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.

Organisms must continuously navigate complex environments, balancing the drive to seek rewards with the need to avoid potential threats. This tradeoff between approach and avoidance behaviors, known as approach-avoidance conflict, is a critical determinant of survival. The medial prefrontal cortex (mPFC) plays a key role in regulating these behaviors, with the ventromedial (vmPFC) and dorsomedial components thought to suppress and promote, respectively, behavioral responses to threats. Within the vmPFC, neural populations expressing the opioid peptide dynorphin (Dyn) and its receptor, the kappa opioid receptor (KOR), have been implicated in stress responses. However, the specific role of the vmPFC Dyn system in encoding threat-related information and shaping behavioral responses remains largely unexplored. To address this, we employed a multi-faceted approach, utilizing fiber photometry, calcium imaging, shRNA-mediated knockdown, and DREADD-mediated inhibition to investigate the vmPFC Dyn system in various threat-related paradigms. These included the platform-mediated avoidance (PMA) task, which assesses approach-avoidance conflict; the repeated looming disk test, a pain-free model of innate fear suppression; and standard fear conditioning, a well-established paradigm for studying learned fear responses. Our findings reveal that while the vmPFC Dyn system is not differentially regulated under non-threatening baseline conditions, it is actively recruited upon threat exposure. Fiber photometry recordings during the PMA task showed that vmPFC Dyn neurons bidirectionally signal features related to approach and avoidance behaviors in the presence of threat. Furthermore, shRNA-mediated downregulation of Dyn in the vmPFC led to enhanced avoidance in the repeated looming disk test, indicating that Dyn is necessary for suppressing avoidance in this context. Calcium imaging of the pan-neuronal vmPFC population in conjunction with Dyn knockdown revealed that loss of Dyn impairs cortical activity, as evidenced by reduced synchrony and decreased performance of a logistic regression decoder. These findings suggest that Dyn plays a critical role in shaping the activity of vmPFC neurons during threat processing. Taken together, our results highlight a specific role for the vmPFC Dyn system in toggling threat-driven behavioral responses, particularly in the context of approach-avoidance conflict. By demonstrating how Dyn shapes both behavior and neural activity in the vmPFC during threat exposure, this study provides novel insights into an understudied area of opioidergic circuitry. Moreover, our findings contribute to a deeper understanding of how distinct cell types within the vmPFC encode threat-related features to promote or suppress avoidance behaviors, shedding light on the neural mechanisms underlying adaptive responses to environmental challenges.

The opioid receptors and their endogenous ligands have long been implicated in a variety of traits including addiction, impulsive behaviors and substance dependence. Using phenotypic measurements collected from the IASPSAD, data from a latent class analysis and data from a SNP array and additional genotyping assays, association and regression tests were performed to determine the effects of common SNPs encoded in the genes of the opioid receptors and ligands on various traits relating to alcohol dependence. Although only one SNP can be reported as significant for substance dependence within alcoholics, there were a few results approaching significance that may offer some insight into variation within alcoholism.

This research developed validated QSPKR and PK-AS models for predicting human systemic PK properties of three, preselected, pharmacological classes of drugs, namely opioids, β-adrenergic receptor ligands (β-ARL) and β-lactam antibiotics (β-LAs) using pertinent human and animal systemic PK properties (fu,, CLtot, Vdss, fe) and their biologically relevant unbound counterparts from the published literature, followed by an assessment of the effect of different molecular descriptors on these PK properties and on the PK-AS slopes for CLtot and Vdss from two species (rat and dog). Lipophilicity (log (D)7.4) and molecular weight (MW) were found to be the most statistically significant and biologically plausible, molecular properties affecting the biologically relevant, systemic PK properties: For compounds with log (D)7.4 > -2.0 and MW < 350 D (e.g., most opioids and β-ARL), increased log (D)7.4 resulted in decreased fu and increased Vdssu, CLtotu and CLnonrenu, indicating the prevalence of hydrophobic interactions with biological membrane/proteins. As result, the final QSPKR models using log (D)7.4 provided acceptable predictions for fu, Vdssu, CLtotu and CLnonrenu. CLnonrenu and CLtotu. For both the datasets, inclusion of drugs undergoing extrahepatic clearance worsened the QSPKR predictions. For compounds with log (D)7.4 < -2.0 and MW > 350 D (e.g., β-LA), increased MW (leading to more hydrogen bond donors/acceptors) resulted in a decrease in fu, likely indicating hydrogen bonding interactions with plasma proteins. In general, it was more difficult to predict PK parameters for β-LAs, as their Vdssu approached plasma volume and CLrenu and CLnonrenu were low - as a result of their high hydrophilicity and large MW, requiring specific drug transporters for distribution and excretion. The PK-AS analysis showed that animal body size accounted for most of the observed variability (r2> 0.80) in systemic PK variables, with single species methods, particularly those using dog, gave the best predictions. The fu correction of PK variables improved goodness of fit and predictability of human PK. There were no apparent effects of molecular properties on the predictions. CLren, CLrenu, CLnonren, and CLnonrenu were the most difficult variables to predict, possibly due to the associated interspecies differences in the metabolism, renal and hepatobiliary drug transporters.

