Class of 2012 Abstract / Specific Aims: The purpose of this study is to identify the incidence of symptoms associated after exposure to “bath salts,” a term for synthetic cathinones in Arizona. Methods: This is a retrospective chart review of reported exposures to synthetic cathinones to the Arizona Poison and Drug Information Center and the Banner Good Samaritan Poison and Drug Information Center. Main Results: There were 306 cases of synthetic cathinone exposures reviewed and 76.5% were males (n=234) and 23.5% were females (n=72). They were ingested, inhaled, snorted, or injected. The mean age of exposure to synthetic cathinones was 29 years old. The most common symptoms included agitation (48.7%), hallucinations (27.1%), confusion (17.6%), hypertension (21.9%), tachycardia (50.6%), CK elevation (17.3%) and chest pain (9.5%). Less frequent symptoms exhibited in synthetic cathinone abuse included other CNS effects, gastrointestinal symptoms, muscular dysfunction, visual disturbances, and respiratory issues. Conclusions: The symptoms exhibited after exposure to synthetic cathinones were mainly neurologic and cardiovascular. In most cases, symptoms were effectively resolved within 24 to 48 hours after treatment with intravenous fluids and benzodiazepines. In some reports, patients were also given oxygen, anti-emetics, sedatives and anti-psychotic medications. Medical outcomes included major (1.6%), moderate (42.2%) and minor effects (26.1%) while 92 patients were lost to follow-up.

Oxycodone is a semi-synthetic opioid originally developed as a safer alternative to morphine. It is commonly prescribed for its pain-relieving effects, but has recently been implicated as a major underlying cause of the current opioid epidemic due to its clinical limitations that include tolerance, dependence and a high abuse liability. Simultaneous consumption of opioids and ethanol has been shown to increase the risk of overdose and death from opioids in opioid-tolerant individuals. We hypothesized that ethanol reversed opioid tolerance and previous studies showed that ethanol reversed morphine tolerance. This dissertation investigated whether ethanol reversed tolerance to other opioids in mice, primarily oxycodone. We found that tolerance developed to the antinociceptive effects of both oxycodone and hydrocodone, and that the same dose of ethanol (1 g/kg i.p.) reversed that tolerance. Oral ethanol (2 g/kg) also effectively reversed oxycodone tolerance. Ethanol did not significantly alter either acute or chronic oxycodone brain concentrations, suggesting that the reversal effect was mediated by neuronal mechanisms. DRG neurons were isolated from adult mice and the effects of oxycodone were assessed using whole-cell patch clamp electrophysiology experiments. Oxycodone [3µM] acutely reduced neuronal excitability as measured by a shift in threshold potentials to a more positive value. DRG neurons incubated overnight with 10µM oxycodone did not respond to the 3µM oxycodone challenge, indicating tolerance developed within these neurons. To test if ethanol was reversing tolerance through neuronal mechanisms, we incubated DRG neurons overnight with 10µM oxycodone and applied 20mM ethanol to the media prior to recording. Tolerance was robustly reversed in these neurons, as indicated by a response to 3µM oxycodone. The PKC inhibitor, Bis XI, also reversed oxycodone tolerance. In these studies we have clearly shown that tolerance develops to oxycodone in both the whole animal in an isolated neuronal preparation. In addition we have shown that the tolerance produced in these two preparations was reversed by ethanol at blood levels similar to those seen in humans. Further we have also included preliminary data that suggest that this reversal of oxycodone tolerance by ethanol may well be due to its actions on PKC.

