Rationale: Varenicline (VAR), a smoking cessation aid that is a partial agonist at nicotinic receptors, mimics the reinforcement-enhancing effects of nicotine. Varenicline, when accompanied by non-drug cues, is self-administered by rats, though it is unclear whether this results from varenicline acting as a primary reinforcer or a reinforcement enhancer of the cues. Objectives: This study sought to disentangle these two potential actions. Methods: Rats were allowed to self-administer intravenous nicotine, saline, or varenicline during 1-h sessions in operant chambers equipped with two levers. Five groups had concurrent access to drug infusions and a moderately reinforcing visual stimulus (VS) for responding on separate levers. Meeting the reinforcement schedule on one lever was reinforced with VAR (0.01, 0.06, 0.1 mg/kg/infusion), nicotine (0.06 mg/kg/infusion), or saline, while meeting the same schedule on the other lever delivered the VS. Additional groups were reinforced for pressing a single "active" lever and received VAR paired with the VS, the VS with response-independent infusions of VAR, or VAR alone (0.1 mg/kg/infusion). Results: Rats readily responded for VAR paired with VS on a single lever. However, when VAR was the only reinforcer contingent on a response, rats did not respond more than for saline. Conclusions: These findings show that VAR does not serve as a primary reinforcer in rats at doses that increase responding for non-drug reinforcers. These data are consistent with research showing that the primary reinforcing effects of VAR are weak, at best, and that the primary reinforcing and reinforcement-enhancing actions of nicotinic drugs are pharmacologically distinct.

Some studies have demonstrated that the effects of a drug may be different, depending on whether the drug is self-administered or passively received by the subject. Most of the studies which have examined this phenomenon have not examined the effects of a drug following each of a series of administrations. Moreover, the mechanism mediating differences between self-administered and passively received drugs has not been determined. The present experiments used a yoked-control design to examine the development of tolerance to the ataxic effects of heroin and of ethanol in rats that self-administer the drugs and rats that passively received them. Results demonstrate that rats that passively received heroin, but not those that self-administered the drug, were significantly impaired following the initial administrations. During the first administration sessions, rats that self-administered ethanol were as impaired as their partners that passively received, but within a few sessions self-administering rats developed tolerance to the ataxic effect of the ethanol, while their yoked partners did not. The results also suggest that the faster tolerance development in rats that self-administered ethanol may have been mediated by differences in Pavlovian conditioning in these subjects, which demonstrated larger compensatory conditional responses in the form of “hypertaxia” than did their yoked partners. The results indicated that some component of the self-administration process contributed to the Pavlovian conditioning, and hence, faster tolerance development, of self-administering animals. The data suggest that studies in which drugs are passively received may overestimate the dose that is necessary to produce tolerance in self-administering animals. Models based on such studies, then, may require modification before they are applied to situations which involve self-administration of drugs. / Thesis / Doctor of Philosophy (PhD)

