With approximately 7% of the adult population reporting to have taken illicit substances over the course of a year and the chronically relapsing nature of substance use disorders there is a great need for effective forms of treatment and therapies to reduce relapse. Deep brain stimulation (DBS) is a process of neuromodulation where electrodes are implanted in a target region to modulate the electrophysiological activity of the target region. DBS has been postulated as a potential therapy for treatment-refractory addiction, with a great deal of focus on the nucleus accumbens (NAc). Forty male Long Evans rats were implanted with unilateral stimulating electrodes within the right NAc prior to exposure to chronic cocaine self-administration (0.5 mg/kg/infusion). Following self administration, the animals were withdrawn from cocaine and treated with 14 consecutive days of sham, low frequency (LF, 20 Hz) or high frequency (HF, 160 Hz) stimulation sessions (30 min/day). The animals underwent drug seeking tests on days 1, 15 and 30 of the withdrawal phase with context-induced relapse paired with a drug challenge (5 mg/kg i.p). Relapse rates were highest on day 15 after withdrawal, with both LF and HF attenuating cocaine during this drug-seeking test, however this was not the case for tests on days 1 and 30. Motivation to respond for saccharin solution (0.1 %) remained intact following both LF and HF stimulation intake sessions. These results demonstrate that unilateral DBS of the NAc effectively attenuated cocaine-seeking following chronic exposure to stimulation although these beneficial effects appeared to diminish following cessation of daily treatment with stimulation. The results obtained in this experiment provide support for DBS as a potential therapy for patients with treatment-resistant cases of substance use disorders.

Impulsive choice refers to the inability to delay gratification and is associated with increased drug abuse vulnerability. Understanding the underlying neural mechanisms linking impulsive choice and drug abuse can contribute to improved treatment options for individuals with substance use disorders. Evidence suggests a major role for nucleus accumbens core (NAcc) in impulsive choice and the reinforcing effects of drugs of abuse. The neurotransmitters glutamate (Glu) and dopamine (DA) are implicated in the neural adaptations observed in drug addiction; however, the role of intra-NAcc Glu and DA in impulsive choice is unclear. Rats were trained in a delay discounting task, in which animals chose between a small, immediate reinforcer and large, delayed reinforcer. Consistently choosing the small, immediate reinforcer was considered to reflect increased impulsivity. Following delay discounting, in vitro receptor autoradiography was performed to quantify the number of N-methyl-D-aspartate (NMDA) receptors and dopamine transporters (DAT) in NAcc and nucleus accumbens shell (NAcSh). In a separate experiment, rats were trained in delay discounting and were implanted with guide cannulae into NAcc. Following surgery, rats received microinfusions of either a) the Glu-selective ligands MK-801 (noncompetitive NMDA receptor channel blocker; 0, 0.3, and 1.0 μg), AP-5 (competitive NMDA receptor antagonist; 0, 0.3, and 1.0 μg), ifenprodil (NMDA NR2B subunit antagonist; 0, 0.3, and 1.0 μg), and CNQX (AMPA receptor antagonist; 0, 0.2, and 0.5 μg) or b) the DA-selective ligands SKF 38393 (D1-like receptor agonist; 0, 0.03, and 0.1 μg), SCH 23390 (D1-like receptor antagonist; 0, 0.3, and 1.0 μg), quinpirole (D2-like receptor agonist; 0, 0.3, and 1.0 μg), and eticlopride (D2-like receptor antagonist; 0, 0.3, and 1.0 μg). In NAcc and NAcSh, NMDA receptor and DAT expression did not differ between high and low impulsive rats. Furthermore, intra-NAcc administration of NDMA and DA receptor ligands did not significantly alter impulsive choice. These results suggest that Glu and DA systems within NAcc do not directly mediate impulsive decision making. Future work is needed to determine the precise role of NAcc in mediating impulsive choice.

