published_or_final_version / Chinese Medicine / Master / Master of Philosophy

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Thesis (Ph. D.)--Northeastern University, 2008. / Title from title page (viewed March 3, 2009). Graduate School of Arts and Sciences, Dept. of Psychology. Includes bibliographical references (p. 148-156).

Thesis (M. Sc.)--Carleton University, 1992. / Also available in electronic format on the Internet.

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.

Cocaine abuse is a world-wide public health and social problem without a U.S. Food and Drug Administration (FDA)-approved medication. An ideal anti-cocaine medication would accelerate cocaine metabolism producing biologically inactive metabolites by administration of an efficient cocaine-specific exogenous enzyme. Recent studies in our lab have led to discovery of the desirable, highly efficient human cocaine hydrolases (hCocHs) that can efficiently detoxify and inactivate cocaine without affecting normal functions of central nervous system (CNS). Preclinical and clinical data have demonstrated that these hCocHs are safe for use in humans and effective for accelerating cocaine metabolism. However, the actual therapeutic use of a hCocH in cocaine addiction treatment is limited by the short biological half-life (e.g. 8 hours or shorter in rats) of the hCocH. In the investigation described in this thesis, we have demonstrated that mCocH and hCocH have improved the catalytic efficiency of mBChE and hBChE against cocaine by ~8- and ~2000-fold, respectively, although the catalytic efficiencies of mCocH and hCocH against other substrates, including acetylcholine (ACh) and butyrylthiocholine (BTC), are close to those of the corresponding wild-type enzymes mBChE and hBChE. In addition, we have identified the first benzoylecgonine-metabolizing enzymes that can hydrolyze benzoylecgonine and accelerate its clearance in rats. The developed LC-MS/MS method has enabled us to simultaneously determine cocaine and nine cocaine-related metabolites in whole blood samples. In development of the long-acting hCocHs, we have designed and discovered a novel hCocH form, catalytic antibody analog, which is an Fc-fused hCocH dimer (hCocH-Fc). The hCocH-Fc has not only a high catalytic efficiency against cocaine, but also a considerably longer biological half-life. A single dose of hCocH-Fc was able to accelerate cocaine metabolism in rats even after 20 days and, thus, block cocaine-induced hyperactivity for a long period of time. In consideration of the general observation that the biological half-life of a protein drug in humans is significantly longer than that in rodents, the hCocH-Fc could allow dosing once every 2-4 weeks, or longer for cocaine addiction treatment in humans.

Understanding the process of associative learning between environmental stimuli and cocaine is essential for the prevention of drug-use relapse and long-term treatment of cocaine dependence. Based on contemporary learning theories, empirical studies using natural rewards have shown that cognitive factors, such as uncertainty and prediction errors, play an important role in the process of reward associative learning. Uncertainty is the lack of an accurate predictor for reward while prediction error is defined as the discrepancy between expected and received reward. In this dissertation, we focused on the role of uncertainty and prediction error in cocaine-associative learning. Olfactory and visual cues during self-administration/conditioning sessions were used to induce cocainereward expectation and uncertainty in operant trained catheterized Sprague Dawley rats. The influence of cue-induced uncertainty and prediction error on nucleus accumbens dopamine (NAcc DA) following self-administration of cocaine and saline in these conditioned animals was then measured using in-vivo microdialysis. Results showed that cocaine-stimulated NAcc DA was enhanced in the presence of cues signaling cocaine reward uncertainty (Uncertainty) as compared to animals expecting to get cocaine (Certainty). Also omission of expected cocaine reward (Prediction Error) resulted in a significant depression of NAcc DA levels below baseline. Recently diazepam (a positive GABAA modulator) has been shown to disrupt cocaine-induced LTP and it has been suggested that this disruption can block the acquisition of drug-associated memories. We therefore hypothesized that diazepam-pretreatment during conditioning sessions would disrupt the learned responses to cocaine and saline in the presence of cue-induced uncertainty and prediction error. Our results show that diazepam pretreatment duringconditioning sessions, blocked the differential cocaine-stimulated NAcc DA response to cue-induced certainty and uncertainty. Moreover, on omission of expected cocaine reward (Prediction Error) there was no significant depression of NAcc DA below baseline. The findings of this dissertation thus highlight the importance of cognitive factors (uncertainty and prediction errors) in the process of cocaine-associative learning. They also provide a platform to further explore the influence of these factors on other neuroadaptations during cocaine-associative learning, which will help us develop effective behavioral and pharmacological therapies to prevent drug-use relapse.

