Studio elettrofisiologico di modificazioni a lungo termine della forza della trasmissione sinaptica nel sistema nervoso centrale

Il nucleo accumbens (NAc), il maggior componente del sistema mesocorticolimbico, è coinvolto nella mediazione delle proprietà di rinforzo e nella dipendenza da diverse sostanze d’abuso. Le sinapsi glutammatergiche del NAc possono esprimere plasticità, tra cui una forma di depressione a lungo termine (LTD) dipendente dagli endocannabinoidi (eCB). Recenti studi hanno dimostrato un’interazione tra le vie di segnalazione del sistema eCB e quelle di altri sistemi recettoriali, compreso quello serotoninergico (5-HT); la vasta colocalizzazione di recettori serotoninergici e CB1 nel NAc suggerisce la possibilità di un’interazione tra questi due sistemi. In questo studio abbiamo riscontrato che una stimolazione a 4 Hz per 20 minuti (LFS-4Hz) delle afferenze glutammatergiche in fettine cerebrali di ratto, induce una nuova forma di eCB-LTD nel core del NAc, che richiede l’attivazione dei recettori CB1 e 5-HT2 e l’apertura dei canali del Ca2+ voltaggio-dipendenti di tipo L. Inoltre abbiamo valutato che l’applicazione esogena di 5-HT (5 M, 20 min) induce una LTD analoga (5-HT-LTD) a livello delle stesse sinapsi, che richiede l’attivazione dei medesimi recettori e l’apertura degli stessi canali del Ca2+; LFS-4Hz-LTD e 5-HT-LTD sono reciprocamente saturanti. Questi risultati suggeriscono che la LFS-4Hz induce il rilascio di 5-HT, che si lega ai recettori 5-HT2 a livello postsinaptico incrementando l’influsso di Ca2+ attraverso i canali voltaggio-dipendenti di tipo L e la produzione e il rilascio di 2-arachidonoilglicerolo; l’eCB viaggia a ritroso e si lega al recettore CB1 a livello presinaptico, causando una diminuzione duratura del rilascio di glutammato, che risulta in una LTD. Queste osservazioni possono essere utili per comprendere i meccanismi neurofisiologici che sono alla base della dipendenza da sostanze d’abuso, della depressione maggiore e di altre malattie psichiatriche caratterizzate dalla disfunzione della neurotrasmissione di 5-HT nel NAc.

Original analytical methods for the determination of psychoactive compounds in complex matrices

This thesis work aims to develop original analytical methods for the determination of drugs with a potential for abuse, for the analysis of substances used in the pharmacological treatment of drug addiction in biological samples and for the monitoring of potentially toxic compounds added to street drugs. In fact reliable analytical techniques can play an important role in this setting. They can be employed to reveal drug intake, allowing the identification of drug users and to assess drug blood levels, assisting physicians in the management of the treatment. Pharmacological therapy needs to be carefully monitored indeed in order to optimize the dose scheduling according to the specific needs of the patient and to discourage improper use of the medication. In particular, different methods have been developed for the detection of gamma-hydroxybutiric acid (GHB), prescribed for the treatment of alcohol addiction, of glucocorticoids, one of the most abused pharmaceutical class to enhance sport performance and of adulterants, pharmacologically active compounds added to illicit drugs for recreational purposes. All the presented methods are based on capillary electrophoresis (CE) and high performance liquid chromatography (HPLC) coupled to various detectors (diode array detector, mass spectrometer). Biological samples pre-treatment was carried out using different extraction techniques, liquid-liquid extraction (LLE) and solid phase extraction (SPE). Different matrices have been considered: human plasma, dried blood spots, human urine, simulated street drugs. These developed analytical methods are individually described and discussed in this thesis work.

Was bietet die Spezialklinik den Suchtpatienten?