The present thesis examined the behavioural and brain mechanisms of associative change in the rat during Pavlovian fear conditioning as measured by freezing. The first series of experiments (Chapter 3) used compound test designs to study how learning is distributed among excitatory and neutral conditional stimuli (CSs). More was learned about a neutral CSB than an excitatory CSA when trained in isolation, indicating that fear learning is negatively accelerated. CSA blocked fear learning to CSB when trained in compound. Unblocking of CSB occurred if the AB compound signalled an increase in unconditional stimulus (US) intensity or number. Assessments of associative change during blocking showed that more was learned about CSB than CSA. Such assessments during unblocking revealed that more was learned about CSB than CSA following an increase in US intensity but not US number. These US manipulations had no differential effects on single-cue learning. The results show that variations in US intensity or number produce unblocking of fear learning, but for each there is a different profile of associative change and a potentially different mechanism. The second series of experiments (Chapter 4) demonstrated that these stimulus selection effects are mediated, at least in part, by nucleus accumbens shell (AcbSh). AcbSh lesions augmented overshadowing during compound conditioning and promoted learning about CSA at the expense of CSB during blocking designs. Lesioned rats could learn normally about the novel CSB if it was rendered more informative regarding shock in Stage II. These results identify an important role for AcbSh and ventral striatum in distributing attention and learning among competing predictors of danger.

Stuttgart, Univ., Diss., 2003.

Made available in DSpace on 2015-12-06T23:45:23Z (GMT). No. of bitstreams: 0 Previous issue date: 2012 / Associação Fundo de Incentivo à Psicofarmacologia (AFIP) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)'' / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / O alcoolismo e um problema mundial que resulta em milhoes de mortes. No entanto, somente uma pequena parcela dos usuarios de alcool torna-se dependente desta droga. Os substratos neurais responsaveis por tais diferencas individuais nao sao completamentes conhecidos. Em camundongos Suicos Albinos, existe grande diferenca individual quanto ao desenvolviento da sensibilizacao comportamental ao etanol, fenomeno caracterizado como um progressivo aumento da resposta locomotora durante tratamento com a droga. A variabilidade na resposta comportamental ao tratamento cronico com etanol poderia levar a diferentes neuroadaptacoes na regiao no nucleo accumbens (regiao do sistema de recompensa),principalmente das neurotransmissoes dopaminergica e glutamatergica, o que poderia influenciar a vulnerabilidade a dependencia de alcool. Neste estudo investigamos se camundongos com diferentes niveis de sensibilizacao(sensibilizados e nao-sensibilizados) apresentantavam diferencas farmacologicas bioquimicas e/ou eletrofisiologicas na atividade dos receptores dopaminergico D1 e glutamatergico NMDA na regiao do nucleo accumbens, duas semanas apos o tratamento com etanol. Na primeira etapa, observamos que animais sensibilizados ao etanol, quando comparados aos animais nao-sensibilizados ou controle, apresentaram hiperresponsividade dos receptores D1 no nucleo accumbens que se refletiu em um aumento da fosforilacao em treonina 34 da proteina DARPP-32.Este resultado indica que um aumento da sensibilidade da cascata intracelular associada a ativacao dos receptores D1 representa um componente neurobiologico asssociado ao desenvolvimento da sensibilizacao. esta cascata pode influenciar a atividade dos receptores glutamatergicos NMDA. Desta maneira, nas segunda etapa do estudo verificamos com tecnicas de eletrofisiologia (patch-clamp) e bioquimica (western-blots) que animais sensibilizados ao etanol apresentavam menor atividade e expressao dos receptores NMDA no nucleo accumbens que se traduzia em um deficit na expressao de LTD (depressao de longa duracao). Nao houve diferencas significativas entre animais controle e nao-sensibilizado. Na terceira etapa, investigamos se a variabilidade no desenvolvimento da sensibilizacao ao estanol estaria associada a diferentes niveis de consumo voluntario de etanol. Observamos que animais sensibilizados beberam voluntariamente maiores quantidades de etanol