of the thesis Introduction: This dissertation focuses on socioeconomic status and problems with law of problematic opioid and methamphetamine users. Long-term intensive use of drugs leads not only to health impacts, but also social such as the inability of financial autonomy, indebtedness, unemployment, failure to comply with the respective social roles, fiduciary social functioning, poor housing etc. Great number of users are influenced by the drug in situations such as interpersonal relationship, family functioning and partnerships, there is a change of social status, social isolation or exclusion. Effective interventions and service development should always start with a good knowledge of the situation and needs of the user, who claims the service. Claim: The goal of this thesis is finding socioeconomic status and criminal situation of problematic methamphetamine and opioids users consequently draw recommendations towards services that work with these clients. Methods: Cross-sectional questionnaire study was carried among clients who have started a treatment episode or contacted selected facility type such as a contact centre, psychiatric AT ambulance, therapeutic community, medium-term inpatient treatment or replacement therapy. Recruitment into the study took place from June 2015 until October...

Charles University in Prague First Faculty of Medicine Study programme: Specialization in Health Care Branch of Study: Addictology PharmDr. Bc. Zbyněk Oktábec, Ph.D. et Ph.D. Design of Pilot Clinical Trial of Treatment of Hepatitis C in Polyvalent Problem Drug Users with Pharmacological Substitution of Opioids and Methamphetamine (HCV-PPDUSOM) Master's Thesis Advisor: Mgr. Roman Gabrhelík, Ph.D. Prague, 2016 Abstract Hepatitis C is one of the most serious blood-borne complications of somatic health status of drug users. The HCV-positive injecting drug users are therefore directly indicated for the treatment of this type (and other types also) of hepatitis. Problematic adherence and treatment compliance is obvious in this group. Both foreign and domestic experiences show that stabilization of the use of illegal (and/or illegally acquired) substances is the essential part of the treatment of hepatitis. The interaction of the high quality treatment of somatic, psychosocial and add-on pharmacological care, including the substitution of illegal (and/or illegally acquired) drugs, leads to patient's increased compliance and adherence to HCV treatment. This diploma thesis is presenting both the theoretical frame and the study design of the pilot clinical trial of HCV treatment with the supportive substitution...

