Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 5 uppsatser.

Thesis (M.S.)--University of Michigan, 1991. / eContent provider-neutral record in process. Description based on print version record.

Thesis (M.S.)--University of Michigan, 1991. / eContent provider-neutral record in process. Description based on print version record.

abstract: The capability of cocaine-associated stimuli in eliciting craving in human addicts, even after extended periods of abstinence, is modeled in animals using cue reinstatement of extinguished cocaine-seeking behavior. This study aimed to examine brain activation in response to cocaine cues in this model apart from activation produced by test novelty using a novel cue control. Rats trained to self-administer cocaine paired with either an oscillating light or tone cue underwent daily extinction training and were then tested for reinstatement of extinguished cocaine-seeking behavior elicited by response-contingent presentations of either their assigned cocaine-paired cue or the alternate, novel cue. Additional controls received saline infusions and cue presentations yoked to a cocaine-trained rat. Brains were harvested for Fos immunohistochemistry immediately after the 90-min reinstatement test. Surprisingly, conditioned and novel cues both reinstated responding to a similar degree; however magnitude of reinstatement did vary by cue modality with the greatest reinstatement to the light cues. In most brain regions, Fos expression was enhanced in rats with a history of cocaine training regardless of cue type with the exception of the Cg1 region of the anterior cingulate cortex, which was sensitive to test cue modality. Also Fos expression within the dorsomedial caudate-putamen was correlated with responding in the novel, but not conditioned, cue groups. In subsequent experiments, we observed a similar pattern of reinstatement in rats trained and tested for sucrose-seeking behavior, whereas rats trained and tested with the cues only reinstated to a novel light and tone, but not a familiar cue. The results suggest that novel cues reinstate responding to a similar extent as conditioned cues regardless of whether animals have a history of operant-delivered drug or a natural reinforcer. Furthermore, similar brain circuits as those involved in cocaine-seeking behavior are activated by novel cues, suggesting converging processes exist to drive conditioned and novel reinforcement seeking. / Dissertation/Thesis / M.A. Psychology 2012

Nous avons étudié l'influence de la voie du cGMP sur le comportement d'auto-administration de cocaïne chez le rat. Les injections, dans le cortex préfrontal médian, de trois activateurs différents de cette voie diminuent le nombre d'injections que les rats déclenchent, indiquant une réduction de l'effet renforçant de la cocaïne et de leur motivation pour la drogue. Des études immunohistochimiques nous ont permis de mettre en évidence que cette effet comportemental s'accompagnait d'une diminution de l'expression de marqueurs épigénétiques (MeCP2, HDAC2) et d'une augmentation des niveaux d'acétylation des histones. Des résultats complémentaires confirment que la voie du cGMP est bien en mesure de réguler des protéines impliquées dans les mécanismes épigénétiques. La découverte d'une action via ces régulations nous permet de suggérer des pistes originales quant aux phénomènes mis en jeu dans la diminution observée des propriétés renforçantes de la cocaïne. / We studied the influence of the cGMP pathway on cocaine self-administration by rats. When injected in the medial prefrontal cortex, three distinct activators of this pathway reduced the number of self-injections triggered by rats, suggesting a reduction of the reinforcing properties of cocaine and a lesser motivation of the animals for the drug. Immunohistochemical studies revealed that this behavioural effect was accompanied by a reduced expression of epigenetic markers (MeCP2, HDAC2), as well as inceased levels of histone acetylation. Complementary results indicate that the cGMP pathway is indeed able to regulate proteins implied in epigenetic mechanisms. The uncovering of an implication of these types of regulations leads us to suggest original hypotheses about the processes underlying the reduction of the reinforcing properties of cocaine.

abstract: Globally, addiction to stimulants such as methamphetamine (METH) remains a significant public health problem. Despite decades of research, no approved anti-relapse medications for METH or any illicit stimulant exist, and current treatment approaches suffer from high relapse rates. Recently, synthetic cathinones have also emerged as popular abused stimulants, leading to numerous incidences of toxicity and death. However, contrary to traditional illicit stimulants, very little is known about their addiction potential. Given the high relapse rates and lack of approved medications for METH addiction, chapters 2 and 3 of this dissertation assessed three different glutamate receptor ligands as potential anti-relapse medications following METH intravenous self-administration (IVSA) in rats. In chapters 4 through 7, using both IVSA and intracranial self-stimulation (ICSS) procedures, experiments assessed abuse liability of the popular synthetic cathinones 3,4-Methylenedioxypyrovalerone (MDPV) , methylone, α-pyrrolidinovalerophenone (α-PVP) and 4-methylethylcathinone (4-MEC). Results from these seminal studies suggest that these drugs possess similar abuse potential to traditional illicit stimulants such as METH, cocaine, and 3,4-methylenedioxymethamphetamine (MDMA). Finally, studies outlined in chapter 8 assessed the potential neurotoxic or adverse cognitive effects of METH and MDPV following IVSA procedures for the purpose of identifying potential novel pharmacotherapeutic targets. However, results of these final studies did not reveal neurotoxic or adverse cognitive effects when using similar IVSA procedural parameters that were sufficient for establishing addiction potential, suggesting that these parameters do not allow for sufficient drug intake to produce similar neurotoxicity or cognitive deficits reported in humans. Thus, these models may be inadequate for fully modeling the adverse neural and psychological consequences of stimulant addiction. Together, these studies support the notion for continued research into the abuse liability and toxicity of METH and synthetic cathinones and suggest that refinements to traditional IVSA models are needed for both more effective assessment of potential cognitive and neural deficits induced by these drugs and screening of potentially clinically efficacious pharmacotherapeutics. / Dissertation/Thesis / Doctoral Dissertation Psychology 2014

