Thesis (Ph. D.)--Virginia Commonwealth University, 2005. / Prepared for: Dept. of Pharmacology and Toxicology. Bibliography: leaves 142-153.

O procedimento de omissão do reforço, em esquemas de reforçamento em intervalo-fixo, produz uma redução na pausa pós-reforço e, consequentemente, um aumento na frequência de respostas no próximo intervalo. Existem diferentes interpretações relacionadas ao efeito de omissão do reforço (EOR), baseadas em componentes atencionais / motivacionais. Estudos preliminares têm examinado o papel da ativação de alguns núcleos da amígdala na modulação destes componentes. Estudos recentes sugerem que as subestruturas da amígdala podem estar envolvidas em diferentes processos, e as conexões entre diferentes núcleos da amígdala e estruturas corticais / subcorticais também parecem estar envolvidas em processos relacionados a recompensas e expectativa. Outros estudos sugerem que a interação entre a amígdala e nucleus accumbens (NAC) é importante para a modulação de processos motivacionais. No entanto, não há estudos na literatura avaliando se lesões neurotóxicas em diferentes regiões corticais e subcorticais podem interferir nos EORs. Este estudo teve como objetivo analisar os EORs sobre o repertório comportamental em ratos com lesões do NAC, em procedimentos de condicionamento clássico e reforçamento não-contingente. Trinta ratos Wistar machos, divididos nos grupos accumbens e controle sham, foram submetidos a 28 sessões de treinamento com 8 práticas cada uma: 20 sessões pré-lesão, duas sessões de retreino e seis sessões pós-lesão (com omissão de reforço). Cada prática constituía de um sinal de 20 segundos (tom), seguindo-se a libertação de uma gota de água no 19º segundo. Em sessões com omissão, a água foi liberada em metade das práticas. Foram analisadas dez categorias comportamentais. A comparação entre taxas de duração durante as práticas de liberação e omissão do reforço mostrou que os grupos accumbens e controle sham apresentaram EORs. O grupo accumbens foi menos sensível aos EORs. Em relação às categorias comportamentais Farejar o bebedouro e Farejar a região do bebedouro, as taxas de duração do grupo controle sham durante a omissão foram maiores em relação às taxas do grupo accumbens. Já para as categorias Lamber o bebedouro, Farejar distante do bebedouro, Levantar, Locomoção e Limpeza, as taxas de duração do grupo controle sham foram menores do que o grupo accumbens. Os resultados sugerem que o NAC pode fazer parte da circuitaria envolvida na modulação dos EORs e também indicam a necessidade de se considerar o envolvimento de uma rede neural mais complexa para avaliação dos EORs. / The reinforcement omission procedure, in fixed-interval schedules of reinforcement, produces a reduction in post-reinforcement pause and, consequently, an increase in frequency responses in the next interval. There are different interpretations related to reinforcement omission effect (ROE), based upon motivational and / or attentional components. Preliminary studies have examined the role of activation of some amygdala nuclei to modulate these components. Recent studies suggest that the substructures of the amygdala may be involved in different processes, and connections between different amygdala nuclei and cortical/subcortical structures seem to be involved in processes related to rewards and expectancy. Other studies suggest that the interaction between the amygdala and nucleus accumbens (NAC) is important for the modulation of motivational processes. However, there are no studies in the literature assessing whether neurotoxic lesions in different cortical and subcortical regions may interfere in ROEs. This study aimed to examine the ROEs on the behavioral repertoire of rats with lesions of the NAC, in classical conditioning procedures and non-contingent reinforcement. Thirty male Wistar rats, divided in NAC and SHAM groups, were submitted to 28 training sessions with 8 practices each one: 20 pre-lesion, two retraining sessions and six post-lesions sessions with omission of reinforcement. Each practice constituted of a 20 seconds signal (tone), followed by the release of a drop of water in the 19th second. In sessions with omission, the water was released in the half of practices. Ten categories of behaviors were analyzed. Comparison between duration rates during omission and reinforcement practices showed that NAC and SHAM groups showed the ROEs. NAC group was less sensitive to the ROEs. Regarding the behavioral categories Magazine sniffing and Near magazine sniffing, the duration rates of SHAM group during omission were higher in relation to rates of NAC group. For the categories Magazine licking, Far from magazine sniffing, Rearing, Locomotion and Grooming duration rates of SHAM group were lower than the NAC group. The results suggest that NAC can be part of circuitry involved in the modulation of ROEs and indicate the need to consider the involvement of more complex neural network for evaluating the ROEs.