p. 1-134 / Submitted by Santiago Fabio (fabio.ssantiago@hotmail.com) on 2013-03-19T20:27:59Z No. of bitstreams: 1 3,333333tdtdt.pdf: 971954 bytes, checksum: 4a5ea95473e71ab828d4282bd3de7e6f (MD5) / Approved for entry into archive by Tatiana Lima(tatianasl@ufba.br) on 2013-04-22T18:24:45Z (GMT) No. of bitstreams: 1 3,333333tdtdt.pdf: 971954 bytes, checksum: 4a5ea95473e71ab828d4282bd3de7e6f (MD5) / Made available in DSpace on 2013-04-22T18:24:45Z (GMT). No. of bitstreams: 1 3,333333tdtdt.pdf: 971954 bytes, checksum: 4a5ea95473e71ab828d4282bd3de7e6f (MD5) Previous issue date: 2004 / Este trabalho trata da temática autogestão em cooperativas populares. O objetivo é identificar e discutir os desafios à autogestão em cooperativas populares. Partimos da premissa de que a heterogestão (gestão hierarquizada de diferentes ou desiguais) é o modo hegemônico de organização do trabalho na sociedade capitalista, desta maneira a autogestão seria uma novidade e por isso apresentaria desafios na sua efetivação. Entende-se autogestão como a não separação entre trabalho manual e intelectual, em que a posse dos meios de produção é coletiva e caracterizada como um processo em construção na organização. O objeto de pesquisa foi a Cooperativa Juvenil de Serviços Turísticos de São Bartolomeu – COOPERTUR, incubada pelo PANGEA – Centro de Estudos Sócio-ambientais e localizada no Subúrbio Ferroviário de Salvador. Foram utilizados os níveis de consciência de Paulo Freire para tentar identificar o grau de maturidade do grupo e os níveis de participação de Bordenave para perceber a atuação da diretoria e a transparência nas informações na cooperativa. Constatou-se, na pesquisa que a autogestão só se torna viável quando os cooperados se percebem no nível de consciência crítica (Paulo Freire), que pode ser caracterizado pela capacidade do indivíduo de se afastar da sua realidade objetiva e problematizá-la. No caso da COOPERTUR, foi identificada a situação a que se denominou autogestão funcional, caracterizada por cooperados em diferentes níveis de consciência, em que mesmo com os instrumentos de participação disponíveis, um grupo de cooperados opta por não participar, delegando aos demais as tomadas de decisão. A autogestão funcional seria, então, uma fase pela qual a organização passa para chegar à autogestão plena (estado ótimo). A autogestão funcional é um ponto de inflexão na trajetória da organização rumo à autogestão, e a cooperativa pode, a partir deste momento, evoluir ou retroceder (ou, ainda, deixar de existir) na construção da autogestão, dependendo dos desdobramentos desta fase, intimamente ligada ao nível de consciência dos cooperados. Quanto à atuação da diretoria, percebeu-se que a “inércia participativa” de um grupo de cooperados faz com que a cooperativa possa ser classificada no nível de participação denominado “consulta obrigatória”. Outro problema identificado na cooperativa está relacionado ao processo de comunicação, sendo identificados problemas para que a informação possa chegar até aos cooperados. / Salvador

Doctor of Philosophy / Department of Psychology / Stephen W. Kiefer / Methamphetamine is a potent psychomotor stimulant and a major drug of abuse. There is currently no effective medication available for treatment for methamphetamine addiction. The present study investigated the role of the dopamine D3 receptor on IV methamphetamine self-administration and its effect on methamphetamine induced neurochemical changes. Acute administration of the putative D3 receptor antagonists PG-01037 (10, 30 mg/kg, ip) and SB-277011A (12, 24, mg/kg, ip) significantly decreased the break-point for methamphetamine self-administration under a progressive-ratio (PR) schedule by 45 - 70%. Furthermore, both drugs dose dependently attenuated methamphetamine -triggered reinstatement of drug-seeking behavior in the reinstatement model of relapse. As with other drugs of abuse, the rewarding effects of methamphetamine are believed to be mediated by elevated levels of extracellular dopamine in the mesocorticolimbic system. The present study utilized in vivo microdialysis to examine the neurochemical mechanisms modulating the rewarding effects of methamphetamine actions evident in the various animal models of addiction. In the nucleus accumbens and ventral pallidum, acute methamphetamine (1.0 mg/kg, i.p.,) increased extracellular dopamine by 800 - 900% and decreased GABA by 60 – 65 % in the nucleus accumbens and ventral pallidum. Pretreatment with SB-277011A (12, 24 mg/kg) potentiated the methamphetamine induced dopamine increase but attenuated the methamphetamine-induced GABA decrease. Take together these data suggest that D3 selective antagonists’ pharmacotherapeutic potential in the treatment of methamphetamine addiction may involve a GABAergic mechanism.

