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America is engulfed in an opioid epidemic. Whether this is depicted through the tens of thousands of lives claimed by the number of drug overdoses each year, the unprecedentedly high and increasing rates of opiate abuse, or the broadening demographic profile of the addict, it is clear that the current issue is one that requires serious attention. As informed by the negative attitudes toward drug addiction that have prevailed since the War on Drugs was declared, it is hypothesized that much of the contemporary predicament is a result of this misinformation that did not resolve, but exacerbated the drug crisis. Despite the concurrent emergence of evidence asserting that addiction is a disease, instead, the idea that drug addiction is a failure prevails. As with many brain diseases, drug addiction displays both pathological alterations in the transmission of signals within the neural circuitries and the morphological defects associated with non-random regions of the brain. The alteration that is observed during opioid tolerance is the desensitization of mu opioid receptors to dopamine, resulting in the need of increased dosage of opiates to achieve the same high. During opioid dependence, key changes that are seen in the locus ceruleus and the mesolimbic reward system increase both the likelihood of an overdose event and withdrawal when an exogenous opioid is present or absent, respectively. There are two models that describe additional changes that occur during the transition from frequent abuse to addiction: (1) the “Changed Set Point Model” and (2) the “Cognitive Deficits Model.” All three variants of the “Changed Set Point Model” portray a shift in the physiological set points of dopamine and glutamate levels in the reward system and regions that control it. The “Cognitive Deficits Model” theorizes that the modifications localized to the prefrontal cortex are responsible for the ultimate transition. Once the abuser is thrust into the addiction cycle, additional changes in the neural networks are observed. These changes are seen in each of the three phases: (1) Binge and Intoxication, (2) Withdrawal and Negative Affect, and (3) Preoccupation and Anticipation. In the first phase, a process called drug-induced neuroplasticity occurs, resulting in the amplification of signals originating from dopaminergic neurons. Next, during Withdrawal and Negative Affect phase, among other changes, the amygdala is shown to be re-wired in such a way that the addict is more sensitive to stress. And finally in the last phase, the changes that occur, secondary to processes similar to drug-induced, are indicated in the prefrontal cortex. The current FDA-approved medication-assisted therapies include methadone, buprenorphine, and naltrexone. The single outstanding abstinence-based treatment is the 12-step program. In the evaluation of medical and non-medical interventions the relative efficacies were measured using the metrics: (1) rates of abstinence achievement, (2) rates of opioid use, and (3) retention in treatment. Individually, all therapies show moderate success when measured against each metric, which further validates the brain disease model for addiction, and also indicates that the future direction of addressing the opioid epidemic should point at combination therapies. What is most imperative now is for there to be more widespread recognition of the brain disease model for addiction.

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BACKGROUND:Opioids are the cornerstone of treatment for moderate to severe pain, but chronic use leads to maladaptations that include: tolerance, dependence and opioid-induced hyperalgesia (OIH). These responses limit the utility of opioids, as well as our ability to control chronic pain. Despite decades of research, we have no therapies or proven strategies to overcome this problem. However, murine haplotype based computational genetic mapping and a SNP data base generated from analysis of whole-genome sequence data (whole-genome HBCGM), provides a hypothesis-free method for discovering novel genes affecting opioid maladaptive responses.RESULTS:Whole genome-HBCGM was used to analyze phenotypic data on morphine-induced tolerance, dependence and hyperalgesia obtained from 23 inbred strains. The robustness of the genetic mapping results was analyzed using strain subsets. In addition, the results of analyzing all of the opioid-related traits together were examined. To characterize the functional role of the leading candidate gene, we analyzed transgenic animals, mRNA and protein expression in behaviorally divergent mouse strains, and immunohistochemistry in spinal cord tissue. Our mapping procedure identified the allelic pattern within the netrin-1 receptor gene (Dcc) as most robustly associated with OIH, and it was also strongly associated with the combination of the other maladaptive opioid traits analyzed. Adult mice heterozygous for the Dcc gene had significantly less tendency to develop OIH, become tolerant or show evidence of dependence after chronic exposure to morphine. The difference in opiate responses was shown not to be due to basal or morphine-stimulated differences in the level of Dcc expression in spinal cord tissue, and was not associated with nociceptive neurochemical or anatomical alterations in the spinal cord or dorsal root ganglia in adult animals.CONCLUSIONS:Whole-genome HBCGM is a powerful tool for identifying genes affecting biomedical traits such as opioid maladaptations. We demonstrate that Dcc affects tolerance, dependence and OIH after chronic opioid exposure, though not through simple differences in expression in the adult spinal cord.

