Nicotine is the primary addictive substance in tobacco, and most smokers who quit will relapse within a year. Evidence shows that cigarette craving increases over time, termed “incubation.” The purpose of these studies was to see if protracted abstinence from chronic nicotine increases rat self-administration, an animal model with good face validity for human tobacco use, and if nicotine self-administration during daily exposure/after 8+ days of abstinence is regulated by extracellular signal-regulated kinase (ERK) signaling in the nucleus accumbens (NAc) shell or anterior cingulate cortex (PFC). ERK kinase inhibitor U0126 was infused in the NAc shell or PFC of Long Evans rats immediately prior to daily self-administration sessions and following 8+ days of abstinence. U0126 in the PFC decreased responding for nicotine during daily sessions. Following 8+ days of abstinence, animals showed a robust increase in responding for nicotine, blocked by U0126 in the NAc shell, but not the PFC. Western blots revealed that nicotine treatment decreased levels of a substrate of ERK, ribosomal s6 kinase (RSK), in the NAc shell and increased it in the PFC, which occurred independent of abstinence period. In contrast, levels of RSK were increased in the NAc shell following a nicotine challenge during the abstinence period. In summary, our data show that the ERK signaling pathway plays a vital role in nicotine addiction during daily nicotine exposure and following periods of abstinence.

Epidemiological data indicate that patients who experience a traumatic brain injury (TBI) have an elevated risk of developing a substance use disorder (SUD), but the underlying neurobiological connections remain unclear. To further understand the relationship between TBI and SUD, we investigated the effects of TBI on the abuse-related effects of oxycodone in preclinical models. Our evaluation utilized a lateral fluid percussion injury of moderate severity in adult male Sprague-Dawley rats. In the first aim, we tested the hypothesis that moderate TBI increases the risk for relapse to an opioid use disorder as measured by reinstatement of lever-pressing behavior following extinction in an intravenous oxycodone self-administration procedure. In the second aim, we tested the hypothesis that moderate TBI increases physiological dependence to oxycodone as measured by decreases in food-reinforced lever-pressing behavior and increases in other withdrawal behaviors in both precipitated withdrawal and spontaneous withdrawal. In tests for self-administration, brain-injured subjects, relative to non-injured subjects, showed no significant differences in the number of oxycodone-reinforced sessions required to meet stable maintenance criteria for lever-pressing behavior. Likewise, brain-injured subjects showed no significant differences in the number of non-reinforced sessions to meet extinction criteria for lever-pressing behavior relative to non-injured subjects. In tests for reinstatement, non-injured subjects reinstated responding under oxycodone-associated cue- and oxycodone prime-induced conditions, however, brain-injured subjects did not reinstate lever-pressing behavior under any conditions. In tests for physical dependence, brain-injured subjects showed no significant differences from non-injured subjects with regards to their mean withdrawal scores or food-reinforced lever-pressing behavior. Overall, these data suggest that brain-injured patients no significant pre-morbid history of opioid abuse are at a lesser risk of relapse to opioid use disorders. Moreover, the characteristic withdrawal syndrome in opioid-dependent patients may not contribute to continued opioid abuse to a greater degree in brain-injured patients than compared to non-injured patients.