This thesis aims to investigate and deconstruct the relationship between the narcotic, its narrative, and western modernity. To reveal the relationship, this thesis argues that it is possible to understand the philosophical, political, cultural and ethical dimensions of western modernity through the ulterior lens of the narcotic. As such, this thesis investigates western modernity's relationship to (a) cocaine as a specific narcotic, and (b) the concept of the narcotic with all its attendant connotations of addictions, illegitimacy, transgression, illegality, and so on. Accordingly, the thesis is both interpretive of the historical narrative of the narcotic of cocaine, and generative in its deconstruction of the relationship between western modernity and the concept of the narcotic. The deconstruction of this relationship ultimately reveals both prior narratives not as oppositional, but as supplementary. This has radical consequences for the manner in which we engage with narcotic use and the user - if the narcotic is supplement to the logic of western modernity, at each attempt to expel the use and user of the narcotic, rather then create difference, we self implicate ourselves in that expulsion and distance. To seek a new and more just means of dealing with the concept of the narcotic, and its use, therefore requires a new epistemological framework which can at once contemplate both narratives at the same time. To this end, the thesis suggests the use of critical complexity theory as one such methodological tool, if supplemented by the thoughts and strategies of Derridian deconstruction and Foucauldian discourse analysis.

The main purpose of this research was to investigate the phenomenon of tolerance to cocaine. Tolerance is operationally defined as a decreased drug effect due to prior history of drug administration. The animal model that was chosen to investigate tolerance to cocaine was the drug discrimination model, which is an animal analogue of human subjective drug effects. In the drug discrimination procedure, animals are trained to emit one behavior when injected with saline. In the present experiments, rats were trained to press one lever when injected with cocaine, 10 mg/kg, and a different lever when injected with saline for food reinforcement. Once rats are trained, they can accurately detect the cocaine stimulus greater than 95% of the time.

Poisoning is frequently associated with psychological and physiological co-morbidities that can be assessed in order to improve patients' management and reduce cost. The primary objective of this study is to conduct a review of emergency department (ED) poisonings to characterize its demographics and assess associated co-morbidities. The second objective is to explore correlation between personal history of diseases and poisonings. Predictors for poisonings and its outcomes were investigated and risk factors for suicidal poisoning and how it relates to mental illnesses were explored. Six hundred and forty nine cases admitted to ED between 2004 and 2007 were studied. Results indicate that difference in ethnic background was substantial as poisoning cases were predominantly African Americans (79.9%) between 36-45 years old with a male to female ratio of 1.3. Intentional illicit drug overdose was the greatest risk factor for ED poisonings, and among the 649 cases, heroin overdose was the most common cause of poisoning at 35.4% (n=230), cocaine overdose at 31.7% (n=206), heroin and cocaine overdose at 4.3% (n=28), multiple drug poisoning at 5.5% (n=36), and antidepressant/antipsychotic poisoning at 6% (n=39). A significant correlation between heroin poisonings and asthma (F=20.29, DF=1, p= .0001) was found, as well as between cocaine poisoning and hypertension (F=33.34, DF=1, p=.0001), and cocaine poisoning and cardiovascular diseases (F=35.34, DF=1, p=.0001). Another significant finding is the change in the pattern of the route of illicit drug use from injection to inhalation; it is thought this may reduce the rate of HIV and Hepatitis transmission via hypodermic needles among illicit drug users. As well, inhalation and insufflation may be risk factors that aggravate preexisting asthma. Mental illnesses, chiefly depression, remain one of the greatest risk factors for suicidal poisoning beside age, Hispanic race, gender, ingestion route and unemployment. This study provides supporting evidence that poisoning, particularly deliberate poisoning with illicit drugs remains a serious issue that significantly aggravates co-morbidities and raises treatment cost by increasing both the rate of hospitalization and hospital length of stay (LOS). Pragmatic guidelines and innovations in reducing heroin and cocaine abuse in these patients may lessen the severity of diseases and reduce its burden on the healthcare system and on society.