants identify street-based sex work as the main method of income generation and highlight the harms that result from combining these practices. However, there has been little exploration into the way these practices are shaped by the environments in which they occur or the ways in which women manage these harms. This thesis aims to provide an in-depth exploration of the daily lives of women who inject psychostimulants and engage in street-based sex work in Kings Cross, Sydney. Over 18 months between 2005 and 2007, the author conducted ethnographic fieldwork with women who injected psychostimulants and engaged in street-based sex work in Kings Cross, Sydney. Data sources included observations recorded as fieldnotes and transcripts of in-depth interviews with 12 women. Thematic analysis of the data was employed with particular attention to the women???s shared narratives. Key findings of the thesis were that 1) the Kings Cross environment plays a prominent role in shaping the lives of women, their psychostimulant injecting and street-based sex work practices; 2) psychostimulant injecting reinforces the opportunistic nature of street-based sex work as the primary method of income generating for women, restricting the development of occupational norms; 3) synergies exist between the drug and sex markets in Kings Cross, increasing the harms associated with both injecting and street-based sex work practices; 4) public health messages relating to sharing of injecting equipment and condom use fail to account for contextually driven decision-making and risk prioritising; 5) women develop lay epidemiological understandings as they attempt to reconcile the public health messages with the lived reality. The value of these findings is in the insights they provide into the everyday lives of these women in Kings Cross that have not been documented previously and their potential for informing ???bottom-up??? rather than ???top down??? approaches to future policy, practice and research.

abstract: Serotonin 1B receptor (5-HT1BR) agonists enhance cocaine intake in rats during daily self-administration (SA) sessions, yet decrease cocaine intake after prolonged abstinence. The goal of my dissertation was to examine if 5-HT1BRs are suitable targets for treatment development to attenuate psychostimulant intake. I first investigated if 5-HT1BR agonist effects that had been observed with cocaine generalize across psychostimulants, i.e., methamphetamine. Rats trained to self-administer methamphetamine received either CP 94,253 or the clinically-available but less selective 5-HT1D/1BR agonist, zolmitriptan, prior to tests for effects on SA both before and after a 21-day abstinence period. I found that CP 94,253 and zolmitriptan decreased the reinforcing and incentive motivational effects of methamphetamine, regardless of abstinence, unlike the pre-abstinence increase in cocaine SA observed previously with 5-HT1BR agonists. The attenuating effects of CP 94,253 on methamphetamine were antagonized in a 5-HT1BR-mediated manner. Subsequently, I investigated the efficacy and mechanism involved in effects of zolmitriptan on cocaine SA in male and female rats. Rats trained to self-administer cocaine received zolmitriptan prior to tests for effects on SA before a 21-day abstinence period. I found that zolmitriptan decreased cocaine intake in both sexes regardless of abstinence and without altering sucrose intake. I further demonstrated that the zolmitriptan effects on cocaine SA were mediated by both 5-HT1BRs and 5-HT1DRs. Finally, I examined if the abstinence-induced decrease in cocaine intake observed with the selective 5-HT1BR agonist, CP 94,253, persists during relapse after abstinence or reverts to enhancing cocaine intake, similar to effects observed without an abstinence period. Rats trained to self-administer cocaine resumed daily cocaine SA sessions after the forced abstinence period to investigate the effects of CP 94,253 on cocaine relapse. I found that CP 94,253 attenuated cocaine intake in relapse tests, suggesting that the abstinence-dependent attenuation of CP 94,253 on cocaine SA remains even after resumption of daily cocaine intake. The findings suggest that 5-HT1BR agonists like CP 94,253 and zolmitriptan have clinical potential as treatments for psychostimulant use disorders. / Dissertation/Thesis / Doctoral Dissertation Neuroscience 2020