University of Macau / Faculty of Social Sciences / Department of Sociology

Research on the determinants of injection drug use behavior has traditionally concentrated on factors operating at the individual level. However, more recent studies have found that behaviors surrounding injection drug use are shaped, not only by individual-level characteristics, but also by the environment in which they occur. The risk environment paradigm, proposed by Rhodes and colleagues, describes how factors exogenous to the individual influence high-risk injection behavior and blood borne virus (BBV) transmission among people who inject drugs (PWID). To date, few elements of the risk environment have been evaluated as potential determinants of high-risk injection behavior. The purpose of this dissertation was to study the influence of two elements of the risk environment on unsafe injection practices among PWID – neighborhood socioeconomic disadvantage and social discomfort surrounding the acquisition of sterile syringes from syringe exchange programs (SEPs) and pharmacies. To this end, a systematic literature review was conducted on the relation between neighborhood context and injection drug use behavior. Research gaps and methodological challenges identified in this review were used to design analyses exploring relations among neighborhood disadvantage, social discomfort, and high-risk injection behavior. These analyses were conducted using data collected from 484 PWID enrolled in the Pharmacists as Resources Making Links to Community Services (PHARM-Link) study, combined with data from the American Community Survey. Poisson regression with robust error variance was used to estimate associations between measures of neighborhood socioeconomic disadvantage and high-risk injection behavior. SEP accessibility and drug-related police activity were evaluated as potential modifiers of these relations. Similar methods were used to estimate associations between measures of social discomfort and high-risk injection behavior, including neighborhood socioeconomic disadvantage as a potential effect modifier. The systematic literature review on neighborhood context and injection drug use behavior identified few articles pertaining to this relation (n=22). Selected studies primarily investigated the influence of structural aspects of the neighborhood environment on behaviors surrounding injection drug use, while aspects of the social environment and potential modifiers of neighborhood-behavior relations were understudied. Subsequent quantitative analyses revealed that neighborhood socioeconomic disadvantage was associated with safer injection behaviors among PWID. Injectors in disadvantaged neighborhoods reported less receptive syringe sharing and less unsterile syringe use than their counterparts in relatively better off neighborhoods. Drug-related police activity attenuated associations between neighborhood disadvantage and unsterile syringe use, while the direction of associations between neighborhood disadvantage and the use of unsafe syringe sources varied with levels of SEP accessibility. In neighborhoods with high SEP accessibility, neighborhood disadvantage was associated with decreased use of unsafe syringe sources, while in neighborhoods with low SEP accessibility, neighborhood disadvantage was associated with increased use of unsafe syringe sources. Social discomfort was not associated with high-risk injection behavior, but effect modification was detected between neighborhood disadvantage and two items measuring the quality of relationships between participants and syringe staff: “Pharmacists care about my health and well-being” and “The staff at syringe exchange programs seems to care about my health and well-being.” In disadvantaged neighborhoods, participants who reported positive relationships with syringe staff were less likely to engage in receptive syringe sharing. However, in relatively better off neighborhoods, positive relationships with syringe staff were associated with increased receptive syringe sharing. Overall, the results of this dissertation support the validity of the risk environment paradigm in shaping high-risk injection behavior among PWID. Future studies should continue to investigate contextual factors as determinants of behavior surrounding injection drug use. Understanding how aspects of local-area environments influence injection risk behavior will be essential to eliminating the transmission of BBVs among PWID.

This dissertation investigates how the settings of drug use influence the affective and neurobiological response to heroin versus cocaine in addicts. Chapter 1 reviews the neuropharmacology of heroin and cocaine and the theoretical background for drugs-settings interactions, including a detailed discussion of findings from previous studies in animals and humans that show how the same settings can influence in opposite directions the reinforcing effect of heroin and cocaine. Cocaine self-administration, for example, was greatly facilitated when rats were tested outside the home environment relative to rats test at home. The opposite pattern was found for heroin. Translational studies in humans yielded similar results. Indeed, heroin and cocaine co-abusers reported using the two drugs in distinct settings: heroin preferentially at home and cocaine preferentially outside the home. The aim of this dissertation is to determine whether the setting could also influence in opposite manner the affective and neurobiological response to heroin and cocaine in human addicts. Chapter 2 illustrates the findings of a study aimed at testing the hypothesis that the affective state experienced under cocaine or heroin is the result of an interaction between central and peripheral drug effects and the surroundings of drug use. According to this hypothesis, when cocaine is taken at home there is a mismatch between the familiar environment and the peripheral effects such as arousal, increased heart rate, increased respiratory rate, and increased muscular tension (which are usually produced in stressful situations). This mismatch dampens cocaine-rewarding effects. A mismatch would also occurs when heroin (which produces sedation and decreases heart rate, respiratory rate, and muscular tension) is used outside the home in contexts requiring vigilance. We found indeed that co-abusers subjectively experienced opposite changes in arousal, heart rate, respiratory rate, and muscular tension in response to cocaine (increase) versus heroin (decrease). Most important, using a novel two-dimensional visual test, we found that in agreement with the working hypothesis the valence of the affective state produced by heroin and cocaine shifted in opposite directions as a function of the setting of drug use: heroin was reported to be more pleasant at home than outside the home, and vice versa for cocaine. Chapter 3 illustrates the results of in which emotional imagery was combined with fMRI to investigation the neurobiological underpinnings of drug and setting interactions in addicts. Heroin and cocaine co-abusers were asked to recreate real-world settings of drug use during fMRI. In agreement with the working hypothesis, we found that heroin and cocaine imagery produced opposite changes in BOLD in the prefrontal cortex and in the striatum, regions implicated in brain reward in humans. Furthermore the same pattern of dissociation was observed in the cerebellum, suggesting that that a fronto-triatal-cerebellar network is implicated in processing drug-setting interactions. Chapter 4 includes a summary of the results, a general discussion, and suggestions for future research and implication. The major finding is that the environment surrounding drug use can influence in opposite manner the affective and neurobiological response to heroin and cocaine, suggesting that therapeutic approaches to the treatment of drug addiction should take into account the distinctive effects of different classes of drugs as well as the contexts of drug use. The Appendix includes reprints of two papers reporting on additional studies conducted during the course of the Ph.D. program, which are not directly germane to the aims of the dissertation. Other three papers are in the pre-submission stage.

