Indiana University-Purdue University Indianapolis (IUPUI) / Alcohol use disorder (AUD) and nicotine dependence often result in serious health problems and are top contributors to preventable deaths worldwide. Co-addiction to alcohol and nicotine is the most common form of polysubstance abuse. Epidemiological studies indicate that more than 80% of individuals diagnosed with AUD concurrently use nicotine. The prevalence of alcohol and nicotine comorbidity may stem from interconnected mechanisms underlying these disorders. A better understanding of how these drugs interact and the biological basis behind the high comorbidity rates could generate key targets for the development of more effective treatments for AUD and nicotine dependence. The following experiments utilized four similar overall groups consisting of vehicle, ethanol (EtOH), nicotine (NIC), and EtOH+NIC. Chapter Two investigated the efficacy of naltrexone and varenicline, the pharmacological ‘gold standards’ for treating AUD and nicotine dependence, on voluntary drug intake by rats selectively bred for high EtOH drinking. The results indicated that the standard treatments for AUD and nicotine dependence were effective at reducing consumption of the targeted reinforcer but neither reduced EtOH+NIC co-use/abuse. Chapter Three examined the effects of peri-adolescent EtOH drinking on the ability of NIC infused into the posterior ventral tegmental area (pVTA) to stimulate dopamine release within the nucleus accumbens (NAc) shell during adulthood. The results suggest a cross-sensitization to NIC produced by peri-adolescent EtOH consumption demonstrated by a leftward and upward shift in the dose response curve. Chapter Four investigated the effects of intra-pVTA infusions on NAc shell neurochemistry, EtOH reward within the NAc shell, and the role of brain-derived neurotrophic factor (BDNF) on EtOH reward within that region. The data indicated that only EtOH+NIC significantly increased glutamate, dopamine, and BDNF in the NAc shell. Repeated pretreatment with EtOH+NIC also enhanced EtOH reward in the NAc shell and BDNF infusions were sufficient to recapitulate these findings. Collectively, the data indicate that concurrent exposure to EtOH and NIC results in unique neuroadaptations that promote future drug use. The failure to develop effective pharmacotherapeutics for AUD or nicotine dependence could be associated with examining potential targets in models that fail to reflect the impact of polydrug exposure. / 2020-04-03

Female sheep exposed to excess testosterone (T) in utero display symptoms similar to those observed in women with polycystic ovarian syndrome (PCOS). Prenatal T-treated ewes display masculinized sexual behavior and increased food-reward seeking behavior. A neural substrate critical for these goal-directed behaviors is the dopaminergic system in the ventral tegmental area. We have recently shown that in adult ewes dopamine expression in the VTA is increased by prenatal T exposure. In this thesis, I tested the hypothesis that alterations of the VTA dopamine system by prenatal-T are caused via activation of androgen (AR) and/or insulin receptors (IR). Analysis of immunohistochemical staining shows an increase of tyrosine hydroxylase (TH) expression, AR, or IR, along with changes in co-expression of AR/TH and IR/TH. These changes were blocked or reversed by prenatal treatments with flutamide or rosiglitazone, or postnatal treatments with rosiglitazone or metformin, implicating AR and IR in alterations of the VTA

Projection neurons of nucleus accumbens (NAC) of the rat were identified by either antidromic activation from stimulation of midbrain ventral tegmental area-substantia nigra (VTA-SN) regions, or by tracing axons of intracellularly labeled NAC neurons into the ventral pallidum. The morphology of these NAC projection neurons were determined to be medium spiny neurons similar to those identified in the caudate-putamen.

