GABAa α2-subunit containing receptors are known to be expressed in brain regions associated with anxiety, conditioning and the rewarding properties of drugs of abuse, particularly the amygdala and nucleus accumbens (NAcc). Generation of a GABAa α2-subunit knockout mouse has enabled the role of this subunit to be investigated in these behaviours.

La prise répétée de cocaïne entraine la mise en place d’une addiction durable. Cette maladie neuropsychiatrique est un problème de santé public majeur en France et dans le monde. Les effets aigus de la cocaïne sont maintenant bien connus mais il est encore difficile d’établir un consensus des conséquences d’une administration répétée de ce psychostimulant au niveau central. En effet, les résultats rapportés dans la littérature actuelle présentent de nombreuses disparités. Nous pensons que cela pourrait être dû aux différences de protocole d’administration utilisés par chaque laboratoire. Nous émettons l’hypothèse que si à l’heure actuelle il n’existe pas de traitement efficace pour traiter les cocaïnomanes, c’est que les thérapies ne prennent pas en compte les différentes modifications neurobiologiques induites par les différents profils de consommation. Afin de tester cette hypothèse, nous avons comparé deux profils d’administration différents de cocaïne chez le rat. Nous nous sommes intéressés aux conséquences comportementales, neurochimiques et cellulaires après un sevrage court et un sevrage long. Nous avons mis en évidence que les adaptations comportementales (activité locomotrice et exploratoire), neurochimiques (dopamine extracellulaire) et cellulaires (récepteurs dopaminergiques) basales et en réponse à une dose de rappel, sont différentes selon le profil d’administration de cocaïne. Nous avons également mis en évidence une anticipation neurochimique dopaminergique et locomotrice, exactement à l’heure habituelle d’injection et qui varie selon le profil d’administration. Dans un deuxième temps, nous avons montré que le BDNF (Brain Derived Neurotrophic Factor), qui est une neurotrophine du système catécholaminergique, varie à la fois au niveau central et au niveau périphérique, de façon spécifique pour chaque profil d’administration de cocaïne. L’utilisation en clinique de ce biomarqueur périphérique (BDNF), permettrait d’évaluer les variations neurobiologiques centrales chez les patients cocaïnomanes et d’établir un traitement thérapeutique approprié à leur profil de consommation. L’ensemble des résultats obtenus au cours de cette thèse, ont permis de montrer que le profil d’administration a une grande importance sur les conséquences neurobiologiques de la cocaïne / Pas de résumé en anglais

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Addiction is a complex social phenomenon resulting from psychological and physiological dependence. The aim of the study was to create a clinical impression of the lived experiences of cocaine dependents. A transcendental phenomenological approach was used to elicit the essence of addiction as experienced by the participants. Theoretical sampling ensured relevant participants were selected through haphazard sampling procedures. Data was collected through the use of biographical questionnaires and individual, semi-structured interviews with three cocaine dependents. Data was processed according to the four phenomenological principles epoche, phenomenological reduction, imaginative variation and synthesis using Tesch’s eight steps. The essence of cocaine dependency is contained in the psychological experiences of the drug which define and perpetuate that addiction. The psychological addiction develops prior to physical dependence resulting in an entrenched addiction before treatment is sought by the cocaine dependents.

Rats were trained to discriminate an injection of cocaine, 5.0 mg/kg, from an injection of saline, using a two-lever choice paradigm: one lever was correct after cocaine injection, the other lever was correct after a saline injection. After training, cocaine and methamphetamine were generalized to the cocaine lever, but phenethylamine (PEA) was only partially generalized. Cocaine was injected every 8 hrs, 20.0 mg/kg, and the discriminability of 5.0 mg/kg was tested every other day. Redetermination of the cocaine generalization curve after 6 days of chronic administration showed a shift to the right, from an ED50 of 4.1 mg/kg in the pre-chronic condition to 10.0 mg/kg. Tolerance did not develop to the behavioral effects of cocaine, measured by time to the first reinforcement and response rate. There was cross-tolerance to methamphetamine; however, no evidence for cross-tolerance to PEA was obtained. Following the acquisition of tolerance, chronic administration of cocaine was terminated, and the discriminability of 5.0 mg/kg was tested every other day for loss of tolerance. After 8 days the ED50 returned to 5.0 mg/kg.

A sizeable portion of the societal drain from cocaine abuse results from the complications of in utero drug exposure. Because of challenges in using humans and mammalian model organisms as test subjects, much debate remains about the impact of in utero cocaine exposure. Zebrafish offer a number of advantages as a model in longitudinal toxicology studies and are quite sensitive physiologically and behaviorally to cocaine. In this study, we have used zebrafish to model the effects of embryonic pre-exposure to cocaine on development and on subsequent cardiovascular physiology and cocaine-induced conditioned place preference (CPP) in longitudinal adults. Larval fish showed a progressive decrease in telencephalic size with increased doses of cocaine. These treated larvae also showed a dose dependent response in heart rate that persisted 24 h after drug cessation. Embryonic cocaine exposure had little effect on overall health of longitudinal adults, but subtle changes in cardiovascular physiology were seen including decreased sensitivity to isoproterenol and increased sensitivity to cocaine. These longitudinal adult fish also showed an embryonic dose-dependent change in CPP behavior, suggesting an increased sensitivity. These studies clearly show that pre-exposure during embryonic development affects subsequent cocaine sensitivity in longitudinal adults.