Nas últimas décadas, assistimos ao aumento da preocupação com a saúde e à consolidação da concepção de que ser saudável depende tão somente da sistematização dos hábitos cotidianos e de comportamentos considerados corretos para manter a longevidade. A adoção de um estilo de vida saudável padronizado por critérios científicos vem se tornando, aparentemente, uma obrigação que independe da escolha voluntária, tamanha é a pressão social que demanda do indivíduo autocuidado. A propalada concepção de saúde enquanto amplo bem-estar inclui a adoção de hábitos preventivos que mantenham a saúde física e mental pelo máximo número de anos, de preferência conservando a beleza, o bom humor e a disposição produtiva da juventude. Ao mesmo tempo evidencia-se uma nova moralidade pautada nos riscos de saúde, na qual a responsabilidade sobre o próprio adoecimento condena os não saudáveis à condição de irresponsáveis e desviantes. O objetivo desta tese é problematizar a retórica acerca da vida saudável, a partir do noticiário semanal veiculado em revistas brasileiras de variedades, procurando identificar o que poderia ter contribuído para a sobrevalorização da saúde como norteadora dos comportamentos. Do ponto de vista da discussão efetuada, o atual ideário de saúde e bemestar é resultado de um processo abrangente, de âmbito mundial, que envolve tanto aspectos macroeconômicos como modificações nos valores culturais que confluíram para a legitimação da responsabilidade individual por todas as condições de existência, inclusive por aquelas advindas das circunstâncias sociais. O autocuidado em matéria de saúde seria parte de uma conduta racional de gestão de si, como se o indivíduo fosse uma empresa, legitimada como ideal de bem-viver, que pressupõe a autodisciplina corporal e emocional para maximização da vitalidade ou do capital humano. O indivíduo passa a ser, ele próprio, objeto de trabalho para alcançar uma vida melhor e mais longa, que, de acordo com o noticiário, estaria apenas nas mãos de cada um / In recent decades we have witnessed the increasing concern about health and the consolidation of the view that being healthy depends solely on the systematization of daily habits and supposedly correct behaviors to maintain longevity. The adoption of a healthy lifestyle based on scientific criteria has become, apparently, an obligation that is independent of voluntary choice, such is the social pressure imposed to the individual by the self-care demand. The broad conception of health as wellness includes taking preventive habits to keep physical and mental health for as long as possible, preferably by retaining beauty, good mood and the productive energy of the youth. At the same time there is evidence of a new morality based on health risks, in which taking the responsibility for ones own illnesses condemns the unhealthy ones to be considered irresponsible and devious. The objective of this thesis is to problematize the rhetoric about healthy living, based on empirical research on the weekly news of Brazilian varieties magazines. We try in this work to identify the factors that might have contributed to the overvaluation of health in its role of determining behaviors. From the point of view of the discussion made, the current ideals of health and wellness are the result of a worldwide comprehensive process, involving both macroeconomic issues and changes in cultural values that led to the legitimization of individual responsibility for all his conditions, even those stemming from social circumstances. Self-care in health would be part of a rational conduct of self-management that extends the enterprise logic to the individual behavior and is legitimized as an ideal of good living, which presupposes the body and the emotional self-discipline to maximize vitality or human capital. The individual works on himself to achieve a better and longer life, which, according to the news, would be each ones responsibility

Nas últimas décadas, assistimos ao aumento da preocupação com a saúde e à consolidação da concepção de que ser saudável depende tão somente da sistematização dos hábitos cotidianos e de comportamentos considerados corretos para manter a longevidade. A adoção de um estilo de vida saudável padronizado por critérios científicos vem se tornando, aparentemente, uma obrigação que independe da escolha voluntária, tamanha é a pressão social que demanda do indivíduo autocuidado. A propalada concepção de saúde enquanto amplo bem-estar inclui a adoção de hábitos preventivos que mantenham a saúde física e mental pelo máximo número de anos, de preferência conservando a beleza, o bom humor e a disposição produtiva da juventude. Ao mesmo tempo evidencia-se uma nova moralidade pautada nos riscos de saúde, na qual a responsabilidade sobre o próprio adoecimento condena os não saudáveis à condição de irresponsáveis e desviantes. O objetivo desta tese é problematizar a retórica acerca da vida saudável, a partir do noticiário semanal veiculado em revistas brasileiras de variedades, procurando identificar o que poderia ter contribuído para a sobrevalorização da saúde como norteadora dos comportamentos. Do ponto de vista da discussão efetuada, o atual ideário de saúde e bemestar é resultado de um processo abrangente, de âmbito mundial, que envolve tanto aspectos macroeconômicos como modificações nos valores culturais que confluíram para a legitimação da responsabilidade individual por todas as condições de existência, inclusive por aquelas advindas das circunstâncias sociais. O autocuidado em matéria de saúde seria parte de uma conduta racional de gestão de si, como se o indivíduo fosse uma empresa, legitimada como ideal de bem-viver, que pressupõe a autodisciplina corporal e emocional para maximização da vitalidade ou do capital humano. O indivíduo