Posttraumatic stress disorder (PTSD) co-occurs with substance use disorders at high rates, but the neurobiological basis of this relationship remains largely unknown. Identifying mechanisms that underlie this association is necessary, and recognizing pathologies shared by these disorders may provide pertinent information in understanding their functional relationship. Separate lines of evidence suggest that PTSD and drug addiction may share a common feature, that is, dysregulation of the brain's reward circuitry. We hypothesize that PTSD results in reduced dopaminergic neurotransmission which may contribute to deficient reward function and vulnerability to drug-seeking behavior. To address this hypothesis, we combined single-prolonged stress (SPS), a rodent model of PTSD, with a series of behavioral and neuropharmacological assays to assess dopaminergic reward function and cocaine intake. The results of the studies presented herein extend our understanding of the effects of severe stress on drug reinforcement and consumption, and establish a potential mechanism by which PTSD produces deficient reward function through alterations in the dopamine system. A modified SPS procedure consisting of 2 hours of restraint, 20 minutes of group swimming, isoflurane exposure until loss consciousness, and 7 days of isolation was used to induce severe stress in our studies. Initial studies were conducted to examine the effect of SPS on cocaine-conditioned reward and anhedonia-like behavior in adult male Sprague-Dawley rats. Using a biased conditioned place preference paradigm, unstressed controls demonstrated a significant preference for the cocaine-paired context following four pairings with cocaine (5-20 mg/kg, i.p.). Preference for the cocaine-paired side was significantly lower in rats exposed to SPS, suggesting a deficit in the rewarding properties of cocaine following exposure to severe stress. Anhedonia-like behavior was assessed by a two-bottle choice sucrose preference test. Robust consumption of sucrose solution (0.25-1%) was observed in rats that underwent control handling, however, SPS significantly reduced sucrose intake compared to controls. These results suggest an increase in anhedonia-like behavior or a reduction in the rewarding effects of sucrose as a non-drug reinforcer. Finally, basal behavioral activity in SPS rats was compared to unstressed controls in a 24-hour test. Results indicate a significant reduction in spontaneous nocturnal activity following SPS versus control handling. In contrast, hyperlocomotion induced by an acute cocaine injection (5-20 mg/kg, i.p.) was unaltered between rats that underwent SPS or control handling. These data suggest that deficient behavioral activity may be specific to voluntary movements or behavior, and support an increase in anhedonia following exposure to SPS. Intravenous cocaine self-administration was conducted to examine the effect of SPS on the acquisition, motivation, and escalation of cocaine intake. Acquisition of cocaine self-administration was studied using an escalating dose regimen in which rats had sequential access to 0.1875, 0.375, and 0.75 mg/kg/infusion on a fixed-ratio 1 schedule of reinforcement. Rats exposed to SPS did not significantly differ from control handled animals in the latency to meet acquisition criteria (consumption of 6.75 mg/kg/day for 3 consecutive days) or the general pattern and level of cocaine intake at each dose. A subsequent study assessing the breakpoint for cocaine self-administration using a progressive-ratio schedule of reinforcement determined a dose-dependent increase in motivation to work for cocaine (0-1.5 mg/kg/infusion) across both experimental groups. However, motivation to obtain cocaine was similar between SPS and unstressed rats, as there was no significant difference in breakpoint for cocaine self-administration at any dose of cocaine tested. To evaluate potential differences in the transition to escalated cocaine intake, self-administration was measured using an extended-access procedure in which unlimited cocaine (0.375 mg/kg/infusion) was available for six hours daily. Upon extended-access to cocaine, SPS significantly attenuated cocaine intake compared to control handling over 14 sessions. Despite a significant reduction in cocaine intake, rats exposed to SPS still significantly escalated their cocaine intake over the course of 14 days. These results suggest that escalation of cocaine intake occurred in the presence of lower total doses of cocaine in the SPS exposed animals compared to controls. In addition, SPS rats demonstrated a greater percent increase in cocaine consumption compared to controls. This finding suggests that rats exposed to SPS compensated for a decrease in cocaine reinforcement by escalating their intake to a greater magnitude than controls. These studies indicate that SPS may not alter the acquisition of cocaine self-administration or motivation for cocaine. However, the finding of reduced cocaine intake upon extended-access in SPS rats is consistent with a deficit in cocaine-induced reward. The ability of SPS rats to escalate cocaine intake in the