Animals with one of septal, medial thalamic or tegmental reticular formation lesions were compared on three measures of spontaneous activity (a brief test in a novel maze and seven-day tests in running wheels or photocells cages) and on active avoidance learning. Wheel running was depressed by all the lesions (especially septal and tegmental lesions) while locomotion in the maze and photocell cages was unaffected. Avoidance learning was depressed by septal and thalamic lesions but not by tegmental lesions. These results are discussed in terms of the hypothesis that these brain structures form part of systems which facilitate or inhibit somatomotor activity. / Thesis / Master of Arts (MA)

Thesis advisor: Michael A. McDannald / The ability to appropriately respond to threats is critical for survival. Disruptions in the neural circuits underlying threat responding are studied in animal models and have clinical implications for anxiety disorders in humans. Pavlovian fear conditioning has been extensively used to study the behavioral and neural basis of defensive systems for threat in animals. In a typical procedure, a cue is paired with foot shock, and subsequent cue presentation elicits freezing, a behavior linked to predator detection. Studies have since shown a fear conditioned cue can elicit locomotion, a behavior that - in addition to jumping, and rearing - is linked to imminent or occurring predation. Yet, the full neural circuit for conditioned, activity-promoting behaviors (e.g. locomotion, jumping, and rearing) remains unclear. The overarching goal of this dissertation is to demonstrate that a fear conditioned cue elicits a variety of defensive behaviors and to probe the neural circuit responsible for the expression of such activity-promoting defensive behaviors. To address the lack of research on activity-promoting defensive behaviors, I conducted experiments to observe multiple behaviors during fear discrimination over a baseline of reward seeking and constructed temporal ethograms of behavior. To improve efficiency in behavior scoring for future projects, I devised and trained a machine learning pipeline using convolutional neural networks. To aid in the understanding of the full neural circuit for activity-promoting defensive behaviors, I investigated the role of dopaminergic neurons of the ventral tegmental area in the expression of the defensive behaviors we observed during fear discrimination. Ultimately, the findings in this dissertation contribute to our general understanding of fear behavior in animals and may inform therapeutic strategies for anxiety disorders. / Thesis (PhD) — Boston College, 2024. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Psychology and Neuroscience.

Thesis advisor: Michael A. McDannald / The ability to appropriately respond to threats is critical for survival. Disruptions in the neural circuits underlying threat responding are studied in animal models and have clinical implications for anxiety disorders in humans. Pavlovian fear conditioning has been extensively used to study the behavioral and neural basis of defensive systems for threat in animals. In a typical procedure, a cue is paired with foot shock, and subsequent cue presentation elicits freezing, a behavior linked to predator detection. Studies have since shown a fear conditioned cue can elicit locomotion, a behavior that - in addition to jumping, and rearing - is linked to imminent or occurring predation. Yet, the full neural circuit for conditioned, activity-promoting behaviors (e.g. locomotion, jumping, and rearing) remains unclear. The overarching goal of this dissertation is to demonstrate that a fear conditioned cue elicits a variety of defensive behaviors and to probe the neural circuit responsible for the expression of such activity-promoting defensive behaviors. To address the lack of research on activity-promoting defensive behaviors, I conducted experiments to observe multiple behaviors during fear discrimination over a baseline of reward seeking and constructed temporal ethograms of behavior. To improve efficiency in behavior scoring for future projects, I devised and trained a machine learning pipeline using convolutional neural networks. To aid in the understanding of the full neural circuit for activity-promoting defensive behaviors, I investigated the role of dopaminergic neurons of the ventral tegmental area in the expression of the defensive behaviors we observed during fear discrimination. Ultimately, the findings in this dissertation contribute to our general understanding of fear behavior in animals and may inform therapeutic strategies for anxiety disorders. / Thesis (PhD) — Boston College, 2024. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Psychology and Neuroscience.