<p>Opioid addiction has become a global epidemic and a national health crisis in recent years. In 2016, approximately 64,000 Americans under 50 years old were killed because of opioid overdoses. The aim of developing an abuse deterrent opioid is to render any form of manipulation that encourages abuse challenging and therefore, non-profitable. With this goal, the Food and Drug Administration (FDA) is extensively supporting research into the development of abuse deterrent technologies and prioritizing their production as a public health necessity. Abuse deterrent approaches include but are not limited to the following: (1) using a physical barrier (e.g., Polyethylene oxide PEO) that basically limit the release of the drugs in the blood or the digestive tract and prevent mechanical alteration of the drugs by crushing, grating, grinding, chewing etc, (2) using chemical barriers that employ gelling agents that prevent the aqueous or organic extraction of the drugs, and (3) combining the drug with an antagonist that blocks the post-abuse euphoria.</p> <p>PEO is a popular polymer used as a matrix in these complex opioid products. The polymer is responsible for the abuse deterrent properties as well as extended release behavior of opioid drugs. PEO hinders the extraction of Opioid drugs from Abuse Deterrent Formulations (ADF), makes it challenging to be injected, and resists mechanical stress and pulverization when crushed. PEO can be subjected to thermal processing such as thermal curing, compression molding, melt extrusion, and injection molding owing to its thermoplasticity.</p> <p>Assessment of the impact of using various manufacturing processes to develop ADFs and the effect of using various grades of this polymer is essential to improve upon the next generation of ADFs. There are three main categories of premarket studies: Category 1 – laboratory based (in-vitro manipulations and drug extractions), category 2 – pharmacokinetic and category 3 –clinical. These studies are required by the FDA to demonstrate that a given formulation exhibit abuse deterrent properties before a drug product is released to the market. In vitro laboratory based manipulation and extraction studies which are used to assess AD properties of these products are challenging, but essential for product development and generic abuse deterrent product approvals. It is important to realize that there is a great correlation between the laboratory based in vitro manipulation and extraction studies and the expectations of potential abuse and misuse of opioid drugs. The ability of these studies to mimic the manipulation techniques applied by abusers to defeat the abuse deterrent properties of a given formulation optimizes predictions on post-market abuse and misuse potential of ADFs. These studies should also correlate well with <i>in-vivo</i> studies since there is a direct correlation with the concentration (mg/mL in water) and the “high” obtained by an abuser. </p> <p>This research aimed to conduct laboratory based in vitro manipulation and extraction studies to investigate failure modes of PEO-based prescription opioids and Promethazine Hydrochloride PMZ HCl tablets. It highlighted the formulation components and the manufacturing parameters that might affect the dose dumping of Active Pharmaceutical Ingredients (APIs). Furthermore, this research identified model compounds that can be used as surrogates for Oxycodone and the best experimental setup that can be used to conduct smoking simulation experiments. Moreover, it provided an overview of the societal impacts of the opioid crisis in the state of Indiana.</p> <p>Investigations of the failure modes of the PEO-based prescription opioids and PMZ HCL tablets showed that physical manipulation techniques via chopping or grinding are much more effective in the destruction of the PEO matrix than thermal manipulation via the application of heat thus promoting the fast release. The factor with the most significant effect on the failure modes of PMZ HCL tablets was the application of physical manipulation, while the one with the lowest impact was the polymer grade. Moreover, producing PEO-based matrix tablets via Direct Compression DC significantly affected dose dumping behavior of the API from the drug products. The production of the PEO-based matrix tablets via DC was found to be favored over the usage of the melt extrusion method and molding techniques. It was clear that DC kept the integrity of the polymer, allowed for slow and controlled release fashion of the API, and rendered the extraction process relatively hard compared to the Hot Melt Extrusion HME and Molding techniques.</p> <p>Furthermore, the release profile of the investigated PMZ HCL products consisted of various phases of polymer swelling and API release. Thermal manipulations via the application of heat were found to accelerate the dose dumping behavior (90% release) of the APIs from the compressed, extruded, and molded PEO-based matrix formulations similarly. On the other hand, heating was much more effective in the extraction of APIs than chopping or grinding thus promoting the ability to<b> </b>draw a solution containing the API into a syringe for injection relatively easy and facilitate higher % API recovery.</p> <p>Among the formulation components that might have an impact on the AD properties of the PEO-based drug products are; the choice of the antioxidant, the use of complexing agents, chelating agents, and plasticizers. On the other hand, manufacturing process variables that might have a critical impact on AD properties of the PEO-based drug products include but are not limited to; processing temperature compared to the melting point of the polymer and time of exposure</p> <p>PMZ HCl was used as a model drug for Oxycodone in dissolution and extractability studies, while Caffeine and L-Nicotine were used as model drugs in smoking simulation experiments. The combination of the propane torch and Kugelrohr apparatus mimic the real-world scenario for smoking Opioids; however, this experimental setup caused thermal degradation rather than vaporization of some model drugs.</p> <p>According to the National Center for Health Statistics; a statistically significant increase in drug overdose death rates was reported in 2016 in the state of Indiana among other states. The number of deaths related to opioid pain relievers increased by 3732 folds in 2017 compared to the number of deaths in 2014. Moreover, Males were more affected by the opioid crisis than females. On the other hand, the age group 25-44 years, and white people were the most affected by the opioid crisis in Indiana. </p>