Der stationäre Klinikaufenthalt von Patienten mit Abhängigkeitserkrankungen ist häufig ein unverzichtbarer Teil in der Behandlungskette von Suchterkrankungen. Es werden die verschiedenen Phasen der Behandlung, deren Therapieelemente sowie Vor- und Nachteile eines stationären Aufenthalts diskutiert. Anhand der Klinik Südhang, welche Patienten und Patientinnen mit einer Alkohol- und/oder Medikamentenabhängigkeit stationär behandelt, zeigt sich die Bedeutung eines individualisierten Therapieangebots je nach Entzugs- und Entwöhnungsphase. Um Patienten mit einer Abhängigkeitserkrankung einen erfolgreichen Entzug, bzw. Entwöhnung zu gewährleisten, ist eine interdisziplinäre Betreuung und Nachsorge essentiell.

Opioid maintenance therapy in Switzerland: an overview of the Swiss IMPROVE study

BACKGROUND/AIMS: Switzerland’s drug policy model has always been unique and progressive, but there is a Need to reassess this system in a rapidly changing world. The IMPROVE study was conducted to gain understanding of the attitudes and beliefs towards opioid maintenance therapy (OMT) in Switzerland with regards to quality and Access to treatment. To obtain a “real-world” view on OMT, the study approached its goals from two different angles: from the perspectives of the OMT patients and of the physicians who treat patients with maintenance therapy. The IMPROVE study collected a large body of data on OMT in Switzerland. This paper presents a small subset of the dataset, focusing on the research design and methodology, the profile of the participants and the responses to several key questions addressed by the questionnaires. METHODS: IMPROVE was an observational, questionnaire-based cross-sectional study on OMT conducted in Switzerland. Respondents consisted of OMT patients and treating physicians from various regions of the country. Data were collected using questionnaires in German and French. Physicians were interviewed by phone with a computer-based questionnaire. Patients self-completed a paper-based questionnaire at the physicians’ Offices or OMT treatment centres. RESULTS: A total of 200 physicians and 207 patients participated in the study. Liquid methadone and methadone tablets or capsules were the medications most commonly prescribed by physicians (60% and 20% of patient load, respectively) whereas buprenorphine use was less frequent. Patients (88%) and physicians (83%) were generally satisfied with the OMT currently offered. The current political framework and lack of training or information were cited as determining factors that deter physicians from engaging in OMT. About 31% of OMT physicians interviewed were ≥60 years old, indicating an ageing population. Diversion and misuse were considered a significant problem in Switzerland by 45% of the physicians. CONCLUSION: The subset of IMPROVE data presented gives a present-day, real-life overview of the OMT landscape in Switzerland. It represents a valuable resource for policy makers, key opinion leaders and drug addiction researchers and will be a useful basis for improving the current Swiss OMT model.

Tabulation of multiple responses

Although multiple-response questions are quite common in survey research, Stata’s official release does not provide much capability for an effective analysis of multiple-response variables. For example, in a study on drug addiction an interview question might be, “Which substances did you consume during the last four weeks?” The respondents just list all the drugs they took, if any; e.g., an answer could be “cannabis, cocaine, heroin” or “ecstasy, cannabis” or “none”, etc. Usually, the responses to such questions are stored as a set of variables and, therefore, cannot be easily tabulated. I will address this issue here and present a new module to compute one- and two-way tables of multiple responses. The module supports several types of data structure, provides significance tests, and offers various options to control the computation and display of the results. In addition, tools to create graphs of multiple-response distributions are presented.

"La recuperación es para obedientes" : Algunas articulaciones y ajustes metodológicos para el análisis de un tratamiento de adicción a las drogas