abstract: Evidence from the 20th century demonstrated that early life stress (ELS) produces long lasting neuroendocrine and behavioral effects related to an increased vulnerability towards psychiatric illnesses such as major depressive disorder, post-traumatic stress disorder, schizophrenia, and substance use disorder. Substance use disorders (SUDs) are complex neurological and behavioral psychiatric illnesses. The development, maintenance, and relapse of SUDs involve multiple brain systems and are affected by many variables, including socio-economic and genetic factors. Pre-clinical studies demonstrate that ELS affects many of the same systems, such as the reward circuitry and executive function involved with addiction-like behaviors. Previous research has focused on cocaine, ethanol, opiates, and amphetamine, while few studies have investigated ELS and methamphetamine (METH) vulnerability. METH is a highly addictive psychostimulant that when abused, has deleterious effects on the user and society. However, a critical unanswered question remains; how do early life experiences modulate both neural systems and behavior in adulthood? The emerging field of neuroepigenetics provides a potential answer to this question. Methyl CpG binding protein 2 (MeCP2), an epigenetic tag, has emerged as one possible mediator between initial drug use and the transition to addiction. Additionally, there are various neural systems that undergo long lasting epigenetics changes after ELS, such as the response of the hypothalamo-pituitary-adrenal (HPA) axis to stressors. Despite this, little attention has been given to the interactions between ELS, epigenetics, and addiction vulnerability. The studies described herein investigated the effects of ELS on METH self-administration (SA) in adult male rats. Next, we investigated the effects of ELS and METH SA on MeCP2 expression in the nucleus accumbens and dorsal striatum. Additionally, we investigated the effects of virally-mediated knockdown of MeCP2 expression in the nucleus accumbens core on METH SA, motivation to obtain METH under conditions of increasing behavioral demand, and reinstatement of METH-seeking in rats with and without a history of ELS. The results of these studies provide insights into potential epigenetic mechanisms by which ELS can produce an increased vulnerability to addiction in adulthood. Moreover, these studies shed light on possible novel molecular targets for treating addiction in individuals with a history of ELS. / Dissertation/Thesis / Doctoral Dissertation Psychology 2015

abstract: Social influences are important determinants of drug initiation in humans, particularly during adolescence and early adulthood. My dissertation tested three hypotheses: 1) conditioned and unconditioned nicotine and social rewards elicit unique patterns of neural signaling in the corticolimbic neurocircuitry when presented in combination versus individually; 2) play behavior is not necessary for expression of social reward; and 3) social context enhances nicotine self-administration. To test the first hypothesis, Fos protein was measured in response to social and nicotine reward stimuli given alone or in combination and in response to environmental cues associated with the rewards in a conditioned place preference (CPP) test. Social-conditioned environmental stimuli attenuated Fos expression in the nucleus accumbens core. A social partner elevated Fos expression in the caudate-putamen, medial and central amygdala, and both nucleus accumbens subregions. Nicotine decreased Fos expression in the cingulate cortex, caudate-putamen, and the nucleus accumbens core. Both stimuli combined elevated Fos expression in the basolateral amygdala and ventral tegmental area, suggesting possible overlap in processing both rewards in these regions. I tested the second hypothesis with an apparatus containing compartments separated by a wire mesh barrier that allowed limited physical contact with a rat or object. While 2 pairings with a partner rat (full physical contact) produced robust CPP, additional pairings were needed for CPP with a partner behind a barrier or physical contact with an object (i.e., tennis ball). The results demonstrate that physical contact with a partner rat is not necessary to establish social-reward CPP. I tested the third hypothesis with duplex operant conditioning chambers separated either by a solid or a wire mesh barrier to allow for social interaction during self-administration sessions. Nicotine (0.015 and 0.03 mg/kg, IV) and saline self-administration were assessed in male and female young-adult rats either in the social context or isolation. Initially, a social context facilitated nicotine intake at the low dose in male rats, but suppressed intake in later sessions more strongly in female rats, suggesting that social factors exert strong sex-dependent influences on self-administration. These novel findings highlight the importance of social influences on several nicotine-related behavioral paradigms and associated neurocircuitry. / Dissertation/Thesis / Doctoral Dissertation Psychology 2015