passa a ser, ele próprio, objeto de trabalho para alcançar uma vida melhor e mais longa, que, de acordo com o noticiário, estaria apenas nas mãos de cada um / In recent decades we have witnessed the increasing concern about health and the consolidation of the view that being healthy depends solely on the systematization of daily habits and supposedly correct behaviors to maintain longevity. The adoption of a healthy lifestyle based on scientific criteria has become, apparently, an obligation that is independent of voluntary choice, such is the social pressure imposed to the individual by the self-care demand. The broad conception of health as wellness includes taking preventive habits to keep physical and mental health for as long as possible, preferably by retaining beauty, good mood and the productive energy of the youth. At the same time there is evidence of a new morality based on health risks, in which taking the responsibility for ones own illnesses condemns the unhealthy ones to be considered irresponsible and devious. The objective of this thesis is to problematize the rhetoric about healthy living, based on empirical research on the weekly news of Brazilian varieties magazines. We try in this work to identify the factors that might have contributed to the overvaluation of health in its role of determining behaviors. From the point of view of the discussion made, the current ideals of health and wellness are the result of a worldwide comprehensive process, involving both macroeconomic issues and changes in cultural values that led to the legitimization of individual responsibility for all his conditions, even those stemming from social circumstances. Self-care in health would be part of a rational conduct of self-management that extends the enterprise logic to the individual behavior and is legitimized as an ideal of good living, which presupposes the body and the emotional self-discipline to maximize vitality or human capital. The individual works on himself to achieve a better and longer life, which, according to the news, would be each ones responsibility

Rationale: Nicotine is the addictive component in cigarettes which maintains cigarette smoking that subsequently leads to morbidity and mortality. There are growing regulatory efforts to lower the nicotine content in cigarettes so that they are minimally addictive. Valid methods for assessing the abuse liability of cigarettes are essential to these efforts. While subjective effect measures and hypothetical purchase tasks are appealing because they are far easier to administer, it is unclear whether these methods can be used to evaluate acute relative reinforcing, a critical component of abuse liability. This secondary analysis sought to evaluate the utility of one subjective effects measure, the modified Cigarette Evaluation Questionnaire (mCEQ), and one hypothetical purchase task, the Cigarette Purchase Task (CPT), for predicting acute relative reinforcing efficacy as measured by concurrent choice Self-Administration (SA) Method: Current smokers (N=169) belonging to one of three vulnerable populations (socioeconomically disadvantaged women of childbearing age, opioid-maintained individuals, or individuals with affective disorders) participated in a multi-site, double blind study evaluating research cigarettes with varying levels of nicotine content (0.4, 2.4, 5.2, 15.8 mg/g). In Phase 1 (4 sessions, 1 research cigarette per session) participants completed the mCEQ and CPT following ad-lib smoking of the research cigarette. In Phase II (6 sessions) cigarette preference was assessed using two-dose concurrent choice tests. Difference scores were calculated for each of the five mCEQ subscales and five CPT indices for all six possible dose comparisons evaluated in Phase II. We evaluated the utility of the mCEQ subscale and CPT index difference scores for predicting preference for the higher dose in a given dose comparison using a mixed-model of repeated measures analysis of variance. Finally, we used stepwise regressions to determine which subscales and indices served as independent predictors of concurrent choice SA. Results: Among mCEQ subscales, higher Satisfaction and Enjoyment of Respiratory Tract Sensation were independently predictive of higher dose preference in the choice testing regardless of dose comparison. There was a significant Satisfaction X Vulnerable Population interaction where increases in Satisfaction difference scores corresponded to greater changes in higher dose preference among socioeconomically disadvantaged women of childbearing age compared to other Vulnerable Populations. Among CPT indices, Elasticity was the only independent predictor of choice. However, there was a significant Elasticity X Dose Comparison X Vulnerable Population interaction associated with its predictive utility where the relationship between elasticity and choice differed by dose among opioid-maintained individuals. In a final model, including all subscales and indices, Satisfaction and Enjoyment of Respiratory Tract Sensations remained the only significant predictors of choice. Discussion: Concurrent choice testing, subjective effects and hypothetical purchase tasks capture some common features of abuse liability. Concurrent choice testing and the Satisfaction subscale were the most concordant measures. The observation that CPT indices are not robust predictors of choice in a concurrent arrangement suggests this measure may have greater utility for capturing individual differences as opposed to isolating the acute relative reinforcing effects of nicotine. Nevertheless, all three measures can contribute to efforts to assess the abuse liability of cigarettes varying in nicotine dose and important work aimed at regulating these products to improve human health.