Le tabagisme est la cause de longues maladies, responsables chaque année de 6 millions de décès. Le principal composant du tabac, la nicotine, est l'un des psychotropes les plus addictifs. L’abandon du tabac est difficile et les pharmacothérapies les plus efficaces, telles que la varénicline, ne viennent en aide qu’à une proportion limitée des 70% de fumeurs qui souhaitent stopper. Des études cliniques et précliniques ont démontré que plusieurs mécanismes psychopharmacologiques différents contribuent au maintien de la prise de nicotine. Des données psychologiques, génétiques et neurobiologiques, issues d’études cliniques, indiquent désormais que le poids respectif de ces mécanismes psychopharmacologiques pourrait varier d’un fumeur à l’autre. Cette hétérogénéité pourrait contribuer à l’inégale efficacité de la varénicline, dont les cibles psychopharmacologiques sont encore mal connues, ainsi qu’à la faible validité prédictive des modèles précliniques, qui ne tiennent pas compte de cette possible hétérogénéité individuelle. Dans ce travail de thèse, au moyen de l’auto-administration intraveineuse de nicotine chez le rat, nous avons exploré les variations individuelles dans la sensibilité aux effets renforçants primaires de la nicotine et aux effets de la nicotine sur la sensibilité aux effets renforçants de stimuli environnementaux associés. Nous avons mis en évidence trois sous-populations d'individus dont la recherche de nicotine est contrôlée par une contribution différente de ces deux types d’effets de la nicotine. Les phénotypes de ces sous-populations ont été validés par des marqueurs comportementaux préexistants à la consommation de nicotine (l’approche conditionnée pavlovienne), par des marqueurs du métabolisme de la nicotine et des marqueurs neurobiologiques des neurotransmissions cholinergique et dopaminergique dans des structures cérébrales clés. En parallèle, nous avons exploré les cibles psychopharmacologiques de la varénicline. En utilisant une nouvelle approche qui permet de manipuler, pendant l’autoadministration, les effets de la nicotine sur les effets renforçants d’un stimulus environnemental associé, nous avons montré que la varénicline antagonise à la fois ces effets de la nicotine et ses effets renforçants primaires. Néanmoins, dans le premier cas, la varénicline agit d’autant plus que la sensibilité individuelle aux effets de la nicotine est élevée, alors que l’intensité de son effet ne dépend pas de l’amplitude des effets renforçants primaires de la nicotine. Ce travail de thèse met en évidence et valide des variations individuelles dans les mécanismes qui régissent le comportement de recherche de nicotine dans un modèle préclinique. Il offre pour perspective d'explorer les mécanismes neurobiologiques responsables de ces variations individuelles et l’impact à long terme de ces variations sur le développement de la dépendance à la nicotine, ainsi que de tester si la varénicline est plus efficace chez l’une des sous-populations identifiées. / Tobacco use leads to 6 million deaths every year due to severe long lasting diseases. The main component of tobacco, nicotine, is recognized as one of the most addictive drugs, making smoking cessation difficult, even when 70% of smokers wish to do so. Critically, even the most effective pharmacotherapies for smoking cessation, such as varenicline, have only limited efficacy. Clinical and preclinical studies have demonstrated consistently that nicotine seeking is a complex behavior involving various psychopharmacological mechanisms. Critically, converging psychological, genetic and neurobiological data from clinical studies support that the mechanisms controlling nicotine seeking may vary from individual to individual. This heterogeneity could explain the unequal efficiency of treatments, notably of varenicline, whose psychopharmacological targets are still poorly understood, and the poor predictive validity of preclinical models, which do not consider possible individual variations in the mechanisms of nicotine seeking. In this PhD work, using intravenous nicotine self-administration in the rat, we have explored individual variations in the control of nicotine seeking, by the primary reinforcing effects of nicotine, nicotine’s impact on environmental cues, or both. We have evidenced three sub-populations of individuals whose nicotine seeking is controlled by distinct contributions of nicotine primary reinforcing effects and nicotine-cue interactions. Their phenotypes of nicotine seeking have been supported and validated by pre-existing behavioral markers of Pavlovian conditioned approach, as well as by markers of nicotine metabolism, and neurobiological markers of cholinergic and dopamine transmissions in key brain structures. In parallel, we have explored psychopharmacological targets of varenicline. Using a novel approach that allows manipulating the reinforcing-enhancing effects of nicotine on cues, during nicotine self-administration, we evidenced that varenicline antagonizes both these cue reinforcing-enhancing effects and the primary reinforcing effect of nicotine, but as a function of the individual response amplitude for the former, and not for the latter. This PhD work evidences and validates preclinical individual variations in the mechanisms of nicotine seeking. It opens the perspective of exploring the neurobiological causal mechanisms for these individual variations, their long term impact on the development of nicotine dependence and whether varenicline efficacy benefits more to the subpopulation mostly driven by nicotine-induced enhancement of cue reinforcing effects.