A área tegmental ventral (VTA) contém neurônios dopaminérgicos do grupamento A10 e envia projeções muito densas para o estriado ventral. Esta circuitaria está crucialmente envolvida em mecanismos de recompensa. Recentemente, a organização destas projeções foi reexaminada por Ikemoto S. (Brain Res. Rev., 56:27-78, 2007), em um estudo de rastreamento retrógrado minucioso, sendo proposto a subdivisão destas projeções em um sistema dopaminérgico mesoestriatal ventromedial que inerva a concha medial do accumbens e o tubérculo olfatório medial, e um sistema dopaminérgico mesoestriatal ventrolateral que inerva o cerne e a concha lateral do accumbens e o tubéculo olfatório lateral. Afim de complementar o conhecimento destas projeções, no presente estudo elas foram examinadas com a técnica anterógrada da leucoaglutinina do Phaseolus vulgaris. Nossos resultados indicam que há um extenso embricamento dos campos terminais estriatais inervados por diferentes setores/núcleos da VTA e reforçam a noção de que as eferências da VTA podem ser subdivididas em um sistema mesoestriatal ventromedial e um sistema mesoestriatal ventrolateral. Eles revelam ainda que as projeções da VTA para o estriado ventral têm uma organização topográfica médio-lateral mais complexa do que previamente reconhecido, a faixa médio-lateral do estriado ventral inervada depende de uma combinação da região médio-lateral e dorsoventral da VTA. Assim, as regiões mais ventrais e mediais da VTA (correspondendo ao núcleo interfascicular) inervam os distritos mais mediais do estriado ventral (a concha dorsomedial do accumbens e a extremidade medial do tubérculo olfatório), e as regiões mais dorsais e laterais da VTA (correspondendo à região dorsolateral do núcleo parabraquial pigmentoso) se projetam para os distritos mais laterais do estriado ventral (o cerne lateral e a concha lateral do accumbens, o caudado-putâmen ventral e o tubérculo olfatório lateral). Por outro lado, as projeções da VTA para o estriado ventral não possuem uma organização topográfica rostrocaudal. Outro fato a ser destacado é que a organização das projeções mesoestriatais da VTA lembra o padrão das projeções córticoestriatais, sendo observado no estriado, além de um campo terminal principal, pequenos focos isolados de marcação. / The ventral tegmental area (VTA) contains dopaminergic neurons of the A10 group and sends dense projections to the ventral striatum. This circuitry is critically involved in reward mechanisms. Recently, the organization of these projections was reexamined by Ikemoto S. (Brain Res. Rev., 56:27-78, 2007) in a detailed retrograde tracing study, being proposed that these projections can be subdivided into two main systems, a ventromedial mesostriatal dopaminergic system that innervates the medial shell of the accumbens and medial olfactory tubercle, and a ventrolateral mesostriatal dopaminergic system that targets the core and lateral shell of the accumbens and lateral olfactory tubercle. In order to complement these data, in the present study the VTA mesostriatal projections were examined with a sensitive anterograde tracing technique using the Phaseolus vulgaris leucoaglutinin. Our results indicate that there is an extensive overlap of terminal fields innervated by different sectors / nuclei of the VTA and reinforce the notion that VTA efferents can be subdivided into a ventromedial and a ventrolateral mesostriatal system. They also show that the VTA projections to the ventral striatum have a mediolateral topographical organization more complex than previously acknowledged. In fact, projections along the mediolateral dimension of the ventral striatum depends on a combination of the mediolateral and dorsoventral axis of the VTA. In other words, the most ventral and medial parts of the VTA (corresponding to the interfascicular nucleus) innervates the most medial districts of the ventral striatum (corresponding to the dorsomedial shell of the accumbens and medial tip of the olfactory tubercle), and the most dorsal and lateral parts of the VTA (corresponding to the dorsolateral region of the parabrachial pigmented nucleus) project to the most lateral districts of the ventral striatum (lateral core and lateral shell of the accumbens, ventral caudate-putamen and lateral olfactory tubercle). Moreover, VTA projections to the ventral striatum do not seem to have a rostrocaudal topographical organization. It is also of note that the organization of the VTA mesostriatal projections shares features with cortico-striatal projections, in the sense that both fiber systems have a main terminal field and also give rise to small, scattered isolated foci of terminal labeling.