do que animais nao-sensibilizados e controles. E possivel que alteracoes da neurotransmissao dopaminergica e glutamatergica no acccumbens podem refletir no aumento do consumo de etanol em animais sensibiliazados. E importante notar que isso nao esta diretamente relacioando com a exposicao cronica ao etanol uma vez que animais nao- sensibilizados, apear de receberem o mesmo tratamento com etanol, nao apresentaram diferencas dos camundongos controles quanto as neuroadaptacoes e ao consumo de etanol. Compreendendo estas neuroadaptcaoes poderemos, em um futuro proximo, tentar reverte-las e sugerir novos alvos terapeuticos para o trtamento da dependencia e/ou recaida ao uso do alcool / FAPESP: 2008/01819-5 / CAPES/PDEE: BAX: 0321-10-9 / BV UNIFESP: Teses e dissertações

Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências Biológicas. Programa de Pós-Graduação em Neurociências / Made available in DSpace on 2012-10-26T12:29:05Z (GMT). No. of bitstreams: 1 303355.pdf: 1681314 bytes, checksum: f89f4b33b69dcd8966f4ade23802058c (MD5) / Este estudo investigou o efeito de agonistas de a-adrenoceptores microinjetados na região da concha do núcleo accumbens (AcbSh) sobre a alimentação e os comportamentos relacionados à ansiedade em ratos saciados. Ratos Wistar machos com uma cânula cronicamente implantada no AcbSh foram unilateralmente microinjetados com clonidina (CLO, agonista a2) ou fenilefrina (FEN, agonista a1), nas doses de 6 e 20nmol em 0,2 µl e submetidos ao labirinto em cruz elevado (LCE), um teste pré-clínico de ansiedade. Imediatamente após o teste do LCE, os animais foram submetidos à avaliação da ingestão de alimento por 30 minutos. Os dados mostraram que ratos microinjetados com CLO (20 nmol) no AcbSh apresentaram maior % de tempo nos braços abertos, que é compatível com um efeito do tipo ansiolítico. A ansiólise induzida por CLO foi corroborada pelo aumento de imersão de cabeça e diminuição de Stretched-Attend Postures (SAP), dois comportamentos etológicos motivados pelo medo. A atividade locomotora do animal não foi alterada pelas microinjeções de CLO no AcbSh no LCE. No entanto, nenhuma dose de FEN microinjetada no AcbSh foi capaz de alterar as variáveis representativas do medo / ansiedade e locomoção. A ingestão de alimentos não foi alterada por qualquer dose de CLO e FEN microinjetada no AcbSh, mas a microinjeção de CLO na dose de 20nmol induziu aumento da atividade locomotora no teste de ingestão de alimentos o que não aconteceu com CLO 6 nmol. Os dados sugerem que as aferências noradrenérgicas ao AcbSh podem ser a base de modulação do medo / ansiedade através dos receptores adrenérgicos a2, enquanto que o comportamento alimentar não sofre modulação noradrenérgica no AcbSh, pelo menos em ratos saciados. / This study investigated the effect of á-adrenoceptor agonists microinjected into the shell region of the accumbens nucleus (AcbSh) on feeding and anxiety-related behaviours in free-feeding rats. Male Wistar rats with a chronically implanted cannula into the AcbSh were unilaterally microinjected with either clonidine (CLO, á2-adrenoceptor agonist) or Phenylephrine (PHE, á1-adrenoceptor agonist) at the doses of 6 and 20nmol and submitted to the elevated plus-maze (EPM), a pre-clinical test of anxiety. Immediately after the EPM test, the animals underwent food intake evaluation for 30 minutes. The data showed that rats microinjected with CLO (20 nmol/0.2ìl) into the AcbSh exhibited increased %Open arm time, which is compatible with an anxiolytic-like effect. The CLO-induced anxiolysis was corroborated by increased head-dipping and decreased stretched-attend posture (SAP), two ethologically derived behaviours which are fear/anxiety-motivated. The animal's locomotor activity was not changed by 20nmol CLO microinjection into the AcbSh in EPM. However, neither dose of PHE microinjected into the AcbSh was able to alter either the spatial-temporal or ethological variables representative of fear/anxiety and locomotion. Food intake was not altered by any dose of CLO and PHE microinjected into the AcbSh, but the 20nmol CLO microinjection induced increased locomotor activity in the feeding test, this did not happen with CLO 6 nmol. The data suggests that noradrenergic afferents for the AcbSh may underlie fear/anxiety modulation through á2-adrenoceptor in the AcbSh, while feeding behaviour does not suffer noradrenergic modulation in the AcbSh of free-feeding rats.