Le striatum dorsal et le noyau accumbens (NAc) jouent un rôle crucial dans la sélection et l’exécution de mouvements résultant de l’intégration de signaux dopaminergiques et d’informations glutamatergiques sensorielles. A ce jour, les mécanismes moléculaires à travers lesquels la dopamine (DA) régule la plasticité des neurones épineux moyens du striatum (MSNs) sont peu connus. La synthèse des protéines est un événement essentiel requis pour la plasticité synaptique et la mémoire à long terme. Dans de nombreuses régions cérébrales, l’initiation, étant l'étape limitante de la synthèse protéique, est contrôlée par la phosphorylation de facteurs d’initiation de la traduction (eIFs). Notre hypothèse est que la DA pourrait réguler la traduction d’ARNm dans le striatum à travers des mécanismes moléculaires similaires. La première partie de cette thèse visait à étudier le rôle de la DA dans la régulation de la machinerie de traduction dans les MSNs. Pour ce faire, nous avons analysé au niveau du striatum, la phosphorylation de différents eIFs en réponse à l’administration aigue ou répétée de d-amphetamine (d-amph), entraînant une augmentation transitoire ou de longue durée de la transmission dopaminergique, respectivement. Bien que l’administration de la d-amph est associée à une légère augmentation de pS209-eIF4E, l’état de phosphorylation de S1108-eIF4G reste inchangé. En revanche, une forte augmentation de p51-eIF2α a été observée après administration répétée d-amph. Nous démontrons que la phosphorylation de 51-eIF2α est corrélée à une diminution transitoire de la synthèse protéique globale dans le striatum. En outre, la d-amph induit également une importante augmentation de la phosphorylation de la protéine ribosomale S6 (rpS6). Cet effet se produit spécifiquement dans MSNs exprimant le récepteur D1 à la DA et implique la cascade de signalisation AMPc/PKA/DARPP-32, tout en étant indépendant des voies mTORC1/S6K et ERK. La phosphorylation de rpS6 est couramment utilisée pour marquer de l'activité neuronale bien que son rôle biologique dans le cerveau reste énigmatique. Compte tenu sa régulation significative par la DA, la deuxième partie de cette thèse a eu pour but d’acquérir de nouvelles connaissances sur la fonction de la phosphorylation de rpS6 en utilisant un modèle de souris rpS6 déficient de ses sites de phosphorylations, rpS6P-/-. Dans ces souris transgéniques la synthèse protéique globale est normale dans diverses régions du cerveau. Néanmoins, les souris rpS6P -/- présentent une altération de la traduction d'un sous-ensemble de ARNm, ceci sélectivement dans le NAc, suggérant le rôle potentiel de la phosphorylation de rpS6 dans la régulation de la traduction de transcrits bien spécifiques au sein de cette sous-région du striatum. Dans l'ensemble, les résultats présentés dans cette thèse permettent une meilleure compréhension des mécanismes engagés par DA pour contrôler la traduction d’ ARNm dans les MSNs du striatum. / The dorsal striatum and the nucleus accumbens (NAc) process dopamine (DA) signals in order to generate appropriate behavior in response to given glutamatergic sensory cues. The molecular mechanisms through which DA promotes long-lasting changes in striatal GABAergic medium-sized spiny neurons (MSNs) are still not fully understood. It is widely accepted that protein synthesis is an essential event required for several forms of synaptic plasticity and long-term memory. In various brain areas, initiation is the rate-limiting step of translation and is regulated through phosphorylation of translation initiation factors (eIFs). Whether DA could regulate mRNA translation in the striatum through similar mechanisms is yet poorly investigated. A first part of this thesis aimed to shed light on the role of DA in the regulation of the translational machinery in MSNs. Here, we measured the phosphorylation state of eIFs following single and repeated in vivo d-amphetamine (d-amph) administration, resulting in a transient or long-lasting increase of the dopaminergic transmission, respectively. Although d-amph exposure slightly enhances the striatal pS209-eIF4E, pS1108-eIF4G remains unchanged. In contrast, a strong increase in p51-eIF2α is observed after repeated d-amph administration. We demonstrate that d-amph-induced p51-eIF2α is associated to a transient decrease in generall striatal protein synthesis. In addition, d-amph markedly increases the striatal phosphorylation of the 40S ribosomal protein S6 (rpS6). This effect occurs selectively in D1 DA receptor (D1R)-expressing MSNs and requires the cAMP/PKA/DARPP-32 cascade but is independent of mTORC1/S6K and ERK signaling. rpS6 phosphorylation is commonly used as a marker for neuronal activity even though its biological role in the brain remains puzzling. Given the significant regulation of striatal rpS6 phosphorylation by DA, the second part of this thesis sought to gain new insights into the function of this post-translational event by using a phosphodeficient rpS6P-/- mouse model. We showed that rpS6P-/- mice display unaltered global protein synthesis in different brain regions. Nonetheless, rpS6P-/- mice exhibit impaired translation of a subset of mRNA selectively in the NAc, pointing to the potential role of rpS6 phosphorylation in the regulation of transcript-specific translation within this striatal sub-region. Overall, the results presented in this thesis provide a better understanding of the mechanisms engaged by DA to control mRNA translation in striatal MSNs.