presence of less cocaine, or a greater magnitude of escalated cocaine intake than controls, may reflect mechanisms leading to enhanced vulnerability to cocaine abuse. To understand the mechanisms of reduced reward and behavior in the SPS model of PTSD, a series of neurochemical assays was used to assess the ability of SPS to induce dysfunction of dopaminergic neurotransmission. Using high performance liquid chromatography, tissue levels of dopamine and the dopamine metabolites DOPAC and HVA were measured immediately and one week following SPS or control handling. Tissue obtained from SPS rats demonstrated significant decreases in dopamine, DOPAC, and HVA content in both the nucleus accumbens and caudate putamen immediately following SPS and one week later, suggesting a potential deficit in dopaminergic tone. Quantitative autoradiography was used measure the density of dopamine transporters and dopamine D1 and D2 receptors. [3H]WIN35428 binding to dopamine transporters was higher in the nucleus accumbens of SPS rats compared to controls, suggesting an increase in dopamine transporter density following severe stress. The level of [3H]WIN35428 binding in the caudate putamen was not different between groups. [3H]Raclopride binding to D2 receptors was significantly reduced in both the nucleus accumbens and caudate putamen following SPS versus control handling. These results suggest a decrease in the density of striatal D2 receptors. D1 receptor expression was not significantly altered by SPS, as no significant difference in [3H]SCH23390 binding was detected in SPS rats compared to controls. A preliminary functional assessment of dopamine transporters revealed a significant increase in dopamine uptake in the nucleus accumbens of SPS rats compared to controls, whereas uptake in the caudate putamen was unaltered between groups. Enhanced dopamine uptake following SPS is consistent with the increase in dopamine transporter density observed in the nucleus accumbens of SPS rats. Activation of D1 receptors and G-protein mediated transduction was assessed using an adenylyl cyclase assay with the D1 agonist SKF82958. In the caudate putamen, a significant decrease in D1 receptor-stimulated cAMP production was revealed in SPS rats compared to controls, whereas SKF82958-induced cAMP was unchanged in the nucleus accumbens. Finally, the function of D2 dopamine receptors was assessed by D2 receptor-stimulated [35S]GTPγS binding using quinpirole. In the caudate putamen, [35S]GTPγS binding following stimulation of D2 receptors was enhanced by SPS compared to control handling, whereas no difference was observed between groups in the nucleus accumbens. These results indicate increased D2 receptor-mediated activation of G-proteins in the caudate putamen following SPS. In summary, the studies described herein tested the hypothesis that reduced dopaminergic function may be a mechanism for deficient reward and heightened susceptibility to drug use in PTSD. Results demonstrated a significant reduction in cocaine-conditioned reward, as well as attenuated sucrose preference and spontaneous activity in rats exposed to SPS. These findings are consistent with the presence of a dysfunctional reward system which may contribute to anhedonia-like behavior in PTSD. Furthermore, reward deficits may promote altered patterns of cocaine taking behavior and vulnerability to substance abuse. Results demonstrated significant escalation of drug intake following exposure to SPS, which occurred in the presence of less cocaine than controls. A greater increase in cocaine intake was observed in SPS rats over the course of escalation, which may reflect a mechanism for enhanced vulnerability to the development of a substance use disorder in PTSD. Dopaminergic dysfunction may contribute to deficient reward capacity and an altered pattern of cocaine intake in SPS. SPS-induced alterations in dopamine function included a reduction in striatal dopamine content alongside enhanced dopamine transporter levels and function. Mild alterations in D2 receptor density and the function of D1 and D2 receptors were also observed. These findings support the hypothesis that PTSD results in reduced dopaminergic neurotransmission, which may contribute to deficient reward function and altered drug-seeking behavior. Identifying the pathology of PTSD, such as altered dopamine neurotransmission, may lead to enhanced treatment strategies and interventions to prevent substance abuse in persons with PTSD. / Pharmacology