Orientadora : Profª Drª Luana Fischer / Dissetação (mestrado) - Universidade Federal do Paraná, Setor de Ciências Biológicas, Programa de Pós-Graduação em Fisiologia. Defesa: Curitiba, 13/02/2017 / Inclui referências : f. 68-74 / Resumo: Distúrbios de sono alteram a sensibilidade à dor e predispõem ao desenvolvimento de condições dolorosas. No entanto pouco é conhecido a respeito dos mecanismos pelos quais a privação de sono afeta a dor. O Núcleo Accumbens (NAc), no estriado ventral, desempenha importante papel na modulação da dor e na regulação do ciclo sono/ vigília. No entanto, não se sabe se este núcleo medeia o efeito pró-nociceptivo da privação de sono. Desse modo, o objetivo deste trabalho foi testar a hipótese de que o NAc medeia o efeito pró-nociceptivo da privação se sono REM (movimento rápido dos olhos) e, caso medeie, investigar os mecanismos envolvidos. A privação de sono REM por 24 horas através do método de plataforma única induziu um efeito pró-nociceptivo intenso e duradouro, demonstrado pela diminuição do limiar nociceptivo mecânico em ratos Wistar. Esse efeito diminui progressivamente ao longo do período de sono rebote, mas ainda permanece significativo 48 h depois. A atividade motora, aferida por actimetria, é significativamente diminuída na fase escura em ratos privados de sono, o que é compatível com um aumento do tempo de sono após a privação. A lesão excitotóxica induzida por N-metil D-Aspártico (NMDA) no NAc preveniu o efeito pró-nociceptivo da privação de sono REM enquanto o bloqueio agudo do NAc por Qx-314 (2%), um derivado quaternário de lidocaína, reverteu esse efeito. Esses dados mostram que o NAc medeia o efeito pró-nociceptivo da privação de sono REM, sendo essencial à sua indução e manutenção. Uma vez que o NAc regula o ciclo sono-vigília através de um balanço entre a atividade adenosinérgica sobre receptores A2A e a atividade dopaminérgica sobre receptores D2, investigamos se estes receptores também medeiam o efeito pró-nociceptivo da privação de sono REM. A administração de um antagonista do receptor A2A (SCH 58261, 7 ng) ou de um agonista do receptor D2 (Piribedil, 6 ?g) no NAc aumentou a atividade dos animais e bloqueou o efeito pró-nociceptivo da privação de sono REM. De forma complementar, a administração de um agonista do receptor A2A (CGS 21680, 24 ng) ou de um antagonista do receptor D2 (Raclopride, 5 ?g) no NAc diminuiu a atividade e pelo menos o agonista do receptor A2A prejudicou a reversão do efeito pró-nociceptivo durante o período de sono rebote. A privação de sono REM não afetou a expressão da proteína c-fos no NAc. Juntos os dados obtidos no presente trabalho sugerem que privação de sono REM aumenta a dor por aumentar a atividade adenosinérgica sobre receptores A2A e diminuir a atividade dopaminérgica sobre receptores D2 localizados no NAc. Entender os mecanismos pelos quais prejuízos no sono aumentam a dor é essencial para que se obtenha sucesso no complexo manejo da dor em pacientes que sofrem de distúrbios de sono. Palavras-chave: nocicepção; Dor; Núcleo Accumbens; Privação de sono REM; Adenosina; Dopamina. / Abstract: Sleep disorders alter pain sensitivity and predispose the development of painful conditions. However little is known about the mechanisms by which sleep deprivation affects pain. The Nucleus Accumbens (NAc), in the ventral striatum, plays an important role in pain modulation and in sleep-wake cycle regulation. However, it is not known whether NAc mediates the pronociceptive effect of sleep deprivation. Thus, the objective of this study was to test the hypothesis that the NAc mediates the pronociceptive effect of REM (rapid eye movement) sleep deprivation and, if it mediates, investigate