El escrito reflexiona sobre la adecuación teórica y metodológica del recurso a las categorías institución total, dispositivo y disciplina, para investigar problemáticas recientes en el campo de la salud-enfermedad-atención, particularmente las denominadas adicciones a las drogas. De la mano de numerosas investigaciones empíricas, ciertos conceptos se anudan en los análisis, asociándose disciplina-encierro, e institución total-espacio cerrado. El escrito propone el desacople de estas nociones y la recuperación de su productividad analítica, desde la investigación en un dispositivo terapéutico ambulatorio para la adicción a drogas del Area Metropolitana de Buenos Aires. Se aborda esta problemática desde una perspectiva etnográfica, con análisis documental, observación participante y entrevistas realizadas a profesionales de la salud de la institución, personal de apoyo y usuarios. Se concluye que las formulaciones de Goffman y Foucault ayudan a comprender la existencia de modalidades de tratamiento para las adicciones a las drogas que, sin fundarse en el encierro como técnica primordial de control de los cuerpos, sostienen un proceso de clausura y despojo significativos; y que la renuncia a homologar la clausura, y el espacio cerrado a una materialidad, permitió dar realce a una vivencia de despojo subjetivo de parte de quienes se encuentran en tratamiento en la institución

"La recuperación es para obedientes" : Algunas articulaciones y ajustes metodológicos para el análisis de un tratamiento de adicción a las drogas

El escrito reflexiona sobre la adecuación teórica y metodológica del recurso a las categorías institución total, dispositivo y disciplina, para investigar problemáticas recientes en el campo de la salud-enfermedad-atención, particularmente las denominadas adicciones a las drogas. De la mano de numerosas investigaciones empíricas, ciertos conceptos se anudan en los análisis, asociándose disciplina-encierro, e institución total-espacio cerrado. El escrito propone el desacople de estas nociones y la recuperación de su productividad analítica, desde la investigación en un dispositivo terapéutico ambulatorio para la adicción a drogas del Area Metropolitana de Buenos Aires. Se aborda esta problemática desde una perspectiva etnográfica, con análisis documental, observación participante y entrevistas realizadas a profesionales de la salud de la institución, personal de apoyo y usuarios. Se concluye que las formulaciones de Goffman y Foucault ayudan a comprender la existencia de modalidades de tratamiento para las adicciones a las drogas que, sin fundarse en el encierro como técnica primordial de control de los cuerpos, sostienen un proceso de clausura y despojo significativos; y que la renuncia a homologar la clausura, y el espacio cerrado a una materialidad, permitió dar realce a una vivencia de despojo subjetivo de parte de quienes se encuentran en tratamiento en la institución

"La recuperación es para obedientes" : Algunas articulaciones y ajustes metodológicos para el análisis de un tratamiento de adicción a las drogas

El escrito reflexiona sobre la adecuación teórica y metodológica del recurso a las categorías institución total, dispositivo y disciplina, para investigar problemáticas recientes en el campo de la salud-enfermedad-atención, particularmente las denominadas adicciones a las drogas. De la mano de numerosas investigaciones empíricas, ciertos conceptos se anudan en los análisis, asociándose disciplina-encierro, e institución total-espacio cerrado. El escrito propone el desacople de estas nociones y la recuperación de su productividad analítica, desde la investigación en un dispositivo terapéutico ambulatorio para la adicción a drogas del Area Metropolitana de Buenos Aires. Se aborda esta problemática desde una perspectiva etnográfica, con análisis documental, observación participante y entrevistas realizadas a profesionales de la salud de la institución, personal de apoyo y usuarios. Se concluye que las formulaciones de Goffman y Foucault ayudan a comprender la existencia de modalidades de tratamiento para las adicciones a las drogas que, sin fundarse en el encierro como técnica primordial de control de los cuerpos, sostienen un proceso de clausura y despojo significativos; y que la renuncia a homologar la clausura, y el espacio cerrado a una materialidad, permitió dar realce a una vivencia de despojo subjetivo de parte de quienes se encuentran en tratamiento en la institución

Tabulation of multiple responses

Although multiple response questions are quite common in survey research, Stata's official release does not provide much possibility for an effective analysis of multiple response variables. For example, in a study on drug addiction an interview question might be, "Which substances did you consume during the last four weeks?" The respondents just list all the drugs they took if any, e.g., an answer could be "cannabis, cocaine, heroin" or "ecstasy, cannabis" or "none", etc. Usually, the responses to such questions are held as a set of variables and, therefore, cannot be easily tabulated. I will address this issue and present a new module to compute one- and two-way tables of multiple responses. The module supports several types of data structure, provides significance tests, and offers various options to control the computation and display of the results.