This thesis applies catFISH, a variant of the standard fluorescence in situ hybridisation technique, to study the neuronal ensembles activated by heroin and cocaine across brain structures involved in motivated behaviour, in the Sprague-Dawley rat. The first chapter reviews the pharmacology of heroin and cocaine, rodent models of drug-related behaviours, and heroin and cocaine's ability to trigger immediate-early gene expression when administered acutely or chronically. It is suggested that the empirical evidence points towards a significant separation between the neuronal systems engaged by the two drugs. The main goal of this thesis was to test whether this separation can be seen within brain areas playing a key role in motivation and reward (e.g. the nucleus accumbens). Since immediate-early genes serve as markers of neuronal activity, and catFISH is a technique which can detect the expression of such genes in response to two separate stimuli, the technique was chosen as the best method to test if heroin and cocaine activate the same neuronal ensembles when administered acutely. The second chapter summarises the methods used across experiments described in following chapters. The third chapter presents an experiment addressing the methodological issues associated with using catFISH to study pharmacological stimuli. The technique was originally used to study the hippocampus and brain activity triggered by stimuli with well-controlled on- and offset (e.g. exposure to a novel environment or discrete cues). Arguably, acute drug injections comprise a stimulus with an on- and offset which can only be controlled indirectly – they depend on the drug dose and route of administration, among other factors. It was shown that acute intravenous injections of heroin and cocaine at doses usually self-administered by animals are suitable stimuli to use with catFISH. Chapter four describes an experiment showing that, across the striatum, the neuronal ensembles activated by an injection of cocaine followed by an injection of heroin overlap significantly less than the neuronal ensembles activated by two consecutive injections of cocaine. This is interpreted as direct evidence for a significant separation between the neuronal pathways activated by heroin vs. cocaine, even in brain areas often considered a common neurobiological substrate for the effects of the two drugs. It must be noted that the magnitude and the nature of this separation depends on the particular part of the striatum and the order in which drugs are administered. Chapter five describes a pilot experiment attempting to incorporate the logic of the catFISH technique into a rodent drug self-administration paradigm. It was found that the rats preferred self-administering heroin over cocaine, and that there was no detectable expression of the homer 1a gene across the striatum in response to acute heroin and cocaine after extended experience with the two drugs. There was also no change from baseline expression of the homer 1a and arc genes in areas of the prefrontal cortex. Finally, chapter six summarises the main findings and the key methodological considerations from all three experiments. As a whole, it is suggested that the experiments in this thesis provide a proof of concept that heroin and cocaine are processed differently by the brain, even within brain areas considered to be common substrates for the reinforcing and addictive properties of the two drugs. Future studies should take this separation into account, as it may have important implications for understanding drug addiction as a whole. The appendices contain representative fluorescence microscopy images of brain tissue analysed for catFISH.

No description available.