the underline mechanisms. A 24 hours REM sleep deprivation through the single platform method induced an intense and long-lasting pronociceptive effect, demonstrated by the decrease of mechanical nociceptive threshold in Wistar rats. This effect decreases progressively over the rebound sleep period, but still remains significant 48 h later. The activity, measured by actimetry, was significantly decreased in the dark phase in sleep deprived rats, which is compatible with an increase in sleep time after deprivation. N-methyl D-Aspartic (NMDA) induced excitotoxic lesion in NAc, prevented the pronociceptive effect of REM sleep deprivation while the acute blockade by Qx-314 (2%), a quaternary derivative of lidocaine, reversed this effect. These data show that NAc mediates the pronociceptive effect of REM sleep deprivation, being essential to its induction and maintenance. Since NAc regulates the sleep-wake cycle through a balance between adenosine activity on A2A receptors and dopaminergic activity on D2 receptors, we investigated whether these receptors also mediate the pronociceptive effect of REM sleep deprivation. Administration of an A2A receptor antagonist (SCH 58261, 7 ng) or a D2 receptor agonist (Piribedil, 6 ?g) in NAc increased animal activity and blocked the pronociceptive effect of REM sleep deprivation. Complementarily, administration of an A2A receptor agonist (CGS 21680, 24 ng) or a D2 receptor antagonist (Raclopride, 5 ?g) in NAc decreased activity and at least the A2A receptor agonist impaired the reversal of the pronociceptive effect during the sleep rebound period. REM sleep deprivation did not affect expression of c-fos protein in NAc. Together the data obtained in the present study suggest that REM sleep deprivation increases pain by increasing NAc adenosinergic A2A activity and by decreasing NAc dopaminergic D2 activity. The understanding of the mechanisms by which sleep loss affect nociception will contribute to pain management in patients suffering from sleep disorders. Keywords: Nociception; Pain; Nucleus Accumbens; REM sleep deprivation; Adenosine; Dopamine.

Resumo: Nesse estudo avaliamos os efeitos de lesões excitotóxicas bilaterais do núcleo accumbens core (NAc-co), estriado dorsomedial (DMS) ou estriado dorsolateral (DLS) de ratos no aprendizado e extinção do condicionamento de medo (tom-choque) e esquiva ativa de duas vias. Nenhum rato apresentou qualquer défict motor ou no tempo de reação ao choque. Lesões do NAc-co, mas não do DMS ou do DLS, diminuíram os escores de freezing condicionado. Ratos com lesão no NAc-co ou DLS aprenderam a tarefa de esquiva ativa de duas vias mais lentamente e ratos com lesões no NAc-co, DLS ou DMS apresentaram extinção mais rápida das respostas instrumentais de esquiva. Os escores de medo condicionado e de respostas instrumentais de esquiva apresentaram uma correlação negativa no grupo com lesão no NAc-co. Esses resultados sugerem que o NAc-co é necessário para o condicionamento Pavloviano de medo e para a aprendizagem e/ou desempenho de respostas instrumentais de esquiva. Entretanto, apenas o NAc-co parece mediar o impacto do medo condicionado sobre a aprendizagem e desempenho das respostas instrumentais de esquiva. Esses resultados sugerem ainda que o DLS contribui para uma extinção lenta das respostas de hábito instrumentais de esquiva. Porém, o DLS parece não afetar o aprendizado lento dessas respostas. Por outro lado, nossos resultados não suportam a hipótese de que o DMS é importante para um aprendizado rápido de respostas instrumentais de esquiva direcionadas a um objetivo, mas sugere que o DMS pode ser importante para manutenção dessas respostas durante a fase inicial da extinção.