Orientadora: Profa. Dra. Marcela Bermudez Echeverry / Dissertação (mestrado) - Universidade Federal do ABC, Programa de Pós-Graduação em Neurociência e Cognição, 2016. / A Doença de Parkinson (DP) é caracterizada por uma degeneração progressiva dos neurônios dopaminérgicos na substância negra e pela presença de 4 sinais cardinais, bradicinesia, rigidez muscular, tremor em repouso e instabilidade postural. Sua etiologia ainda é desconhecida, no entanto, o aumento do estresse oxidativo é uma das hipóteses a ser analisada. Existe um interesse cada vez maior em compreender o papel funcional e comportamental do estriado dorsolateral (CPU-DL), principalmente sobre o controle do equilíbrio postural. Dessa forma, o presente projeto se propôs a avaliar o efeito de diferentes toxinas, 6-hidroxidopamina (6-OHDA), L-butionina-sulfoximina (BSO) e a rotenona, sobre o CPU-DL e a resposta compensatória do sistema nitrérgico de forma tempo dependente. Foram utilizados ratos Wistar adultos, todos os procedimentos foram aprovados pelo CEUA-UFABC (Protocolo 035/2014). O Estudo 1 foi separado em 2 fases, no experimento 1.1 os animais foram divididos em 3 grupos, os quais receberam microinjeções no CPU-DL direito de 6- OHDA, BSO ou salina, sendo avaliados comportamentalmente 5 dias após a cirurgia e sacrificados no 6º dia. No experimento 1.2 os animais foram divididos em 3 grupos, os quais foram submetidos a uma dupla lesão, recebendo 6-OHDA no CPUDL + salina no PPTg, 6- OHDA no CPU-DL + BSO no PPTg ou salina no CPU-DL + salina no PPTg. Os animais do experimento 1.2 foram avaliados entre os 15º e 44º dias pós cirúrgico, sendo eutanasiados no 45º. No segundo estudo desenvolvido, os animais foram divididos em 5 grupos, os quais receberam 2 microinjeções no CPU-DL direito de rotenona (3mM, 5mM ou 9mM), DMSO (25% - veículo) ou salina, sendo avaliados entre os dias 15º e 44º pós cirúrgicos e sacrificados no 45º dia. Foram utilizados na avaliação comportamental os testes: comportamento rotatório induzido por apomorfina e anfetamina, teste de suspensão na grade, teste da cauda suspensa, teste do cilindro, equilíbrio vertical e labirinto em cruz elevado. Vinte e quatro horas após as análises comportamentais os animais foram sacrificados e procedimentos para analise imunohistoquímica foram realizados. No experimento 1.1 não se detectou alteração comportamental significativa, entretanto, no experimento 1.2 observou-se uma redução na performance dos grupos tratados em relação ao controle salina. Nossos resultados sugerem que tanto a 6-OHDA como o BSO, quando aplicados no CPU-DL, diminuem a expressão de TH+ na região CPU-DL e CPU-dorsomedial (CPU-DM), com aumento da expressão para a proteína nNOS no CPU-DL, sendo que o grupo 6-OHDA também mostrou aumento no CPUDM e núcleo accumbens. Por outro lado, um aumento escasso na expressão da proteína nitrotirosina foi observado no grupo BSO, no CPU-DM e CPU-ventrolateral (CPU-VL). A avaliação com maior intervalo de tempo realizada com as mesmas toxinas, indicou um possível papel neuroprotetor da injeção de BSO no PPTg contra o efeito neurotóxico da 17 injeção de 6- OHDA na CPU-DL. O segundo estudo desenvolvido corrobora uma potencial qualidade preditiva da microinjeção estriatal de rotenona como modelo de hemiparkinsonismo, pois foi capaz de mimetizar sintomas motores relacionados ao equilíbrio postural (rotarod, grade e equilíbrio vertical) e imunohistoquímicos, com aumento da expressão de nNOS e diminuição da expressão da TH+ de forma dose dependente no CPU e na substância negra. Nossos resultados sugerem que determinadas neurotoxinas, embora pouco exploradas, quando administradas via intra-estriatal, revelaram-se potencialmente efetivas para a indução de alterações no equilíbrio postural em modelos experimentais; corroborando portanto, uma possível interação do sistema dopaminérgico nigro-estriatal atrelado a um desbalanço do sistema nitrérgico, responsável