Eficácia do anti-inflamatório não-esteroidal diclofenaco associado ou não ao opioide codeína para controle da dor, edema e trismo no modelo de extração bilateral de terceiros molares inferiores com alto grau de dificuldade O controle da dor e inflamação após cirurgias bucais é normalmente realizado através do uso de anti-inflamatórios não-esteroidais (AINEs); no entanto a combinação de opioides aos AINEs pode garantir uma melhor analgesia principalmente após cirurgias mais traumáticas. Apesar disso, poucos estudos têm comparado AINEs associados ou não aos opioides após cirurgias bucais e maxilofaciais. Este estudo cruzado, randomizado e duplo-cego comparou a eficácia clínica no controle da dor, edema e trismo pós-operatório em 46 voluntários que consumiram randomicamente os medicamentos diclofenaco sódico (50 mg) associado à codeína (50 mg) e apenas diclofenaco sódico (50 mg) após extrações dos dois terceiros molares em posições complexas como alto grau de dificuldade cirúrgica. Os voluntários enquanto em uso do diclofenaco associado à codeína relataram dor pós-operatória significativamente menor em vários momentos (90 minutos (p=0,043), 2 horas (p=0,014), 3 horas (p=0,001), 5 horas (p=0,010), 10 horas (p=0,005), 12 horas (p=0,006) e 24 horas (p=0,018)) dentro das primeiras 24 horas após a cirurgia e também consumiram significativamente menos (p=0,003) medicação de resgate (paracetamol) ao longo do estudo, comparados com os valores expressos pelos mesmos voluntários enquanto em uso do diclofenaco apenas. Em conclusão, o diclofenaco sódico associado à codeína foi mais eficaz no controle da dor pós-operatória, enquanto que o trismo e o edema não apresentaram diferenças quando comparado com o diclofenaco sem codeína. / Postoperative pain and inflammation after oral surgery is mostly managed using non steroidal anti-inflammatory drugs (NSAIDs); however, opioids combined with NSAIDs may improve pain management in patients especially after traumatic oral surgery. Despite this, few studies have compared NSAIDs with and without opioids after oral and maxillofacial surgery. This randomized double-blinded crossover study compared the clinical efficacy for managing postoperative pain in 46 volunteers consuming either sodium diclofenac (50 mg) plus codeine (50 mg) or only sodium diclofenac (50 mg) after invasive surgeries for extraction of both lower third molar surgeries in different appointments. Volunteers reported significantly less postoperative pain at various time points (90 minutes (p=0,043), 2 hours (p=0,014), 3 hours (p=0,001), 5 hours (p=0,010), 10 hours (p=0,005), 12 hours (p=0,006) e 24 hours (p=0,018)) within 24 hours after surgery and also consumed significantly less(p=0,003) rescue medication (acetaminophen) throughout the study while consuming diclofenac plus codeine when compared to only taking NSAIDs. In conclusion, despite no difference between inflammation aspects, oral sodium diclofenac with codeine was more effective for managing postoperative pain when compared to diclofenac without codeine.