Thesis advisor: Stephen C. Heinrichs / This study investigated the effects of baclofen, a GABAB agonist, on modulating drug seeking and drug reward in a novel model of reinstatement. To investigate drug seeking, rats were trained to nosepoke for cocaine infusions, given a drug holiday, and under a baclofen pretreatment (0, 0.2, 1, or 5 mg/kg i.p.), were exposed to an odor conditioned discriminative stimulus (DS+) that reinstated cocaine self-administration. To investigate drug reward, an odor reactivity test was used. Rats were tested for changes in odor preference after the acquisition, drug holiday, and reinstatement phases of self-administration behavior were each completed. Pretreatment with the low dose of baclofen (0.2) attenuated cocaine seeking primed by a conditioned DS+. Medium doses (1.0) caused no change in drug seeking. High doses (5.0) caused a reduction in drug seeking, but this was due to motor impairment. No doses of baclofen had any affect on the rewarding properties of cocaine or cocaine-associated stimuli. It can be concluded that GABAB receptors have no role in modulating the rewarding properties of drug rewards or drug-associated stimuli, but instead play a role in modulating drug seeking. In rats that were exposed to a drug in the past, low levels of GABAB receptor activation reduce drug-seeking, while medium to high levels could have reduced dopamine levels to the point that increased drug seeking or motor impairment was seen. / Thesis (BA) — Boston College, 2004. / Submitted to: Boston College. College of Arts and Sciences. / Discipline: Psychology. / Discipline: College Honors Program.

Environmental enrichment, for more than fifty years, has shown to increase learning in behaviors and to alter some brain structures (Renner and Rosenzweig). Some brain changes that occur when environmental enrichment is implemented include the following: increases in cortical thickness, especially the occipital cortex, increases in size of neuronal cell bodies, number of dendrites and dendritic spines, increases in astrocyte branching, increases in the number of brain blood capillaries, and increases in mitochondria (an indication of higher metabolic activity) (Stairs and Bard). It has been shown in research studies that rats in the environmental enrichment group are less sensitive to nicotine effects, both repeated and acute, than rats in isolated situations (Green et al). This is so because enrichment changes the intensity of the acute administration of drugs of abuse. Rats are stimulated by the environment, rather than a particular stimulant.

The increase in heroin use is one factor contributing to the current opioid epidemic in the United States. There are three Food and Drug Administration (FDA) approved medications for the treatment of opioid use disorder (OUD), and these include agonist (i.e. methadone and buprenorphine) and antagonist (i.e. naltrexone) therapies. Although these medications are effective for some patients, regulatory constraints for agonist therapies limit access and patient compliance for naltrexone is poor. The development of new therapies, such as immunopharmacotherapies, for the treatment of OUD is a priority for the National Institute of Drug Abuse. A heroin immunopharmacotherapy, or vaccine, produces heroin selective antibodies that bind to and sequester heroin in the periphery. One formulation of a heroin-tetanus toxoid (TT) conjugate vaccine has shown promise in preclinical studies in mice in monkeys but has not been fully assessed to determine independent variables that might impact vaccine effectiveness such as heroin route of administration, species of animal or abuse-related behavioral endpoints. Chapter II of this dissertation aimed to determine effectiveness and selectivity of the heroin-TT conjugate vaccine to alter the antinociceptive effects of subcutaneous and intravenous heroin in male and female rats. In addition, maximal vaccine effects were compared to effects of a positive control naltrexone. Vaccine effectiveness to reduce heroin antinociception was selective, but effectiveness did not depend on route of administration. Furthermore, maximum effects were less than those seen with a clinically meaningful dose of naltrexone. Combining the vaccine with naltrexone enhanced the effectiveness of naltrexone to block the antinociceptive effects of heroin. Chapter III determined vaccine effectiveness and selectivity to block heroin’s discriminative-stimulus effects in nonhuman primates and compared maximal effects produced by vaccine and naltrexone. The heroin vaccine weakly but selectively reduced the abuse-related subjective-like effects of heroin in one of two monkeys. However, chronic naltrexone treatment nonselectively antagonized the abuse-related effects of both heroin and fentanyl, and naltrexone effects were more robust than those of the vaccine. Chapter IV established a translational procedure to assess candidate medication effects on the reinforcing effectiveness of heroin in a heroin versus food choice procedure in rats. In the procedure, rats choose between a liquid food reinforcer and ascending doses of heroin in a 5-component choice procedure. Heroin versus food choice was found to be sensitive to an environmental manipulation of altering response requirement for both reinforcers. Chronic buprenorphine decreased heroin choice, consistent with its FDA-approved indication for treating OUD. Collectively, these data suggest that the current formulation of the heroin-TT conjugate vaccine may not be as effective as naltrexone at decreasing heroin use. However, one potential indication the vaccine may be useful for is as an adjunctive therapy to clinically available agonist or antagonist medications and a heroin versus food choice procedure in rodents would be one way to full assess this preclinically.