In this thesis, the link between substance abuse and family dysfunction is examined, and an argument is made for the assessment of family dysfunction when treating clients with substance abuse issues. Family dysfunction has been associated with a broad range of problems in children (e.g., low self esteem, increased risk of child abuse) through to adolescence and adulthood (e.g., increased risk of mental disorders such as depressive disorders, substance abuse disorders, and personality disorders) (Kaplan & Sadock, 1998). It is not the purpose of this thesis to suggest that family dysfunction causes substance abuse but rather to highlight that family dysfunction can in some cases place the individual at greater risk of substance abuse. Therefore, in order to understand the reasons why substance abuse developed and how it is maintained in the present requires the assessment of family dysfunction. Further, the importance of assessing the role and impact that family dysfunction may have had on the client, may help to better understand the nature and extent of substance abuse so that relevant and appropriate treatment goals for change may be set, progress monitored, and risk of relapse reduced. Chapter 1 provides a brief introduction to this thesis, and Chapter 2 is a review of the literature on the impact of family dysfunction including poor parental attachment and supervision, neglect, physical and sexual abuse, in adolescence and adulthood. Four case studies are presented to illustrate how family dysfunction and substance abuse may be related, thus highlighting the importance of assessing family dysfunction when treating substance abuse clients. All of the case studies include an individual with a substance abuse disorder (namely heroin) but they are diverse in terms of the types and extent of family dysfunction. The final chapter discusses the case studies in relation to the literature reviewed. Lastly, it gives consideration to the implication of a history of family dysfunction, and how it may impact negatively on treatment and therefore prognosis.

The purpose of this study was to investigate how schools/school districts plan to implement Oregon Administrative Rule 581-22-413, specifically: (1) How schools plan to integrate alcohol and drug abuse prevention into the Comprehensive Health Program. (2) How schools plan for age appropriate annual instruction at the senior high level. (3) How schools plan for the alcohol and drug abuse prevention education of the district's staff. An examination of the related literature revealed concerns about the proper type of planning schools/school districts would need to do to effectively satisfy this OAR. The literature further indicated School Health Programs were encouraged by the experts in the field, but few schools had achieved the entire concept. Staff education was an area that the literature indicated needed greater definition and implementation. A survey questionnaire was prepared with the help of a Delphi group to investigate the concerns. The questionnaire was sent to 180 randomly chosen administrators. The data were collected and descriptive analyses were performed. It was determined from this study that most of the Oregon schools administrators are concerned about OAR 581-22-413 and are attempting to meet these regulations. However, they are facing time and financial constraints which make it difficult to fit the new requirements into the curriculum. Staff in-service is becoming a reality for administrators and certified staff but other school personnel have been left out. There are indications that alcohol and drug abuse prevention education is being integrated into senior high school classes such as Science, Social Studies and Physical Education, in addition to comprehensive health courses. This approach can work providing the teachers of those subjects are well prepared to teach alcohol and drug prevention effectively. It was recommended that all college graduates seeking a teaching certificate be required to take a course in alcohol and drug abuse prevention in order to qualify. / Graduation date: 1991

Social factors influence drug abuse in adolescents; this is partially attributed to peer pressure in humans. Similarly, using rodent models, some research suggests that social housing condition can influence rodents' drug taking behavior. Despite this, few studies have examined the role that intoxicated peers have on drug-naive cage-mates. This dissertation examined how social environment affects opioid sensitivity and hormone production. This was accomplished by comparing the opioid sensitivity of mice housed in mixed cages (some animals received opioids and some were drug-naive) to cages where all the mice were treated with the same drug (all saline or all morphine). These studies identified an adolescent-specific vulnerability to social environment-induced alteration of morphine sensitivity. Interaction with drug-intoxicated cage-mates enhanced locomotor sensitivity in previously drug-naive males and altered their production of testosterone. Conversely, interaction of morphine experienced mice with drug-naive cage-mates afforded protection from the rewarding properties of morphine. In other words, morphine-treated mice housed with drug-naive cage-mates demonstrated attenuated reward compared to morphine-treated mice housed with other morphine-treated mice. In addition, part of the neurobiological basis of the social-environment effect was identified. Antagonism of V1b receptors decreased morphine reward in morphine-treated mice housed only with other morphine-treated mice. These results suggest a role of vasopressin in the peer influence on drug sensitivity observed in adolescents. This body of work further elucidates the role of peer influence on opioid sensitivity. Future studies should further reveal the role of healthy peer relationships and should aid in combating drug abuse in this at-risk demographic.