abstract: Patients with schizophrenia have deficits in sensorimotor gating, the ability to gate out irrelevant stimuli in order to attend to relevant stimuli. Prepulse inhibition (PPI) of the startle response is a reliable and valid model of sensorimotor gating across species. Repeated D2-like agonist treatment alleviates prior PPI deficits in rats, termed a PPI recovery, and is observable 28 days after treatment. The aim of the current project is to illuminate the underlying mechanism for this persistent change of behavior and determine the clinical relevance of repeated D2-like agonist treatment. Our results revealed a significant increase in Delta FosB, a transcription factor, in the nucleus accumbens (NAc) 10 days after repeated D2-like agonist treatment. Additionally, we investigated if Delta FosB was necessary for long-lasting PPI recovery and discovered a bilateral infusion of dominant-negative Delta JunD prevented PPI recovery after repeated D2-like agonist treatment. To further develop the underlying mechanism of PPI recovery, we observed that dominant negative mutant cyclic adenosine monophosphate (cAMP) response biding element protein (CREB) prevented repeated D2-like agonist-induced Delta FosB expression in the NAc. We then compared our previous behavioral and intracellular findings to the results of repeated aripiprazole, a novel D2-like partial agonist antipsychotic, to determine if repeated D2-like receptor agonist action is a clinically relevant pharmacological approach. As compared to previous PPI recovery and Delta FosB expression after repeated D2-like agonist treatment, we found similar PPI recovery and Delta FosB expression after repeated aripiprazole treatment in rats. We can conclude that repeated D2-like agonist treatment produces persistent PPI recovery through CREB phosphorylation and Delta FosB, which is necessary for PPI recovery. Furthermore, this pharmacological approach produces behavioral and intracellular changes similar to an effective novel antipsychotic. These findings suggest the underlying intracellular mechanism for sustained PPI recovery is clinically relevant and may be a potential target of therapeutic intervention to alleviate sensorimotor gating deficits, which are associated with cognitive symptoms of schizophrenia. / Dissertation/Thesis / Ph.D. Psychology 2013

Orientador: Carlos Amilcar Parada / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-23T21:05:03Z (GMT). No. of bitstreams: 1 Dias_ElayneVieira_D.pdf: 15528641 bytes, checksum: d53f9d8a514c6239af90a41cfe787afb (MD5) Previous issue date: 2013 / Resumo: O resumo poderá ser visualizado no texto completo da tese digital / Abstract: The complete abstract is available with the full electronic document / Doutorado / Fisiologia / Doutora em Biologia Funcional e Molecular

O núcleo acumbens (Acb) é envolvido em comportamentos adaptativos e emocionais. A maioria dos neurônios do Acb são neurônios de projeção (MSNs) que contém a fosfoproteína DARPP-32 e são modulados por distintos tipos de interneurônios. Há pouca informação sobre os receptores de glutamato (Glu) expressos no Acb. Este estudo investiga, através de técnicas de imunohistoquímica, a distribuição e co-localização de marcadores do sistema dopaminérgico, dos receptores de Glu do tipo AMPA (GluR1-GluR4) e NMDAR1 e marcadores de interneurônios. Nossos resultados mostram que o Acb possui uma neuroquímica semelhante ao estriado dorsal. Porém, detectamos uma distribuição distinta de alguns dos marcadores no Acb. Os estudos de co-localização revelam que quase todos os neurônios no Acb expressam GluR2/3 ou GluR2. Em contraste, GluR1 e GluR4 são fracamente expressas e co-localizam com parvalbumina. Esses resultados indicam que GluR2 e GluR2/3 são expressas em MSNs DARPP-32+ e na maioria dos interneurônios do Acb enquanto GluR1 e GluR4 são exclusivamente expressas em interneurônios. / The nucleus accumbens is involved in adaptive and emotional behaviors. The majority of neurons in the Acb are projection neurons that express the phosphoprotein DARPP-32 and are modulated by distinct types of interneurons. There is little information about the glutamate receptors expressed in the Acb. This study investigates by immunohistochemical methods the distribution and co-localization of markers of the dopaminergic system, AMPA (GluR1-4) and NMDAR1 type Glu receptor subunits and specific markers of interneurons. Our results show that the neurochemistry of the Acb is similar to that of the dorsal striatum. However, we detected a distinct distribution of some markers in the Acb. Our co-localization studies reveal that almost all neurons of the Acb express GluR2/3 or GluR2. In contrast, GluR1 and GluR4 are weakly expressed and are co-localized with parvalbumin. These results indicate that GluR2 and GluR2/3 are expressed by MSNs DARPP-32+ and by the majority of interneurons of the Acb, whereas GluR1 and GluR4 are exclusively expressed by interneurons.

Various small molecules act as neurotransmitters and orchestrate neural communication. Growing evidence suggests that not only classical neurotransmitters but also several small molecules, including amino acid derivatives, modulate synaptic transmission. As conditions of acute and chronic pain alter neuronal excitability in the nucleus accumbens, we hypothesized that small molecules released in the nucleus accumbens might play important roles in modulating the pain sensation. However, it is not easy to identify possible pain modulators owing to the absence of a method for comprehensively measuring extracellular small molecules in the brain. In this study, through the use of an emerging metabolomics technique, namely ion chromatography coupled with high-resolution mass spectrometry, we simultaneously analyzed the dynamics of more than 60 small molecules in brain fluids collected by microdialysis, under both the application of pain stimuli and the administration of analgesics. We identified N-acetylaspartylglutamate as a potential pain modulator that is endogenously released in the nucleus accumbens. Infusion of N-acetylaspartylglutamate into the nucleus accumbens significantly attenuated the pain induced by the activation of sensory nerves through optical stimulation. These findings suggest that N-acetylaspartylglutamate released in the nucleus accumbens could modulate pain sensation.