Avaliou-se, três vezes, ao longo de um mês, a função cognitiva de doentes em tratamento da dor oncológica e comparou-se o desempenho dos que recebiam opióides (Grupo Recebendo Opóides – GRO, n=14) ao dos que não os recebiam (Grupo Sem Opióides – GSO, n=12); analisaram-se também as relações entre função cognitiva, intensidade da dor e dose do opióide. A função cognitiva foi avaliada por meio do Teste de Trilhas, Mini-exame do Estado Mental, Teste de Extensão de Dígitos, Bateria Breve de Rastreio Cognitivo e Inventário de Depressão de Beck. Para a identificação de diferenças, o nível de significância foi estabelecido em 5%. A análise longitudinal para o GSO mostrou melhora da memória incidental (P=0,005) e do aprendizado (P=0,016); entretanto, piora das habilidades construtivas e vísuo-perceptivas (P=0,039). Para o GRO observou-se melhora da memória incidental (P=0,038). Em ambos os grupos não houve modificação no Teste de Trilhas, Mini-exame do Estado Mental, Teste de Extensão de Dígitos e demais testes da Bateria Breve de Rastreio Cognitivo. A comparação entre os grupos mostrou que o GSO teve melhor desempenho na atenção/concentração e memória operacional (2ª avaliação, P=0,029) e funções executivas (1ª avaliação, P=0,023). A análise de correlações no GRO demonstrou que à dor menos intensa corresponderam escores maiores no Mini-exame do Estado Mental (P =0,001), na memória incidental (P =0,030 e 0,014), na memória imediata (P=0,042) e na memória tardia (P =0,037), avaliados pela Bateria Breve de Rastreio Cognitivo. Não se observaram correlações no GSO. Não houve correlação entre a dose do opióide e o desempenho nos testes. O GSO teve melhor desempenho que o GRO em alguns testes, na análise comparativa entre grupos e na análise longitudinal. No entanto, essa superioridade não se expressou nas três avaliações e nem na maioria dos testes. A correlação negativa entre intensidade da dor e função cognitiva no Grupo Recebendo Opióides indicou que a intensidade da dor influenciou o desempenho cognitivo. Há necessidade de outros estudos que ampliem o conhecimento sobre o tema. / The cognitive functions of patients in oncologic pain treatment were assessed three times, over the period of a month. The performance of patients in treatment with opioids (Group Receiving Opioids – GRO, n=14) was compared with that of a group of patients receiving treatment without the administration of opioids (Group Without Opioids – GWO, n=12). Relations between cognitive function, pain intensity and opioid dose were also analysed. The cognitive function was assessed by the Trail Making Test, Mini-mental State Examination, Digit Span Test, Brief Cognitive Screening Battery and Beck Depression Inventory. In order to identify statistical differences, the significance level was established in 5%. The longitudinal analysis to the GWO showed improvement in incidental recall (P=0,005) and learning (P=0,016); however, deterioration in the constructional and visuoperceptual abilities was noticed (P=0,039). Improvement was observed in the incidental recall (P=0,038) of the GRO. In both groups there were no changes in the Trail Making Test, Mini-mental State Examination, Digit Span Test, Beck Depression Inventory and other tests from Brief Cognitive Screening Battery. The comparison between groups showed that GWO had better performance in attention/concentration, working memory (P=0,029) and also in executive functions (P=0,023). The analyses of the correlations in GRO demonstrated that less intense pain corresponds to higher scores in Mini-mental State Examination (P =0,001), in incidental recall (P=0,030 e P =0,014), in immediate recall (P=0,042) and in delayed recall (P=0,037) assessed by the Brief Cognitive Screening Battery. No correlations were observed in GWO. There was no correlation between opioid dose and performance in the results. In the longitudinal tests and comparative analyses between the groups, GWO had better performance than GRO. However, this superiority was not verified in the three assessments, as well as in the case of the majority of the tests results. The negative correlation between pain intensity and cognitive function on the group receiving opioids indicated that pain intensity had an influence on cognitive performance. Further research is necessary to broaden the knowledge about this issue.

Background:Non-medical use of prescription opioids (NMUPO) has become a clear threat to public health. Young adults (aged 18 to 25) have a high risk of NMUPO. My prior work on Chinese undergraduates indicates a high prevalence of lifetime NMUPO (49.2%). Health behavior theories propose that outcome expectancies are robust psychosocial determinants of substance use. Literature has identified the influence of outcome expectancies on alcohol and drug use. However, the role of outcome expectancies in NMUPO in China is unknown, and a scarcity of a valid measures for NMUPO outcome expectancies may be a barrier. Our previous research also found an association of cultural orientation with NMUPD in Chinese college students, implying that cultural orientation may affect NMUPD-related perceptions, such as outcome expectancies. The purposes of this study were to (1) conduct initial work to develop and validate an NMUPO outcome expectancies scale (NMUPOES) for Chinese college students; (2) examine the association of cultural orientation with factors identified in NMUPOES. Method: Partial data (n = 202) derived from a bigger online dataset collected from 849 undergraduates (average age = 19.65) at two universities in Beijing and Macau in Jan-April 2017 was used in this study. Participants completed the NMUPOES and reported their past-3-month NMUPO and cultural orientation. Exploratory factor analysis, confirmatory factor analysis, and structural equation modeling were employed to test the study hypotheses. Results: Findings suggested four subscales in the 50-item NMUPOES (i.e., social enhancement and tension reduction, academic enhancement, physiological discomfort, and guilt and dependence) and two higher-order factors (i.e., positive expectancies and negative expectancies). All subscales were positively correlated and had good internal consistency. The negative expectancies scale was negatively associated with past-3-month NMUPO. No significant association was found between cultural orientation and the two expectancy factors. Conclusion:NMUPOES is a psychometrically appropriate measure of NMUPO expectancies for Chinese college students. Future research may validate the NMUPOES using a large sample size in both clinical and non-clinical populations in China. An intervention program tailored to outcome expectancies may be beneficial to reduce the risk of NMUPO in Chinese college students.