pelo estresse oxidativo/nitrosativo relacionado aos processos neurodegenerativos. Neste sentido novos estudos devem ser conduzidos para uma melhor compreensão e elucidação da etiopatogenia da DP, além de novas perspectivas para futuras estratégias terapêuticas. / Parkinson's disease (PD) is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra and the presence of four cardinal signs, bradykinesia, muscular rigidity, resting tremor, and postural instability. Its etiology is still unknown, however, increased oxidative stress is one of the hypotheses to be analyzed. There is a growing interest in understanding the functional and behavioral role of the dorsolateral striatum (CPU-DL), mainly on the control of postural balance. Thus, this project aimed to evaluate the effect of different toxins, 6-hydroxydopamine (6-OHDA), L-buthionine sulfoximine (BSO) and rotenone on the CPU-DL and the compensatory response nitrergic system time dependent manner. Adult Wistar rats were used, all procedures were approved by CEUA-UFABC (Protocol 035/2014). The first study was separated into two phases in the experiment 1.1 the animals were divided into 3 groups, which were microinjected on the CPU-DL right of 6- OHDA, BSO or saline, being evaluated behaviorally 5 days after surgery and sacrificed on the 6th day. In the 1.2 experiment the animals were divided into 3 groups, which were subjected to a double lesion, receiving 6-OHDA in CPUDL + saline in PPTg, 6-OHDA-CPU-DL + BSO - PPTg or saline + saline. The animals of the experiment 1.2 were evaluated between 15 and 44 days after surgery, being euthanized after 45 days. In the second study developed the animals were divided into 5 groups, which were microinjected the CPU-DL right to rotenone (3 mM, 5 mM or 9mm), DMSO (25% - vehicle) or saline, were evaluated between days 15 and 44 post surgical and sacrificed on the 45th day. Were used for behavioral evaluation tests: rotational behavior induced by apomorphine and amphetamine, the grid test, elevated body swing test, drum test, vertical maze and balance in high cross. Twenty-four hours after the behavioral tests the animals were sacrificed and immunohistochemical analysis procedures were performed. For first study, was not detected behavioral change in the 1.1 experiment, however in the 1.2 experiment, there was a reduced performance of the treated groups compared to saline control on the rotarod test. Nevertheless, our results suggest that both 6- OHDA as BSO, when applied to the CPU-DL decrease TH + expression on the CPU-DL and CPU-DM area with increased expression of nNOS protein in the CPU-DL , and the 6-OHDA group also showed an increase in CPU-DM and nucleus accumbens. Still, a scarce increase in the expression of nitrotyrosine protein was observed in the CPU DM and VL on BSO group. The results of 1.2 suggests a possible neuroprotective role of BSO injection in PPTg after neurotoxic effect of 6-OHDA injection the CPU-DL. To the second study, our findings suggest a potential predictive quality of rotenone striatal microinjection as hemiparkinsonismo model because it was able to mimic motor symptoms related to postural balance (rotarod, grid and vertical balance) and immunohistochemical, an increase of nNOS expression and decreased expression of TH+ dose dependent manner in the CPU and the substantia nigra. Our results suggest that neurotoxins, though little exploited when administered intra-striatal pathway, have proved to be potentially effective for inducing changes in the postural balance in experimental models; corroborating therefore a possible interaction of the nigrostriatal dopaminergic system linked to an imbalance nitrergic system, responsible for the oxidative stress/nitrosative related to neurodegeneration. In this sense new studies should be conducted to better understand and elucidate the pathogenesis of PD, as well as new perspectives for future therapeutic strategies.