A key issue in neuroscience is to determine the connection between neuronal circuits and behaviour. In the adult brain, all neuronal circuits include a glutamatergic component. Three proteins designated Vesicular glutamate transporter 1-3 (VGLUT1-3) possess the capability of packaging glutamate into presynaptic vesicles for release of glutamate at the nerve terminal. The present study aimed at determining the role of VGLUT2 in neuronal circuits of higher brain function, emotion, and reward-pocessing. A conditional knockout (cKO) strategy was utilised, and three different mouse lines were produced to delete VGLUT2 in specific neuronal circuits in a temporally and spatially controlled manner. First, we produced a cKO mouse in which Vglut2 was deleted in specific subpopulations of the cortex, amygdala and hippocampus from preadolescence. This resulted in blunted aspects in cognitive, emotional and social behaviour in a schizophrenia-related phenotype. Furthermore, we showed a downstream effect of the targeted deletion on the dopaminergic system. In a subsequent analysis of the same cKO mice, we showed that female cKO mice were more affected their male counterparts, and we also found that female schizophrenia patients, but not male patients, had increased Vglut2 levels in the cortex.  Second, we produced and analysed cKO mice in which Vglut2 was deleted in the cortex, amygdala and hippocampus already from midgestation, and could show that this deletion affected emotional, but not cognitive, function. Third, we addressed the role of VGLUT2 in midbrain dopamine neurons by targeting Vglut2 specifically in these neurons. These cKO mice showed a blunted activational response to the psychostimulant amphetamine and increased operant self-administration of both sugar and cocaine reinforcers. Further, the cKO mice displayed strongly enhanced cocaine-seeking in response to cocaine-associated cues, a behaviour of relevance for addiction in humans. In summary, this thesis work has addressed the role of the presynaptic glutamatergic neuron in different neuronal circuits and shown that the temporal and spatial distribution of VGLUT2 is of great significance for normal brain function.