Thesis advisor: Stephen J. Pope / This dissertation attends to the crisis of addiction in the United States. The increasing number in annual overdoses and the inadequacy of national responses to curtail these preventable deaths demands an immediate moral response. In the last year, deaths caused by overdose increased by nearly 29 percent, and 20.8 million people in the United States are currently living with substance use disorders. The number of families affected by addiction presents a striking testimony to the scope of the problem. Nevertheless, there is still enormous disagreement over the nature of addiction and therefore how to best treat it. This dissertation will therefore offer a theological approach to addiction in order to advocate for a social response to this crisis.This dissertation proceeds in five chapters. In the first chapter, I evaluate the medical and moral models of addiction. This first chapter engages research in neurobiology and psychology and argues that these models are premised upon a false dichotomy between determinism and freedom of the will. The second chapter explores disagreements in bioethics over the meanings of health, disease, and illness. These different definitions contribute to the chasm between the medical and moral models of addiction. This chapter proposes a holistic account of health for understanding addiction and healing. The third chapter grounds this holistic account of health in Karl Rahner’s transcendental anthropology in order to uphold the fundamental relationality of human persons and to move past the false dichotomy presented in chapter one between determinism and freedom of the will. This chapter then offers a theological examination of sin as a power or force that preconditions freedom. It concludes by proposing a theological and relational account of autonomy. The fourth chapter engages philosophy of the mind in order to argue for a nonreductive approach to mentality that appreciates the ways in which human persons are co-constituted by bottom up and top down causality. A nonreductive approach to mentality offers a way to understand addiction as an interacting set of processes and patterns. This fourth chapter concludes by considering the possibility for responsibility by examining narrativity, vulnerability, and imagination. It argues that there is a moral responsibility to imagine a better world for people living with addictions, and to bring that world about. Finally, the fifth chapter draws upon the theological virtue of solidarity and the principle of the preferential option for the poor in order to articulate a preferential option for people living with addictions. I argue here that Church institutions can stand in solidarity with people who suffer from addiction by acting as providers, educators, and lobbyers. / Thesis (PhD) — Boston College, 2022. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Theology.

The mesolimbic dopamine (DA) system originates in the ventral tegmental area (VTA) and projects to the nucleus accumbens (NAc) and other areas including the basolateral amygdala (BLA), prefrontal cortex, and the hippocampus. Drug use induces reward and leads to dysregulation in these brain areas and eventually to substance use disorders (SUDs). Chapter 1 introduces the mesolimbic DA system and its relationship to drug use and their relevance to each chapter. Chapter 2 explores opioid effects on BLA circuitry which is known to play a role in the emotional response including anxiety and stress in SUDs. We showed that morphine induced an inhibitory effect on GABAergic lateral paracapsular cells (LPCs). These cells inhibit BLA principal neuron output and are influenced by opioids. Opioid activation in LPCs leads to upregulated BLA output, and activation in the NAc and central amygdala which may have important implications for stress/anxiety response for patients with SUDs. Chapter 3 explores the effect of interleukin-10 on the mesolimbic DA system. Specifically, cell-attached recordings of VTA DA neurons increase their firing rate in the presence of IL-10, and in vivo studies showed increased DA release in the NAc. Interleukin-10 receptors were expressed in VTA DA neurons and signals through the phosphoinositide 3-kinase. Surprisingly, IL-10 induced conditioned place aversion in mice which may be related to depression- and anxiety-like behaviors reported by others. Thus, IL-10 appears to be regulating the mesolimbic DA system and its association with reward which may be important in understanding the relationship between inflammation and SUDs. Chapter 4 explores the DA transporter (DAT) kinetics in the presence of psychostimulants using DA iontophoresis. We showed that iontophoretic DA delivery increased DA concentration and clearance rates compared to evoked release making it an important tool in measuring DAT kinetics. Cocaine was bath applied and slowed DAT reuptake at high concentrations and D2 stimulant quinpirole slowed the reuptake process but did not show any effect on DAT trafficking, and D2 antagonist eticlopride showed no change in reuptake or DAT trafficking. Cocaine-injected mice increased locomotion and reduced anxiety-like behavior, and iontophoresis experiments slowed reuptake with bath-applied cocaine. Thus, DA iontophoresis is useful in studying DAT blocker kinetics but has limitations in studying the effects of DAT trafficking. Chapter 5 discusses the impact these studies have on society, the limitations of each chapter, and future directions for this dissertation. Together these studies explore the reward system and its relationship with SUDs. The overarching aim has been to understand the involvement of DA in motivation and reward in the context of SUDs and the influence of opioids, cytokines, and psychostimulants.