abstract: The maternal separation (MS) paradigm is an animal model of early life stress. Animals subjected to MS during the first two weeks of life display altered behavioral and neuroendocrinological stress responses as adults. MS also produces altered responsiveness to and self-administration (SA) of various drugs of abuse including cocaine, ethanol, opioids, and amphetamine. Methamphetamine (METH) causes great harm to both the individual user and to society; yet, no studies have examined the effects of MS on METH SA. This study was performed to examine the effects of MS on the acquisition of METH SA, extinction, and reinstatement of METH-seeking behavior in adulthood. Given the known influence of early life stress and drug exposure on epigenetic processes, group differences in levels of the epigenetic marker methyl CpG binding protein 2 (MeCP2) in the nucleus accumbens (NAc) core were also investigated. Long-Evans pups and dams were separated on postnatal days (PND) 2-14 for either 180 (MS180) or 15 min (MS15). Male offspring were allowed to acquire METH SA (0.05 mg/kg/infusion) in 15 2-hr daily sessions starting at PND67, followed by extinction training and cue-induced reinstatement of METH-seeking behavior. Rats were then assessed for MeCP2 levels in the NAc core by immunohistochemistry. The MS180 group self-administered significantly more METH and acquired SA earlier than the MS15 group. No group differences in extinction or cue-induced reinstatement were observed. MS15 rats had significantly elevated MeCP2-immunoreactive cells in the NAc core as compared to MS180 rats. Together, these data suggest that MS has lasting influences on METH SA as well as epigenetic processes in the brain reward circuitry. / Dissertation/Thesis / M.A. Psychology 2013

Submitted by Fabio Sobreira Campos da Costa (fabio.sobreira@ufpe.br) on 2017-07-14T15:57:43Z No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) disertaçãomestradoalexbernardoposneuro2016.pdf: 1482621 bytes, checksum: 6077c9780a49008fbef291d8e14c99fb (MD5) / Made available in DSpace on 2017-07-14T15:57:43Z (GMT). No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) disertaçãomestradoalexbernardoposneuro2016.pdf: 1482621 bytes, checksum: 6077c9780a49008fbef291d8e14c99fb (MD5) Previous issue date: 2016-05-30 / Um aspecto crucial na gestão do cuidado para pacientes com Esclerose Múltipla está na identificação, manutenção e inclusão dos pacientes quanto a aderência ao tratamento. Objetivo: O objetivo desta dissertação foi investigar quais fatores sociodemográficos, clínicos e relacionados à terapêutica medicamentosa influenciam na adoção da prática da autoadministração de imunomoduladores em pacientes de EM e se tal prática resulta em maior adesão ao tratamento. Métodos: trata-se de estudo prospectivo, descritivo e exploratório com abordagem quantitativa. A amostra foi composta por 82 pacientes de EM atendidos em um Centro de Referência do Estado de Pernambuco. Os dados foram coletados através de entrevistas realizadas nos meses de março e abril de 2016. Os dados foram armazenados e analisados no SPSS -21. Para a análise de associação foram utilizados testes estatísticos que considerou significância estatística quando o valor de p< 0,05. Resultados: Apresentaram significância estatística positiva para adoção da prática da autoadministração foram: menor idade (p=0,021), maior escolaridade (p=0,006), permanecia na atividades acadêmicas e/ou profissionais (0,001), realizavam todas as doses prescritas do medicamento (p=0,001). Quanto a adesão ao tratamento as variáveis que apresentaram significância estatística positiva foram: permanecia na atividades acadêmicas e/ou profissionais (p=0,001), menor impacto da doença na qualidade de vida (p=0,042). Os paciente aderentes ao tratamento mudaram menos de imunomodulador (p=0,001). Conclusão: idade, escolaridade e ocupação podem torna-se barreiras para adoção da prática da autoadministração de imunomoduladores em pacientes de Esclerose Múltipla. A prática da autoadministração melhora a aderência ao tratamento, resultado em menor taxa de migração do immunomoduador e menor índice de falha terapêutica. / A crucial aspect of care management for patients with Multiple Sclerosis is the identification, maintenance and inclusion of patients and adherence to treatment. Objective: The aim of this work was to investigate which sociodemographic, clinical factors and related to drug therapy influence the adoption of the practice of selfadministration of immunomodulators in MS patients and the practice results in better treatment adherence.Methods: It is a prospective, descriptive study with a quantitative approach. The sample consisted of 82 patients with MS treated at a State of Pernambuco Reference Cente. Data were collected through interviews conducted in March and April 2016. Data were stored and analyzed using the SPSS -21. For association analysis statistical tests were used which considered statistically significant when the p value <0.05.Results: Showed positive statistical significance for adoption of the practice of self-administration were younger age (p = 0.021), higher education (p = 0.006) remained in academic activities and / or professionals (0,001), performed all prescribed doses of the drug (p = 0.001). The adherence to treatment variables that showed positive statistical significance were remained in academic and / or professional activities (p = 0.001), lower impact of disease on quality of life (p = 0.042). The adherent to treatment immunomodulator changed less (p = 0.001). Conclusion: age, education and occupation can become barriers to adoption of the practice of selfadministration of immunomodulators in multiple sclerosis patients. The practice of self management improves adherence to treatment, results in lower immunomoduador migration rate and lower treatment failure rate.