Doctor of Philosophy / Department of Psychological Sciences / Mary E. Cain / Drug addiction is a chronic cyclical disease characterized by periods of drug use and abstinence. Drug craving increases as a function of abstinence period, such that longer periods of abstinence result in greater feelings of craving. Longer periods of abstinence may render cues to become more powerful motivators of drug seeking behavior because of the greater craving response. Neurobiological evidence suggests that changes in glutamatergic transmission in the nucleus accumbens (NAc) plays a pivotal role in the incubation of craving and drug seeking motivation. Specifically, the upregulation of Ca²⁺ permeable AMPA receptors may increase drug seeking following the presentation of a drug cue. Environmental housing manipulations also change the expression of metabotropic glutamate receptors (mGlur) and psychostimulant self-administration. In the current experiments, Sprague-Dawley rats were reared in enriched (EC) or isolated (IC) conditions from PND 21-51. Then rats were implanted with indwelling jugular catheters and allowed to self-administer amphetamine (0.1 mg/kg/infusion) or saline paired with a cue light for 16 days for 1h. Then rats went through a forced abstinence period of 1 day and were then tested in a cue-induced seeking test. Immediately after the seeking test, half the rats were sacrificed and the NAc was dissected and prepared for western blot analyses. The other half of rats rested for 40 days and were tested again in the cue-induced seeking test. Immediately following the seeking test, rats were sacrificed and their NAc was dissected. Factorial ANOVA results indicate that rearing in the IC environment increased drug seeking when compared to EC rats after 1 day of abstinence and after 40 days of abstinence, but drug seeking did not increase after 40 days. Rats in the saline groups showed an increase in seeking after 40 days of abstinence, providing evidence of increased responding. Saline responding was significantly lower when compared to rats that responded for amphetamine. When rats self-administered saline, generally IC rats had more responding than EC rats. Western blot analyses indicated that expression of AMPA subunits GluA1, and GluA2, as well as metabotropic glutamate receptors 1 and 5 (mGlur1, and mGlur5) were not different across the experimental groups, suggesting another mechanism could be implicated in drug seeking after short and long abstinence periods. These results suggest that early life experience can have long lasting effects into adulthood and increase the vulnerability of drug abuse. Our results provide mixed results of incubated seeking. Positive early life experiences reduce drug seeking motivation after short and long abstinence periods, providing evidence for further research to examine how early life experience changes the reward seeking and subsequent structures in the mesocorticolimbic pathway.