A área tegmental ventral (VTA) contém neurônios dopaminérgicos do grupamento A10 e envia projeções muito densas para o estriado ventral. Esta circuitaria está crucialmente envolvida em mecanismos de recompensa. Recentemente, a organização destas projeções foi reexaminada por Ikemoto S. (Brain Res. Rev., 56:27-78, 2007), em um estudo de rastreamento retrógrado minucioso, sendo proposto a subdivisão destas projeções em um sistema dopaminérgico mesoestriatal ventromedial que inerva a concha medial do accumbens e o tubérculo olfatório medial, e um sistema dopaminérgico mesoestriatal ventrolateral que inerva o cerne e a concha lateral do accumbens e o tubéculo olfatório lateral. Afim de complementar o conhecimento destas projeções, no presente estudo elas foram examinadas com a técnica anterógrada da leucoaglutinina do Phaseolus vulgaris. Nossos resultados indicam que há um extenso embricamento dos campos terminais estriatais inervados por diferentes setores/núcleos da VTA e reforçam a noção de que as eferências da VTA podem ser subdivididas em um sistema mesoestriatal ventromedial e um sistema mesoestriatal ventrolateral. Eles revelam ainda que as projeções da VTA para o estriado ventral têm uma organização topográfica médio-lateral mais complexa do que previamente reconhecido, a faixa médio-lateral do estriado ventral inervada depende de uma combinação da região médio-lateral e dorsoventral da VTA. Assim, as regiões mais ventrais e mediais da VTA (correspondendo ao núcleo interfascicular) inervam os distritos mais mediais do estriado ventral (a concha dorsomedial do accumbens e a extremidade medial do tubérculo olfatório), e as regiões mais dorsais e laterais da VTA (correspondendo à região dorsolateral do núcleo parabraquial pigmentoso) se projetam para os distritos mais laterais do estriado ventral (o cerne lateral e a concha lateral do accumbens, o caudado-putâmen ventral e o tubérculo olfatório lateral). Por outro lado, as projeções da VTA para o estriado ventral não possuem uma organização topográfica rostrocaudal. Outro fato a ser destacado é que a organização das projeções mesoestriatais da VTA lembra o padrão das projeções córticoestriatais, sendo observado no estriado, além de um campo terminal principal, pequenos focos isolados de marcação. / The ventral tegmental area (VTA) contains dopaminergic neurons of the A10 group and sends dense projections to the ventral striatum. This circuitry is critically involved in reward mechanisms. Recently, the organization of these projections was reexamined by Ikemoto S. (Brain Res. Rev., 56:27-78, 2007) in a detailed retrograde tracing study, being proposed that these projections can be subdivided into two main systems, a ventromedial mesostriatal dopaminergic system that innervates the medial shell of the accumbens and medial olfactory tubercle, and a ventrolateral mesostriatal dopaminergic system that targets the core and lateral shell of the accumbens and lateral olfactory tubercle. In order to complement these data, in the present study the VTA mesostriatal projections were examined with a sensitive anterograde tracing technique using the Phaseolus vulgaris leucoaglutinin. Our results indicate that there is an extensive overlap of terminal fields innervated by different sectors / nuclei of the VTA and reinforce the notion that VTA efferents can be subdivided into a ventromedial and a ventrolateral mesostriatal system. They also show that the VTA projections to the ventral striatum have a mediolateral topographical organization more complex than previously acknowledged. In fact, projections along the mediolateral dimension of the ventral striatum depends on a combination of the mediolateral and dorsoventral axis of the VTA. In other words, the most ventral and medial parts of the VTA (corresponding to the interfascicular nucleus) innervates the most medial districts of the ventral striatum (corresponding to the dorsomedial shell of the accumbens and medial tip of the olfactory tubercle), and the most dorsal and lateral parts of the VTA (corresponding to the dorsolateral region of the parabrachial pigmented nucleus) project to the most lateral districts of the ventral striatum (lateral core and lateral shell of the accumbens, ventral caudate-putamen and lateral olfactory tubercle). Moreover, VTA projections to the ventral striatum do not seem to have a rostrocaudal topographical organization. It is also of note that the organization of the VTA mesostriatal projections shares features with cortico-striatal projections, in the sense that both fiber systems have a main terminal field and also give rise to small, scattered isolated foci of terminal labeling.