The prefrontal cortex (PFC) is considered a critical node in the neural circuitry underlying drug-seeking behaviors. However, the mechanisms by which this region influences drug seeking and whether or not the lateral PFC mediates cocaine or heroin seeking are questions that have yet to be answered. To expand on the role of the PFC in drug seeking, rats were trained on either heroin or cocaine self-administration for a minimum of 12 days before undergoing extinction training and subsequent reinstatement tests (cued and drug-prime). All pharmacological manipulations were delivered immediately prior to reinstatement testing and were targeted at either the ventral region of the medial PFC, the infralimbic cortex (IL), the anterior portion of the medial PFC, the medial orbitofrontal cortex (mOFC), the anterior region of the insular cortex, the dorsal agranular insular cortex (AId), or the posterior region of the insular cortex, the posterior insular cortex (PIc). In chapter 1, D1 and D2 antagonists were administered into the IL and mOFC prior to cued and cocaine-prime reinstatement. Although previous studies found that the IL inhibits cocaine seeking, blocking D1 receptor activity in this region reduced cued reinstatement and had no effect on cocaine-prime reinstatement, indicating that the IL can promote cocaine seeking under certain circumstances. In contrast, blocking D1 receptors in the mOFC reduced all forms of reinstatement that were examined. Blocking D2 receptors in either region had no effect on cocaine seeking. Our data are the first to demonstrate a role for the mOFC in cocaine seeking and suggest that although the IL and mOFC lie immediately adjacent to one another, they play distinct roles in mediating cocaine seeking. In chapter 2, we pharmacologically inactivated the AId and PIc via a GABA agonist administered immediately prior to both cocaine and food seeking. Reversible inactivation of the AId reduced cued reinstatement but had no effect on cocaine-prime reinstatement. In contrast, inactivating the PIc had no effect on any form of cocaine seeking. Additionally, blocking the AId during cued and food-prime reinstatement had no effect on food seeking, indicating the role of the AId in reinstatement is specific to cocaine seeking and not general motivated behavior. Additionally, blocking CRF1 receptors in the AId blocked cued reinstatement, suggesting a possible mechanism whereby the AId is influencing cocaine seeking. These data are the first to establish a role for the AId in cocaine seeking and demonstrate that although the PIc influences alcohol and nicotine seeking, it does not mediate cocaine seeking. Chapter 3 further examined the role of the AId in cocaine seeking and expanded the influence of the insular cortex in drug seeking to heroin. AId D1 receptor blockade reduced both cued and cocaine-prime reinstatement following extinction training, whereas D2 receptor blockade had no effect on cocaine seeking. These results establish a role for the AId in cocaine-prime reinstatement, as pharmacological inactivation showed no role for the AId in cocaine-induced drug seeking. Additionally, blocking the AId during heroin seeking potentiated cued reinstatement whereas blocking the PIc during heroin seeking reduced cued reinstatement. These results demonstrate a role for the insular cortex in heroin seeking that has never been shown before and further explain how the AId may be influencing cocaine seeking.

Drug self-administration has proven to be an adequate model for assessing variables that contribute to the maintenance of drug taking. The present experiment was concerned with the persistence of drug self-administration, a defining characteristic of drug dependence and abuse. Findings from studies of the resistance to change of food-maintained responding may contribute to a better understanding of the persistence of drug abuse and dependence. Using an animal model of alcohol self-administration, this study evaluated the effects of rate of reinforcement on the persistence of ethanol self-administration in rats in the face of behavioral (i.e., extinction) and pharmacological (i.e., naltrexone) disruptors. Four experimentally naive Long Evans rats were trained to respond for a 10% (vol/vol) ethanol solution on a multiple variable-interval (VI) 15-s VI 45-s schedule of reinforcement. Baseline response rates were higher in the component that provided higher rates of ethanol delivery. Consistent with behavioral momentum theory, responding was more resistant to extinction in the component with higher rates of ethanol delivery. Conversely, disruption with naltrexone (1.0, 3.0, 10.0 mg/kg, s.c.), injected one hour before the session, resulted in no differential resistance to change of responding. The results are interpreted in terms of the effect of naltrexone on the incentive-motivational properties of the stimulus context.