L'étude de l'impact des facteurs environnementaux sur les effets à long-terme des psychostimulants a montré que des facteurs négatifs, comme le stress, augmentent le risque de développer une addiction, alors que des facteurs positifs, comme l'exposition à des conditions stimulantes, le réduisent. Une partie de cette thèse a consisté à rechercher les mécanismes neurobiologiques et cellulaires qui sous-tendent cette influence environnementale. Ainsi, l'exposition d'animaux à un environnement enrichi (EE), qui procure des conditions stimulantes, diminue leur niveau d'anxiété, un effet qui serait en partie lié à la régulation de gènes appartenant au système cannabinoïde endogène (SCE) dans des régions impliquées dans la réactivité au stress (article 1). Par ailleurs, nos travaux ont mis en évidence des limites de l'exposition à l'EE : quand celle-ci est interrompue, ses effets bénéfiques sont perdus et la vulnérabilité à la cocaïne est même augmentée. Ceci s'expliquerait par l'apparition d'un état émotionnel négatif, associé à une activation du facteur CREB dans l'amygdale étendue, une région carrefour entre la récompense et le stress (article 2). Nous nous sommes aussi intéressés à la toxicité de la méthamphétamine et à sa modulation par le SCE, pour lequel des propriétés neuroprotectives avaient déjà été suggérées. Ainsi, une stimulation pharmacologique du SCE permet de prévenir la neurotoxicité dopaminergique induite par la méthamphétamine (article 3). Nos résultats soulignent la complexité d'utilisation des manipulations environnementales et mettent en lumière les capacités protectives du SCE contre la dépendance et la neurotoxicité engendrées par les psychostimulants. / Studies of the impact of environmental factors on the long-term effects of psychostimulants have shown that negative factors, such as stress, increase the risk of developing drug addiction, while positive factors, such as exposure to stimulating conditions, reduce it. The first aim of this thesis work was to look for the neurobiological and cellular mechanisms that underlie this environmental influence. We found that exposure of animals to stimulating enriched environments (EE) reduces anxiety levels, an effect that may be partly related to the regulation of genes belonging to the endogenous cannabinoid system (ECS) in regions involved in stress reactivity (Article 1). In addition, our work has highlighted some limitations of the exposure to EE since discontinuation of enrichment results not only in the loss of its beneficial effects but also in increased vulnerability to cocaine. This effect is associated with emotional distress associated and changes in the activity of the transcription factor CREB in the extended amygdala, an interface region between reward and stress processes (Article 2). We also investigated whether ECS, for which neuroprotective properties have already been suggested, could reduce the brain toxicity induced by methamphetamine. We found that pharmacological stimulation of ECS provides protection against the methamphetamine-induced dopaminergic neurotoxicity (Article 3). Our results highlight the complex consequences of environmental conditions on brain and behavior and highlight the protective role of ECS against both addiction and neurotoxicity induced by psychostimulants.

Pentameric ligand-gated ion channels are critical mediators of electrochemical signal transduction in neurons and other excitable cells, causing them to be important targets of psychoactive drugs. Structural data for these complex proteins are limited, particularly among eukaryotic family members and for the functionally critical open state. These data limitations cause knowledge gaps regarding the mechanisms of ion channel opening, gating, and modulation. However, a newly discovered bacterial family member, known as sTeLIC, shares numerous structural features with its eukaryotic relatives in our central nervous system. A recently solved electron microscopy structure depicts sTeLIC in an apparent open state with binding pockets in its extracellular domain, compatible with binding a drug with structural similarities to amphetamines, like the 4-bromoamphetamine. This project aims to provide the first structure-function evidence for direct modulation of a pentameric ligand-gated ion channel by an amphetamine. The two most essential tools used in this project to examine the effects of 4-bromoamphetamine on sTeLIC were Xenopus laevis oocytes and two-electrode voltage-clamp. These tools were necessary for the collection of gating and modulation data. Ion channel activities can be analysed by clamping sTeLIC injected Xenopus laevis oocytes into the two-electrode voltage-clamp since it can artificially control the membrane voltage of oocytes. Modulation data show that 4-bromoamphetamine is a bimodal allosteric potentiator, as well as an allosteric agonist. Residues Y104 and W75, located in the binding pocket, were selected by comparing the published open state model with an AlphaFold-generated non-conducting model. Mutating these into valine or alanine reduces the potentiation. One explanation may be that removing tyrosine's aromatic ring complicates retaining essential interactions in the binding pocket while swapping tryptophan for smaller residues could make it easier for the drug to stabilise the closed state.