INTRODUCTION: Smoking is one of the single greatest causes of numerous preventable diseases. We were interested in developing an animal model of nicotine metabolism that can be used to examine the effects of potential CYP2A6 inhibitors on nicotine metabolism and nicotine-mediated behaviours. Pharmacogenetic studies have demonstrated that in humans, smoking behaviour is associated with rates of nicotine metabolism by the CYP2A6 enzyme. Mouse CYP2A5 shares structural and functional similarities to human CYP2A6 and has been implicated in nicotine self-administration behaviours in mice, therefore the mouse represents a potential animal model for studying nicotine metabolism. METHODS: We characterized nicotine and cotinine metabolism in two commonly used mouse strains (DBA/2 and C57Bl/6). We also examined the association between nicotine self-administration behaviours and nicotine metabolism, and the impact of direct manipulation (i.e. inhibition) of nicotine metabolism on nicotine pharmacodynamics (hot-plate and tail-flick tests) in mice. Finally, we studied the effect of selegiline (a known cytochrome P450 mechanism-based inhibitor) on nicotine metabolism in mice and in human CYP2A6. RESULTS: Nicotine metabolism in mice in vitro was mediated by CYP2A5, and this enzyme was responsible for over 70% and 90% of the metabolism of nicotine to cotinine and cotinine to 3-hydroxycotinine as shown by immuno-inhibition studies, respectively. A polymorphism in CYP2A5 between mouse strains, known to alter the probe substrate coumarin’s metabolism, did not affect nicotine metabolism but dramatically altered cotinine metabolism. Nicotine self-administration behaviour in mice was associated with level of hepatic CYP2A5 proteins and rates of nicotine metabolism in male mice. In inhibition studies, the CYP2A5/6 inhibitor methoxsalen inhibited both in vitro and in vivo nicotine metabolism in mice and substantially increased the anti-nociceptive effect of nicotine. Finally, selegiline was found to be an inhibitor of CYP2A5 decreasing nicotine metabolism in vitro and in vivo in mice. Moreover, we showed that selegiline is a mechanism-based inhibitor of CYP2A6 inhibiting nicotine metabolism irreversibly. CONCLUSION: The above data suggested that the mouse model may be suitable for examining the impact of inhibition (and genetic variation) on nicotine metabolism and nicotine-mediated behaviours and may potentially be used to screen for novel inhibitors of nicotine metabolism.

INTRODUCTION: Smoking is one of the single greatest causes of numerous preventable diseases. We were interested in developing an animal model of nicotine metabolism that can be used to examine the effects of potential CYP2A6 inhibitors on nicotine metabolism and nicotine-mediated behaviours. Pharmacogenetic studies have demonstrated that in humans, smoking behaviour is associated with rates of nicotine metabolism by the CYP2A6 enzyme. Mouse CYP2A5 shares structural and functional similarities to human CYP2A6 and has been implicated in nicotine self-administration behaviours in mice, therefore the mouse represents a potential animal model for studying nicotine metabolism. METHODS: We characterized nicotine and cotinine metabolism in two commonly used mouse strains (DBA/2 and C57Bl/6). We also examined the association between nicotine self-administration behaviours and nicotine metabolism, and the impact of direct manipulation (i.e. inhibition) of nicotine metabolism on nicotine pharmacodynamics (hot-plate and tail-flick tests) in mice. Finally, we studied the effect of selegiline (a known cytochrome P450 mechanism-based inhibitor) on nicotine metabolism in mice and in human CYP2A6. RESULTS: Nicotine metabolism in mice in vitro was mediated by CYP2A5, and this enzyme was responsible for over 70% and 90% of the metabolism of nicotine to cotinine and cotinine to 3-hydroxycotinine as shown by immuno-inhibition studies, respectively. A polymorphism in CYP2A5 between mouse strains, known to alter the probe substrate coumarin’s metabolism, did not affect nicotine metabolism but dramatically altered cotinine metabolism. Nicotine self-administration behaviour in mice was associated with level of hepatic CYP2A5 proteins and rates of nicotine metabolism in male mice. In inhibition studies, the CYP2A5/6 inhibitor methoxsalen inhibited both in vitro and in vivo nicotine metabolism in mice and substantially increased the anti-nociceptive effect of nicotine. Finally, selegiline was found to be an inhibitor of CYP2A5 decreasing nicotine metabolism in vitro and in vivo in mice. Moreover, we showed that selegiline is a mechanism-based inhibitor of CYP2A6 inhibiting nicotine metabolism irreversibly. CONCLUSION: The above data suggested that the mouse model may be suitable for examining the impact of inhibition (and genetic variation) on nicotine metabolism and nicotine-mediated behaviours and may potentially be used to screen for novel inhibitors of nicotine metabolism.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2006. / Härtill 4 uppsatser.