published_or_final_version / Sociology / Master / Master of Philosophy

The thesis investigates the dynamics that surround participants' responses to questions about illicit drug activities. By examining the attributional and discursive literatures, the opening chapters (Chapters 1 and 2) outline the difficulties associated with assuming veridicality in question-answer dyads. Emphasis is placed on the essentially social and intentional foundations of the applied research procedure. The existing research on methodological effects in substance research is outlined at the start of Chapter 3. These form the foundation for the empirical investigations that constitute the remainder of the thesis. The studies carried out attempt to examine methodological issues in the context of applied research procedures that combine quantitative outcomes with qualitative considerations such as reflexive consideration of the role of the researcher and the status of the participant. The first investigation demonstrates the influence of treatment status on the discourse provided by adult substance users. Drug users in contact with treatment services provide drug-related explanations distinct from those given by users who are not in treatment. This distinction is assessed in terms of a theoretical model of addiction based on discursive criteria and contextual influence (Chapter 4). These contextual influences are further examined in the empirical studies presented in Chapters 4 and 5 in which the subjects are young people whose drug experiences are assessed in the context of drug education (Chapter 5) and treatment and service needs (Chapter 6). Each of these investigations attempts to demonstrate the sophistication of discourse that respondents exhibit in their drug-related conversations and the ways in which their attitudes and understandings of these topics are shaped by the context of the experiences they have had.

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There is considerable recent experimental evidence that suggests that stress plays a major role in the development of dependence on drugs of abuse, but the potential mechanisms involved are not yet fully understood. The aims of this thesis were (I) to examine the effect of stress, and of drugs that act on the hypothalamic-pituitary-adrenal axis, on alcohol consumption in the C57 strain of mice. (II) to investigate whether corticosterone levels or spontaneous locomotor activity could be used to predict subsequent alcohol consumption in mice. (Ill) to investigate long-term neurochemical changes during abstinence following chronic alcohol administration. (IV) to develop a method for measuring brain corticosterone levels. Neither total corticosterone levels nor spontaneous locomotor activity could predict alcohol preference. Saline vehicle injections increased alcohol preference in low alcohol preferring, and raised both circulating corticosterone levels and brain corticosterone. The brain concentrations of corticosterone were measured by a novel procedure developed during the thesis. A CRF antagonist (a-helical CRF) increased alcohol preference in low preferring mice, as did the ACTH fragment 4-10. In high preferring mice, ACTH 4-10 reduced alcohol preference, whereas a-helical CRF did not alter preference in these mice. Inhibition of corticosterone synthesis reduced alcohol preference in high alcohol preferring mice but, blockade of corticosterone receptors with specific antagonists did not alter alcohol preference. Chronic alcohol treatment followed by six days abstinence increased free circulating corticosterone levels and this treatment also increased hippocampal corticosterone levels. Dopamine Dl-like receptor affinity was increased following the same chronic treatment schedule. These results demonstrate an important link between the activation of the hypothalamic-pituitary-adrenal axis and alcohol consumption. The results of the chronic treatment experiments provide useful information that may aid the understanding of the phenomenon of relapse to drinking common in abstaining alcoholics.

Book Summary: This inspiring resource presents theories, findings, and interventions from Positive Suicidology, an emerging strengths-based approach to suicide prevention. Its synthesis of positive psychology and suicidology theories offers a science-based framework for promoting wellbeing to complement or, if appropriate, replace traditional deficit-driven theories and therapies used in reducing suicidal thoughts and behaviors. Coverage reviews interpersonal, intrapersonal, and societal risk factors for suicide, and identifies protective factors, such as hope and resilience, that can be enhanced in therapy. From there, chapters detail a palette of approaches and applications of Positive Suicidology, from the powerful motivating forces described in Self-Determination Theory to meaning-building physical and social activities. Among the topics covered: Future-oriented constructs and their role in suicidal ideation and enactment. Gratitude as a protective factor for suicidal ideation and behavior: theory and evidence. Considering race and ethnicity in the use of positive psychological approaches to suicide. The Six R’s framework as mindfulness for suicide prevention. Community-based participatory research and empowerment for suicide prevention. Applied resiliency and suicide prevention: a strengths-based, risk-reduction framework. Psychotherapists, counselors, social workers, psychiatrists, and health psychologists, as well as educators, clergy and healthcare professionals, will find A Positive Psychological Approach to Suicide an invaluable source of contemporary evidence-based strategies for their prevention and intervention efforts with suicidal clients.

Thesis advisor: Paul Gray / "Compassion-focused therapy" (CFT) aims to increase the self-compassion of participants while reducing self-stigma. Although CFT is theorized to be effective for alcohol dependents, who suffer from high levels of self-criticism and self-hate, few clinical studies examine which factors facilitate the development of self-compassion and subsequently reduce harmful drinking. This qualitative study therefore values the subjective perspectives of female alcohol dependents as they participate in CFT in Northern Ireland. In doing so, it explores how self-compassion may be increased through modifications in self-labeling and self-concept. It is proposed that the development of a compassionate mindset, along with spirituality and mindfulness, grant alcohol dependents cautious optimism for the future. / Thesis (BA) — Boston College, 2015. / Submitted to: Boston College. College of Arts and Sciences. / Discipline: Departmental Honors. / Discipline: Sociology.