The action of postponing an intended plan is often referred to as procrastination. Research on procrastination generally views the phenomenon as a form of self-regulation failure. Self-regulation refers to the conscious and non-conscious processes that enable individuals to guide their thoughts, feelings, and behaviors purposefully. Research indicates correlations between self-regulation and executive functions providing a fruitful integration. From a neuroscientific perspective, this integration generally associates the prefrontal cortex with top-down control whenever successful self-regulation is achieved. On the contrary, self-regulation failure appears to involve a bottom-up control, in which subcortical regions have greater influence on behavioral outcomes. Subcortical regions involved in emotional and rewarding processes, such as the amygdala and nucleus accumbens appears to lie at the coreof self-regulation failure, whereas cortical executive functions of regulating emotion and impulsive behaviors may contribute to successful self-regulation, thus overcoming procrastination. This thesis aims to obtain a deeper understanding of the mechanisms of procrastination, specifically investigating self-regulation failure and its relationship with executive functions and the neural underpinnings of self-regulation.

This study investigated the effects of repeated administrations of nicotine (0.7 mg/kg) on dendritic morphology in the nucleus accumbens (NAcc), prefrontal cortex (Cg 3), and parietal cortex (Par 1). Animals were habituated for 3 days to a locomotor box, and after habituation, every second day for 5 weeks rats were placed into the locomotor chamber immediately after a subcutaneous injection of nicotine or saline. Rats demonstrated tolerance to an initial hypoactive response after each nicotine injection, and this was followed by an increase in activity after each injection (behavioral sensitization). This increase in activity was still present on a nicotine challenge after a 2-week abstinence period. One week after the nicotine challenge day, all rats were perfused and brains were removed. These brains we stained using Golgi-Cox procedures, and dendrites from the nucleus accumbens (N Acc), medial frontal cortex (Cg 3) and parietal cortex (Par 1) were analyzed using the camera lucida procedure. Results showed that rats receiving nicotine demonstrated an increase in dendritic length and spine density relative to controls in the NAcc and Cg3 brain areas, but not Par 1. The increase observed in the NAcc was significantly greater than what has been found with amphetamine or cocaine, and possible underlying mechanisms were discussed.

Opioid receptors have been a target of pharmacological manipulation in alcohol use disorder (AUD) recovery protocols for many years. Aerobic exercise, a common adjunct in AUD recovery, is known to modulate opioid receptors (ORs) both during both acute and long term exposure. The three subtypes of ORs: mu (MOR), delta (DOR), and kappa (KOR) are all expressed on neurons in the mesocorticolimbic circuitry. Kappa-opioid receptors are expressed directly on dopamine (DA) neuron terminals in the nucleus accumbens (NAc). Mu and Delta ORs are expressed on cholinergic interneurons (CINs) and GABA neurons in the NAc. In alcohol dependent rodents, KORs are hypersensitized. It is theorized that this hypersensitization contributes to EtOH seeking behavior. In contrast, aerobic exercise desensitizes the KORs. Given the high degree of pharmacological overlap between opioid receptors, it is also hypothesized that EtOH and aerobic exercise may have effects on MORs and DORs as well. Here, it is investigated whether a routine of voluntary aerobic exercise decreases EtOH induced changes to KOR modulation of dopamine (DA) release in the nucleus accumbens (NAc) along with possible mechanisms through which this might occur. The responsiveness of MORs and DORs in EtOH dependence, and how aerobic exercise modulates those effects is also investigated. Exercise attenuated EtOH induced hypersensitization of KORs in the NAc. Exercise decreases expression of KORs, which may account for the changes in KOR sensitization. The MOR agonist DAMGO decreased DA reuptake ex vivo, but not signal amplitude while DOR agonist DPDPE had no effect on either reuptake or signal amplitude. Overall, dependent animals that were allowed to exercise, consumed less EtOH in a drinking in the dark model. These data suggest that exercise is a useful adjunct to AUD recovery protocols, and that its effects are likely mediated by KORs. The findings related to MORs and DORs suggest that MORs, but not DORs, may act through acetyl choline receptors to modulate DA reuptake in the NAc, however much more work is needed to characterize this effect.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20075号 / 医博第4168号 / 新制||医||1018(附属図書館) / 33191 / 京都大学大学院医学研究科医学専攻 / (主査)教授 渡邉 大, 教授 林 康紀, 教授 瀬原 淳子 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DGAM