Rationale: Lead-exposure during developmental periods may alter reinforcing patterns of drugs of abuse in adulthood. Anxiety related mechanisms may also influence drug intake. Interactions between the two altering factors may exist. Objectives: The present study examined the effects of perinatal lead-exposure on cocaine self-administration after a GABAA antagonist pre-treatment. Methods: Female rats were exposed to a regimen of 16 mg lead daily for 30 days prior to breeding with un-exposed males. This continued throughout gestation and lactation until postnatal day (PND) 21. On PND 63, animals were implanted with indwelling jugular catheters. After a 7 day recovery period, animals were trained to self-administer 0.50 mg/kg cocaine intravenously [IV]. After stable responding had been established, testing procedures began using combinations of 0.03 and 0.06 mg/kg cocaine [IV] and 0.00, 0.50, 1.00 and 2.00 mg/kg bicuculline (a GABAA antagonist) intraperitoneal [IP]. Results: Bicuculline pre-treatment caused directionally opposite effects in both treatment groups (Group 0-Lead and Group 16-Lead) at the 0.06 mg/kg cocaine dose. Group 0-Lead animals showed an increase in self-administration, while Group 16-Lead animals showed a decrease in responding on the active (cocaine) lever. Results at the 0.03 mg/kg cocaine dose showed no discernable pattern. Group 0-Lead animals decreased in active lever responding at the 2.00 mg/kg bicuculline dose. Group 16-Lead animals showed no differences in responding at any dose of bicuculline. Conclusions: These data further suggest the influential role of GABA in mediating cocaine reward and the ability of developmental lead-exposure to alter mechanisms mediating drug responsiveness even after exposure has terminated.

Synthesis and Pharmacology of Potential Site-Directed Therapeutic Agents for Cocaine Abuse Susanna Moore 235 Pages Directed by Dr. David M. Collard and Dr. Howard M. Deutsch Stimulants such as cocaine continue to dominate the nations illicit drug problem. An effective medication for any aspect of cocaine addiction has not been developed. Cocaine binds, although not selectively, to the dopamine transporter (DAT) and disrupts normal dopamine (DA) neurotransmission between neurons. While the dopamine hypothesis for the mechanism of action of cocaine has been widely accepted, cocaine also possesses the ability to block the uptake of serotonin at the serotonin transporter (5-HTT) and norepinephrine at the norepinephrine transporter (NET). The purpose of the work described herein is directed towards synthesizing and testing compounds selective for the DAT, leading to the identification of candidates as potential pharmacotherapies for cocaine dependence. A series of disubstituted and trisubstituted [2.2.2] and [2.2.1]bicycles were synthesized and tested for inhibitor potency in [3H]WIN 35,428 (WIN) binding at the DAT and for inhibition of [3H]DA uptake. Based on results from some of the pharmacology data new regio- and stereochemical isomers of bicyclic [2.2.1]heptanes and [2.2.2]octanes were synthesized. This will lead to further structure-activity-relationships, which will provide a better understanding of the structural requirements needed to bind at the DAT.

Rationale: Lead-exposure during developmental periods may alter reinforcing patterns of drugs of abuse in adulthood. Anxiety related mechanisms may also influence drug intake. Interactions between the two altering factors may exist. Objectives: The present study examined the effects of perinatal lead-exposure on cocaine self-administration after a GABAA antagonist pre-treatment. Methods: Female rats were exposed to a regimen of 16 mg lead daily for 30 days prior to breeding with un-exposed males. This continued throughout gestation and lactation until postnatal day (PND) 21. On PND 63, animals were implanted with indwelling jugular catheters. After a 7 day recovery period, animals were trained to self-administer 0.50 mg/kg cocaine intravenously [IV]. After stable responding had been established, testing procedures began using combinations of 0.03 and 0.06 mg/kg cocaine [IV] and 0.00, 0.50, 1.00 and 2.00 mg/kg bicuculline (a GABAA antagonist) intraperitoneal [IP]. Results: Bicuculline pre-treatment caused directionally opposite effects in both treatment groups (Group 0-Lead and Group 16-Lead) at the 0.06 mg/kg cocaine dose. Group 0-Lead animals showed an increase in self-administration, while Group 16-Lead animals showed a decrease in responding on the active (cocaine) lever. Results at the 0.03 mg/kg cocaine dose showed no discernable pattern. Group 0-Lead animals decreased in active lever responding at the 2.00 mg/kg bicuculline dose. Group 16-Lead animals showed no differences in responding at any dose of bicuculline. Conclusions: These data further suggest the influential role of GABA in mediating cocaine reward and the ability of developmental lead-exposure to alter mechanisms mediating drug responsiveness even after exposure has terminated.

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