The effects of cocaine self-administration on dendritic spine density in the rat hippocampus are dependent on genetic background

Chronic exposure to cocaine induces modifications to neurons in the brain regions involved in addiction. Hence, we evaluated cocaine-induced changes in the hippocampal CA1 field in Fischer 344 (F344) and Lewis (LEW) rats, 2 strains that have been widely used to study genetic predisposition to drug addiction, by combining intracellular Lucifer yellow injection with confocal microscopy reconstruction of labeled neurons. Specifically, we examined the effects of cocaine self-administration on the structure, size, and branching complexity of the apical dendrites of CA1 pyramidal neurons. In addition, we quantified spine density in the collaterals of the apical dendritic arbors of these neurons. We found differences between these strains in several morphological parameters. For example, CA1 apical dendrites were more branched and complex in LEW than in F344 rats, while the spine density in the collateral dendrites of the apical dendritic arbors was greater in F344 rats. Interestingly, cocaine self-administration in LEW rats augmented the spine density, an effect that was not observed in the F344 strain. These results reveal significant structural differences in CA1 pyramidal cells between these strains and indicate that cocaine self-administration has a distinct effect on neuron morphology in the hippocampus of rats with different genetic backgrounds.

Dopamine-dependent responses to morphine depend on glucocorticoid receptors

Previous work has shown that glucocorticoid hormones facilitate the behavioral and dopaminergic effects of morphine. In this study we examined the possible role in these effects of the two central corticosteroid receptor types: mineralocorticoid receptor (MR), and glucocorticoid receptor (GR). To accomplish this, specific antagonists of these receptors were infused intracerebroventricularly and 2 hr later we measured: (i) locomotor activity induced by a systemic injection of morphine (2 mg/kg); (ii) locomotor activity induced by an infusion of morphine (1 μg per side) into the ventral tegmental area, which is a dopamine-dependent behavioral response to morphine; (iii) morphine-induced dopamine release in the nucleus accumbens, a dopaminergic projection site mediating the locomotor and reinforcing effects of drugs of abuse. Blockade of MRs by spironolactone had no significant effects on locomotion induced by systemic morphine. In contrast, blockade of GRs by either RU38486 or RU39305, which is devoid of antiprogesterone effects, reduced the locomotor response to morphine, and this effect was dose dependent. GR antagonists also reduced the locomotor response to intraventral tegmental area morphine as well as the basal and morphine-induced increase in accumbens dopamine, as measured by microdialysis in freely moving rats. In contrast, spironolactone did not modify dopamine release. In conclusion, glucocorticoids, via GRs, facilitate the dopamine-dependent behavioral effects of morphine, probably by facilitating dopamine release. The possibility of decreasing the behavioral and dopaminergic effects of opioids by an acute administration of GR antagonists may open new therapeutic strategies for treatment of drug addiction.

Hyperactivity and impaired response habituation in hyperdopaminergic mice

Abnormal dopaminergic transmission is implicated in schizophrenia, attention deficit hyperactivity disorder, and drug addiction. In an attempt to model aspects of these disorders, we have generated hyperdopaminergic mutant mice by reducing expression of the dopamine transporter (DAT) to 10% of wild-type levels (DAT knockdown). Fast-scan cyclic voltammetry and in vivo microdialysis revealed that released dopamine was cleared at a slow rate in knockdown mice, which resulted in a higher extracellular dopamine concentration. Unlike the DAT knockout mice, the DAT knockdown mice do not display a growth retardation phenotype. They have normal home cage activity but display hyperactivity and impaired response habituation in novel environments. In addition, we show that both the indirect dopamine receptor agonist amphetamine and the direct agonists apomorphine and quinpirole inhibit locomotor activity in the DAT knockdown mice, leading to the hypothesis that a shift in the balance between dopamine auto and heteroreceptor function may contribute to the therapeutic effect of psychostimulants in attention deficit hyperactivity disorder.