Researchers have argued that a reason for non-medical use of prescription psychostimulants is to self-medicate an undiagnosed case of ADHD. Therefore, this study examined neuropsychological complaints in college students with and without a history of prescription psychostimulant use. College students (N = 615) completed an Internet-based survey assessing behaviors associated with prescription psychostimulant use and symptoms of neuropsychological impairment. The results of the current study support the hypothesis that college students who non-medically use prescription psychostimulants report more symptoms of cognitive impairment (i.e., memory and attention complaints) than college students classified as non-users. Complaints about memory and attention were as common in non-medical users as medical users. Overall, the results suggest that non-medical users may use prescription psychostimulants due to perceived symptoms of ADHD.

Despite the widespread use of caffeine as a central nervous stimulant, the central pharmacodynamic properties of the drug have not yet been conclusively evaluated in humans. The present study was undertaken to assess the acute effects of caffeine on measures of topographical quantitative electroencephalogram (EEG) in normal subjects. Ten healthy male volunteers (mean age ± SD 25 ± 4 years) received placebo and 200 mg of caffeine as powder with oral water solution (caffeine amount = 2 cups of coffee) under randomized, double-blind crossover conditions on two different occasions. Before administration and 30 min afterwards, a 17-channel quantitative EEG was recorded during relaxation with eyes open and closed (15 min each). Caffeine caused a significant reduction of total EEG power at fronto-parieto-occipital and central electrode positions of both hemispheres when the subjects kept their eyes open. Absolute power of the slow and fast alpha and slow beta activities was diminished in various regions of the brain (p < 0.05). The effect was more pronounced with the subjects keeping their eyes open than with eyes closed. It can be concluded that quantitative EEG is a sensitive method to assess the effects of psychostimulants on the human brain. Therefore, in pharmaco-EEG studies, environmental factors such as caffeine have to be excluded. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Bc. Žaneta Jakubová, Specialist in laboratory methods Signs of epilepsy spectrum disorder in persons with psychostimulants addiction Diploma thesis Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Biological and Medical Sciences, Background: The aim of this diploma thesis is to study the occurrence of symptoms of epileptic spectrum disorder in psychostimulant subjects and to demonstrate the effect of psychostimulants on the occurrence of this disorder. Methods: For questionnaire survey was used to collect the data, in which probands submitted a total of 3 questionnaires. Input anamnestic questionnaire to obtain general information, the remaining two are focused on symptoms of epileptic spectrum disorder - Complex Partial Seizure-like Symptoms Inventory (CPSI) and Limbic System Checklist-33 (LSCL-33). Statistical methods of percentage comparison, chi-square test and unpaired t-test were used for evaluation. Results: Unusual scores and scores for epileptic spectrum disorder reached a total of 60 % of respondents in the CPSI. In the LSCL-33 questionnaire, a suspect and abnormal score reached 100 % of respondents. Conclusions: Both hypotheses have been demonstrated, namely that psychostimulants influence the occurrence of symptoms of epileptic spectrum disorder and that...

Despite the widespread use of caffeine as a central nervous stimulant, the central pharmacodynamic properties of the drug have not yet been conclusively evaluated in humans. The present study was undertaken to assess the acute effects of caffeine on measures of topographical quantitative electroencephalogram (EEG) in normal subjects. Ten healthy male volunteers (mean age ± SD 25 ± 4 years) received placebo and 200 mg of caffeine as powder with oral water solution (caffeine amount = 2 cups of coffee) under randomized, double-blind crossover conditions on two different occasions. Before administration and 30 min afterwards, a 17-channel quantitative EEG was recorded during relaxation with eyes open and closed (15 min each). Caffeine caused a significant reduction of total EEG power at fronto-parieto-occipital and central electrode positions of both hemispheres when the subjects kept their eyes open. Absolute power of the slow and fast alpha and slow beta activities was diminished in various regions of the brain (p < 0.05). The effect was more pronounced with the subjects keeping their eyes open than with eyes closed. It can be concluded that quantitative EEG is a sensitive method to assess the effects of psychostimulants on the human brain. Therefore, in pharmaco-EEG studies, environmental factors such as caffeine have to be excluded. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.