This thesis investigated the contribution of the nucleus accumbens core (AcbC) and the hippocampus (H) to choice and learning involving reinforcement that was delayed or unlikely. Animals must frequently act to influence the world even when the reinforcing outcomes of their actions are delayed. Learning with action-outcome delays is a complex problem, and little is known of the neural mechanisms that bridge such delays. Impulsive choice, one aspect of impulsivity, is characterized by an abnormally high preference for small, immediate rewards over larger delayed rewards, and is a feature of attention-deficit/hyperactivity disorder (ADHD), addiction, mania, and certain personality disorders. Furthermore, when animals choose between alternative courses of action, seeking to maximize the benefit obtained, they must also evaluate the likelihood of the available outcomes. Little is known of the neural basis of this process, or what might predispose individuals to be overly conservative or to take risks excessively (avoiding or preferring uncertainty, respectively), but risk taking is another aspect of the personality trait of impulsivity and is a feature of a number of psychiatric disorders, including pathological gambling and some personality disorders. The AcbC, part of the ventral striatum, is required for normal preference for a large, delayed reward over a small, immediate reward (self-controlled choice) in rats, but the reason for this is unclear. Chapter 3 investigated the role of the AcbC in learning a free-operant instrumental response using delayed reinforcement, performance of a previously learned response for delayed reinforcement, and assessment of the relative magnitudes of two different rewards. Groups of rats with excitotoxic or sham lesions of the AcbC acquired an instrumental response with different delays (0, 10, or 20 s) between the lever-press response and reinforcer delivery. A second (inactive) lever was also present, but responding on it was never reinforced. The delays retarded learning in normal rats. AcbC lesions did not hinder learning in the absence of delays, but AcbC-lesioned rats were impaired in learning when there was a delay, relative to sham-operated controls. Rats were subsequently trained to discriminate reinforcers of different magnitudes. AcbC-lesioned rats were more sensitive to differences in reinforcer magnitude than sham-operated controls, suggesting that the deficit in self-controlled choice previously observed in such rats was a consequence of reduced preference for delayed rewards relative to immediate rewards, not of reduced preference for large rewards relative to small rewards. AcbC lesions also impaired the performance of a previously learned instrumental response in a delay-dependent fashion. These results demonstrate that the AcbC contributes to instrumental learning and performance by bridging delays between subjects' actions and the ensuing outcomes that reinforce behaviour. When outcomes are delayed, they may be attributed to the action that caused them, or mistakenly attributed to other stimuli, such as the environmental context. Consequently, animals that are poor at forming context-outcome associations might learn action-outcome associations better with delayed reinforcement than normal animals. The hippocampus contributes to the representation of environmental context, being required for aspects of contextual conditioning. It was therefore hypothesized that animals with H lesions would be better than normal animals at learning to act on the basis of delayed reinforcement. Chapter 4 tested the ability of H-lesioned rats to learn a free-operant instrumental response using delayed reinforcement, and their ability to exhibit self-controlled choice. Rats with sham or excitotoxic H lesions acquired an instrumental response with different delays (0, 10, or 20 s) between the response and reinforcer delivery. H-lesioned rats responded slightly less than sham-operated controls in the absence of delays, but they became better at learning (relative to shams) as the delays increased; delays impaired learning less in H-lesioned rats than in shams. In contrast, lesioned rats exhibited impulsive choice, preferring an immediate, small reward to a delayed, larger reward, even though they preferred the large reward when it was not delayed. These results support the view that the H hinders action-outcome learning with delayed outcomes, perhaps because it promotes the formation of context-outcome associations instead. However, although lesioned rats were better at learning with delayed reinforcement, they were worse at choosing it, suggesting that self-controlled choice and learning with delayed reinforcement tax different psychological processes. Chapter 5 examined the effects of excitotoxic lesions of the AcbC on probabilistic choice in rats. Rats chose between a single food pellet delivered with certainty (probability p = 1) and four food pellets delivered with varying degrees of uncertainty (p = 1, 0.5, 0.25, 0.125, and 0.0625) in a discrete-trial task, with the large-reinforcer probability decreasing or increasing across the session. Subjects were trained on this task and then received excitotoxic or sham lesions of the AcbC before being retested. After a transient period during which AcbC-lesioned rats exhibited relative indifference between the two alternatives compared to controls, AcbC-lesioned rats came to exhibit risk-averse choice, choosing the large reinforcer less often than controls when it was uncertain, to the extent that they obtained less food as a result. Rats behaved as if indifferent between a single certain pellet and four pellets at p = 0.32 (sham-operated) or at p = 0.70 (AcbC-lesioned) by the end of testing. When the probabilities did not vary across the session, AcbC-lesioned rats and controls strongly preferred the large reinforcer when it was certain, and strongly preferred the small reinforcer when the large reinforcer was very unlikely (p = 0.0625), with no differences between AcbC-lesioned and sham-operated groups. These results suggest that the AcbC contributes to action selection by promoting the choice of uncertain, as well as delayed, reward.