Bakgrund: Ett bra bemötande karaktäriseras av ett respektfullt, kompetent och empatiskt samspel som är individanpassat. Patienter med substansbrukssyndrom är en grupp som uppfattas som vårdkrävande och är föremål för stigmatisering, därmed kan bemötandet ses som en utmaning. Patientcentrerad vård innebär att sträva efter individens välmående. Med hjälp av ett motiverande förhållningssätt kan sjuksköterskan öka patienternas empowerment. Syfte: Att undersöka hur patienter med substansbrukssyndrom upplever bemötandet från vårdpersonal, med fokus på sjuksköterskor. Metod: Litteraturöversikt där både kvalitativa och kvantitativa artiklar ingick. Resultat: Tre kategorier angående bemötande identifierades: att se hela individen, vårdande möte och stigma. Under varje kategori urskildes både positiva och negativa upplevelser av bemötande. Diskussion: Ett patientcentrerat förhållningssätt kan förstås som ett empatiskt, omtänksamt, engagerat och hjälpsamt bemötande. Många patienter hade upplevelser av diskriminering och stigmatisering inom vården, detta kunde delvis förklaras som en maktobalans i relationen mellan vårdgivare och patient.  Slutsats: Sjuksköterskans bemötande kan både öka och minska vårdlidande. Ett gott bemötande är betydelsefullt för att främja hälsa och optimera resultatet av vården. Omvårdnaden av personer med substansbrukssyndrom kan förbättras. / Introduction: The responsibility of the nurse is to have competence and to treat every patient with respect and empathy. Patients with substance use disorders are a group that can be viewed as a group with a large demand of care. They are exposed to stigmatization and therefor they need specialized care. The meaning of patient centered care is to strive to optimize every individual’s well-being. Nurses may increase patient’s empowerment through a motivating approach. Aim: To explore patients’ perceptions of the nurse-patient relation of patients with substance use disorder. Method: A literature review, including both qualitative and quantitative studies. Result: Three categories were identified: To see the whole person, caring encounter and stigma. Both positive and negative aspects of every category were discovered. Discussion: A patient centered approach can be understood as an emphatic, caring, committed and helpful encounter. Many patients had experiences of discrimination and stigma during care. This could partly be understood as an unbalanced power-control relationship between caregiver and patient. Conclusion: The nurses actions can increase as well as decrease patients suffering. A caring encounter is important to promote health and to optimize the results of care. There is room for development of nursing skills in care of patients with substance use disorders.