Sociología y drogodependencia: la mirada ténica en la intervención social. Fundamentos para la constitución de una sociología de las drogodependencias

Almost thirty years have passed since the City Council of Madrid approved the first Municipal Plan against Drugs, thus laying the foundations of the current commitment to offer assistance to drug addicts. A Service that has been continuously growing (in funding), maturing (in organizations) and diversifying (in actions) during these decades, in the same manner as the scenario in which these actions are deployed has been evolving. But, what can be said today about the status of drugaddiction intervention? This study adopts a sociological approach that starts with and is focused on what has been defined as the hegemonic vision on drug addiction, with the aim of studying (precisely and progressively) the different and most widely accepted theoretical-practical developments and to understand how certain conceptions or positions determine the form of this social fact. Therefore, the main objective of this study is to understand and evaluate the performative effects of certain practices, techniques and professionals on defining and addressing a reality that is in question and/or in conflict, as a social problem. In addition, this study is focused on identifying a series of fundamental elements to address what is understood as the state of the issue of drug addiction in depth (discourse of drugs Vs. discourse on drugs) in order to offer a series of sociological questions and insights to focus attention onto this reality. For this purpose, once its intentions have been defined and due to the social nature of the object under study, the present research deploys qualitative methodology as a tool for approximation, delimiting the scope that professional technicians assume regarding the issue in question as well as their own professional practices within their organizations. Thus, we have contacted certain public as well as non-governmental organizations with long-term experience in drug addiction, so as to find out first hand, in addition to their writings, the different meanings they find in the performance of their specific practice (micro) as well as the framework within which their practice is defined and materialised (macro) on a population defined or characterised by (drug) addiction...

Role of Dopamine D2 Receptors in the Consolidation of Amphetamine-Cue Memory in Conditioned Activity in Rats

The neurotransmitter dopamine (DA) plays an essential role in reward-related incentive learning, whereby neutral stimuli gain the ability to elicit approach and other responses. In an incentive learning paradigm called conditioned activity, animals receive a stimulant drug in a specific environment over the course of several days. When then placed in that environment drug-free, they generally display a conditioned hyperactive response. Modulating DA transmission at different time points during the paradigm has been shown to disrupt or enhance conditioning effects. For instance, blocking DA D2 receptors before sessions generally impedes the acquisition of conditioned activity. To date, no studies have examined the role of D2 receptors in the consolidation phase of conditioned activity; this phase occurs immediately after acquisition and involves the stabilization of memories for long-term storage. To investigate this possible role, I trained Wistar rats (N = 108) in the conditioned activity paradigm produced by amphetamine (2.0 mg/kg, intraperitoneally) to examine the effects of the D2 antagonist haloperidol (doses 0.10, 0.25, 0.50, 0.75, 1.0, & 2.0 mg/kg, intraperitoneally) administered 5 min after conditioning sessions. Two positive control groups received haloperidol 1 h before conditioning sessions (doses 1.0 mg/kg and 2.0 mg/kg). The results revealed that post-session haloperidol at all doses tested did not disrupt the consolidation of conditioned activity, while pre-session haloperidol at 2.0 mg/kg prevented acquisition, with the 1.0 mg/kg group trending toward a block. Additionally, post-session haloperidol did not diminish activity during conditioning days, unlike pre-session haloperidol. One possible reason for these findings is that the consolidation phase may have begun earlier than when haloperidol was administered, since the conditioned activity paradigm uses longer learning sessions than those generally used in consolidation studies. Future studies may test if conditioned activity can be achieved with shorter sessions; if so, haloperidol would then be re-tested at an earlier time point. D2 receptor second messenger systems may also be investigated in consolidation. Since drug-related incentive stimuli can evoke cravings in those with drug addiction, a better understanding of the mechanisms of incentive learning may lead to the development of solutions for these individuals.

FDA narcotic treatment programs directory.

Mode of access: Internet.