OLIVEIRA, A.R. Envolvimento de receptores dopaminérgicos da área tegmental ventral e do complexo basolateral da amígdala na aquisição e na expressão do medo condicionado. 2010. 93 f. Tese (Doutorado) Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo. O condicionamento Pavloviano é um dos paradigmas mais utilizados para estudar as bases biológicas das emoções, assim como da aprendizagem e memória. A dopamina (DA) é um dos principais neurotransmissores envolvidos na mediação de estados de medo e ansiedade. Um conjunto crescente de evidências dá suporte à hipótese de que a ativação da via mesocorticolímbica, proveniente de neurônios dopaminérgicos da área tegmental ventral (ATV), é particularmente sensível à estimulação aversiva. Entre as regiões inervadas por esta via, o complexo basolateral da amígdala (BLA) é um componente essencial dos circuitos neurais do medo condicionado. Assim, o presente estudo explorou o envolvimento de mecanismos DA da ATV e do BLA, através do uso de agonistas e antagonistas de receptores DA, na aquisição e expressão do medo condicionado à luz. Não houve efeito das drogas DA no sobressalto potencializado pelo medo (SPM), quando injetadas na ATV antes do condicionamento, indicando que os receptores DA da ATV não participam da aquisição do medo condicionado à luz. Ao contrário, quando injetado na ATV antes do teste, quimpirole (agonista D2) reduziu o SPM, enquanto as demais drogas não tiveram efeito. A administração de SCH 23390 (antagonista D1) no BLA não produziu efeitos no SPM, indicando que os receptores D1 do BLA não parecem envolvidos na expressão do SPM. Já a administração de sulpirida (antagonista D2) no BLA inibiu o SPM produzido pela luz. Além disso, a expressão do medo condicionado foi associada a um aumento do congelamento e dos níveis extracelulares de DA no BLA, ambos inibidos com a administração de quimpirole na ATV. A capacidade do quimpirole em diminuir o SPM e o congelamento condicionado parece ser resultado de sua ação em auto-receptores D2 da ATV. A ativação desses receptores diminui os níveis de dopamina em áreas que recebem terminações da via mesocorticolímbica. Os resultados com a sulpirida realçam a importância dos receptores D2 do BLA na expressão do medo condicionado Pavloviano. / OLIVEIRA, A.R. Involvement of dopaminergic receptors of ventral tegmental area and basolateral amygdala in the acquisition and expression of conditioned fear. 2010. 93 p. Thesis (Doctoral) Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo. The Pavlovian fear conditioning is one of the most used paradigms to study the biological basis of emotion, as well as of learning and memory. Dopamine (DA) is one of the most important neurotransmitters involved in mechanisms underlying states of fear and anxiety. A growing body of evidence supports the hypothesis that excitation of the mesocorticolimbic pathway, originating from DA neurons in the ventral tegmental area (VTA), is particularly sensitive to fear-arousing stimuli. Among the forebrain regions innervated by this pathway, the basolateral amygdala (BLA) is an essential component of the neural circuitry of conditioned fear. The present study explored the involvement of VTA and BLA DA receptors, using DA agonists and antagonists, in the acquisition and expression of conditioned fear to a light conditioned stimulus (CS). None of the drugs used produced significant effects on fear-potentiated startle (FPS) when injected in VTA before conditioning, indicating that VTA DA receptors are not involved in the acquisition of conditioned fear to a light-CS. In contrast, when injected before the test session, intra-VTA quinpirole (D2 agonist) significantly reduced FPS, whereas the other drugs had no effect. Intra-BLA SCH 23390 (D1 antagonist) did not produce significant effects on FPS, indicating that BLA D1 receptors do not appear to be involved in the expression of FPS. On the other hand, intra-BLA sulpiride (D2 antagonist) inhibited FPS produced by light-CS previously paired with footshocks. Also, conditioned fear was associated with increased freezing and DA levels in the BLA, both inhibited by intra-VTA quinpirole. Quinpirole\'s ability to decrease FPS and conditioned freezing may be the result of an action on VTA D2 presynaptic autoreceptors. The activation of those receptors decreases dopamine levels in terminal fields of the mesocorticolimbic pathway. Sulpirides results stress the importance of BLA D2 receptors in the fear-activating effects of the Pavlovian conditioning.