Bakgrund: Patienter med substansbrukssyndrom har ofta komplexa problem och sjuksköterskan behöver ha   kunskap och medkänsla för att vårdrelationen skall fungera. Sjuksköterskan behöver hantera både sina egna och patientens känslor för att vårdrelationen skall fungera. Sjuksköterskan behöver vara ett stöd för patienten när hen skall hitta en hälsosam livsstil utan substansbruk. En fungerande vårdrelation mellan sjuksköterska och patient med substansbrukssyndrom är betydelsefull för att omvårdnaden skall fungera. Syfte: Syftet var att beskriva vårdrelationen mellan sjuksköterska och patient med substansbrukssyndrom ur ett sjuksköterskeperspektiv.   Metod: En litteraturstudie valdes som metod. Artiklarna söktes databaserna PubMed och Cinahl. Totalt inkluderades 18 vetenskapliga originalartiklar i resultatet. Resultat: Resultatet visade att synsätt och perspektiv samt negativa erfarenheter påverkar relationen mellan sjuksköterska och patient med substansbrukssyndrom. Sjuksköterskan upplever svårigheter med kunskapsbrist och patienters manipulativa beteende. Slutsats: Vårdrelationen mellan sjuksköterskan och patienten med substansbrukssyndrom kan utvecklas genom stöd och utbildning till sjuksköterskor i deras yrkesroll. / Background: Patients with substance use disorder often have complex problems and the nurse needs knowledge and compassion to make the care relationship work. The nurse needs to handle both her own and the patient's feelings in order for the care relationship to work. The nurse needs to support the patient as he or she finds a healthy lifestyle without substance use. A functioning care relationship between nurse and patient with substance use disorder is important for the care to work successfully. Aim: The aim of the study was to describe the care relationship between nurse and patient with substance use disorder from a nursing perspective. Method: A literature review was chosen as method. The article search was conducted in   the databases PubMed and Cinahl. In total, 18 original scientific articles were included in the results. Results: The results showed that attitude and perspective as well as negative experience   affect the relationship between nurse and patient with substance use disorder. The nurse experiences difficulties related to lack of knowledge and patients' manipulative behavior. Conclusions: The care relationship between the nurse and patient with substance use disorder can be improved by providing support and education for nurses in their professional role.

There are approximately 1.3 million youth who have been diagnosed with a co-occurring disorder. The purpose of this study was to analyze the relationship between the type of therapy (brief strategic family therapy or family functional therapy), demographic factors (age, race, type of drug used), and therapy discharge status (successful or unsuccessful) in male youth with a co-occurring disorder of attention-deficit hyperactivity disorder and substance use disorder. A correlational research design of a cross-sectional nature was used for this study and secondary data were obtained from a mental health agency located in Hampton Roads Virginia. The theoretical basis for this study was Bowens family systems theory. A purposeful convenience sample was used from archival data (n=392). Independent sample t-Tests were conducted to analyze differences between demographic groups and discharge status, and it was found that males whose drug of choice was alcohol had a statistically significant lower successful discharge rate (p=.031). Type of therapy unrelated to discharge status at a statistically significant level (p=.418). Results of a multiple logistic regression analysis showed that non-White/Caucasian males were 1.86 times more likely to have a successful discharge status from the program (p=.048). Age, drug type, and therapy used were unrelated to discharge status at statistically significant levels (p>.05). This study can educate therapists about their preconceived notions regarding ethnicity and the potential to successfully complete therapy. This could result in more empowerment shared with clients of these ethnic groups which could positively impact completion of therapy.

The marriage of perspectives from behavioral economic theory and learning theory has the potential to advance an understanding of substance use and substance use disorder. Behavioral economic demand is a central concept to this interdisciplinary approach. Evaluating demand in the laboratory and clinic can improve previous research on the relative reinforcing effects of drugs by accounting for the multi-dimensional nature of reinforcement rather than viewing reinforcement as a unitary construct. Recent advances in the commodity purchase task methodology have further simplified the measurement of demand values in human participants. This dissertation project presents a programmatic series of studies designed to demonstrate the utility of using a behavioral economic demand framework and the purchase task methodology for understanding substance use disorder through basic and applied science research. Experiments are presented spanning a continuum from theoretical and methodological development to longitudinal work and clinical application. These experiments demonstrate three key conclusions regarding behavioral economic demand. First, behavioral economic demand provides a reliable and valid measure of drug valuation that is applicable to varied drug types and participant populations. Second, behavioral economic demand is a stimulus-selective measure specifically reflecting valuation for the commodity under study. Third, behavioral economic demand provides incremental information about substance use in the laboratory and clinical setting above and beyond traditional measures of reinforcer valuation and other behavioral economic variables. These findings collectively highlight the benefits of behavioral economic demand and provide an important platform for future work in addiction science.

Early stages of the co-occurring, mental health and substance use disorder (MH-SUD) recovery process present various social and physical challenges to the recovering person, including habitual cigarette smoking. Presenting smoking cessation to a person with a co-occurring disorder could also depend on behavioral health professional’s perceptions of implementing supplemental services in early recovery. Behavioral health professionals also face the challenge of assessing people’s motivation to quit smoking. Data was collected through an online survey that shaped this quantitative, cross-sectional study focused on understanding perceptions of smoking cessation in early MH-SUD recovery. The study’s data highlighted that the participants (N = 61) perceive smoking cessation as an appropriate intervention while also reporting high levels of self-confidence when assessing motivation to quit to smoking. Identifying as a smoker and former smoker, highest level of education and gender did not have a significant impact on perceptions of smoking cessation in early MH-SUD recovery. The study created an overview on how behavioral health professionals understand and support smoking cessation that contributes additional knowledge to social work’s existing research on habitual cigarette smoking and co-occurring disorders.

Substance use and substance use disorders continue to impact the health and safety of people across the United States. A population in which substance use and substance use disorders tend to be the highest being with college-age populations. In response to this growing public health concern, Recovery Support Services (RSS) are being implemented across colleges and universities nationwide. With each college or university being diverse based on its location, size, and demographics RSS resources do not look the same as they spread from campus to campus. This research project analyzed the current resources, how they are implemented, and how they correspond to the student population at a midsized public university located in Southern California. Utilizing a focus group and several structured interviews a survey design was assembled. The participants interviewed were asked a series of questions based on possible personal and departmental service viewpoints of pre-existing services as well as the quality of said services. Additionally, participants were asked about services not offered, as well as any issues that are not currently being addressed, and were asked to give feedback about each topic. Qualitative data were transcribed, analyzed, and coded using Microsoft Word as the coding software. Surveys were created and distributed via email, IBM SPSS was used for the statistical analysis, and results were compiled and recorded, with the study being reported to the campus Health Center for possible future program creation.

Anxiety, depression, and substance use disorders are some of the frequently occurring mental illnesses among Canadian children and adolescents that can result in debilitating short and long terms outcomes. The rise in readmission rates for recipients of mental illness in Saskatchewan, coupled with the high incidences of suicide-related deaths, necessitates a patient outcome evaluation for predictors of readmission to youth counseling services among adolescents. The purpose of this secondary data analysis study was to explore the associations between anxiety, depression, substance use disorder, individual counseling, family counseling, group counseling, and the outcome of readmission within 1 year following discharge from youth counseling programs. Age, gender, and socioeconomic status were tested for interactions between the independent and dependent variables. The social ecological model of health behavior was used in understanding the study findings. Data from the Saskatoon Health Region Addiction and Mental Health Information System database were used for chi-square and multiple binary logistic regression analyses. Findings showed a statistically significant association between anxiety and readmission (p = 0.046, odds ratio =. 707). The association for anxiety was modified by age (p = 0.038). Depression showed a strong association with readmission (p = 0.001, odds ratio = 1.722) even after examining for effect modification. Additional prospective cohort studies over a long period of time are needed for at risk youth. The potential positive social change impact of this study is better outcome and overall quality of life of program participants; both of which can be achieved through investments in resources to reduce readmission to youth community counseling program.