RESUMEN
PURPOSE: To determine if a central axonal injury underlies neuropsychiatric symptoms after mild traumatic brain injury (mTBI) by using tract-based spatial statistics analysis of diffusion-tensor images. MATERIALS AND METHODS: The institutional review board approved this study, with waiver of informed consent. Diffusion-tensor imaging and serial neurocognitive testing with the Immediate Post-Concussion Assessment and Cognitive Testing evaluation were performed in 45 patients with mTBI (38 with irritability, 32 with depression, and 18 with anxiety). Control subjects consisted of 29 patients with mTBI without neuropsychiatric symptoms. Fractional anisotropy and diffusivity maps were analyzed by using tract-based spatial statistics with a multivariate general linear model. Diffusion-tensor imaging findings were correlated with symptom severity, neurocognitive test scores, and time to recovery with the Pearson correlation coefficient. RESULTS: Compared with control subjects, patients with mTBI and depression had decreased fractional anisotropy in the superior longitudinal fasciculus (P = .006), white matter around the nucleus accumbens (P = .03), and anterior limb of the internal capsule (P = .02). Patients with anxiety had diminished fractional anisotropy in the vermis (P = .04). No regions of significantly decreased fractional anisotropy were seen in patients with irritability relative to control subjects. Injury in the region of the nucleus accumbens inversely correlated with recovery time in patients with depression (r = -0.480, P = .005). CONCLUSION: Unique white matter injury patterns were seen for two major posttraumatic neuropsychiatric symptoms. Injury to the cerebellar vermis in patients with mTBI and anxiety may indicate underlying dysfunction in primitive fear conditioning circuits in the cerebellum. Involvement of the nucleus accumbens in depression after mTBI may suggest an underlying dysfunctional reward circuit that affects the prognosis in these patients.
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Lesiones Encefálicas/complicaciones , Sustancia Blanca/lesiones , Adolescente , Adulto , Anisotropía , Ansiedad/etiología , Niño , Depresión/etiología , Imagen de Difusión Tensora , Femenino , Humanos , Cápsula Interna/lesiones , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Núcleo Accumbens/lesiones , PronósticoRESUMEN
A previous analysis of the quinpirole sensitisation rat model of obsessive-compulsive disorder revealed that the behavioral phenotype of compulsive checking consists of three constitutive components - vigor of checking performance, focus on the task of checking, and satiety following a bout of checking. As confirmation of this analysis, the aim of the present study was to reconstitute, without quinpirole treatment, each of the putative components, with the expectation that these would self-assemble into compulsive checking. To reconstitute vigor and satiety, the employed treatment was a bilateral lesion of the nucleus accumbens core (NAc), as this treatment was shown previously to exaggerate these components. To reconstitute focus, the employed treatment was a low dose of the serotonin-1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin hydrochloride (DPAT) (0.0625 mg/kg), as high doses of this drug induce compulsive behavior and exacerbate focus. Results showed that injection of DPAT to NAc lesion rats did yield compulsive checking. Neither the drug alone nor the NAc lesion by itself produced compulsive checking. The demonstrated synthesis of compulsive checking by the combined treatment of low-dose DPAT and NAc lesion strengthened the previous fractionation of the model obsessive-compulsive disorder phenotype into three constitutive components, and suggested a role for serotonin-1A receptors outside the NAc in enhanced focus on the task of checking.
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Conducta Compulsiva/fisiopatología , Núcleo Accumbens/fisiopatología , Receptor de Serotonina 5-HT1A/metabolismo , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Animales , Modelos Animales de Enfermedad , Masculino , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/lesiones , Trastorno Obsesivo Compulsivo , Fenotipo , Ratas Long-Evans , Agonistas del Receptor de Serotonina 5-HT1/farmacologíaRESUMEN
Decision-making policies are subject to modulation by changing motivational states. However, so far, little is known about the neurochemical mechanisms that bridge motivational states with decision making. Here we examined whether dopamine (DA) in the nucleus accumbens core (AcbC) modulates the effects of motivational states on effort-based decision making. Using a cost-benefit T-maze task in rats, we examined the effects of AcbC DA depletions on effort-based decision making, in particular on the sensitivity of effort-based decision making to a shift from a hungry to a sated state. The results demonstrated that, relative to sham controls, rats with AcbC DA depletion in a hungry as well as in a sated state had a reduced preference for effortful but large-reward action. This finding provides further support for the notion that AcbC DA regulates how much effort to invest for rewards. Importantly, our results further revealed that effort-based decision making in lesioned rats, as in sham controls, was still sensitive to a shift from a hungry to a sated state; that is, their preferences for effortful large-reward actions became lower after a shift from a restricted to a free-feeding regimen. These finding indicate that AcbC DA is not necessarily involved in mediating the effects of a shift in motivational state on decision-making policies.
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Toma de Decisiones/fisiología , Dopamina/metabolismo , Motivación , Núcleo Accumbens/metabolismo , Adrenérgicos/toxicidad , Análisis de Varianza , Animales , Conducta Animal , Peso Corporal/fisiología , Condicionamiento Operante , Discriminación en Psicología , Ayuno/fisiología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/lesiones , Oxidopamina/toxicidad , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción/efectos de los fármacos , Refuerzo en Psicología , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
There is good evidence that forebrain serotonergic systems modulate cognitive flexibility. Latent inhibition (LI) is a cross-species phenomenon which manifests as poor conditioning to a stimulus that has previously been experienced without consequence and is widely considered an index of the ability to ignore irrelevant stimuli. While much research has focused on dopaminergic mechanisms underlying LI, there is also considerable evidence of serotonergic modulation. However, the neuroanatomical locus of these effects remains poorly understood. Previous work has identified the nucleus accumbens (NAc) as a key component of the neural circuit underpinning LI and furthermore, this work has shown that the core and shell subregions of the NAc contribute differentially to the expression of LI. To examine the role of the serotonergic input to NAc in LI, we tested animals with 5,7-dihydroxytryptamine (5,7-DHT) lesions to the core and shell subregions on LI assessed under experimental conditions that produce LI in shams and subsequently with weak stimulus pre-exposure designed to prevent the emergence of LI in shams. We found that serotonergic deafferentation of the core disrupted LI whereas 5,7-DHT lesions to the shell produced the opposite effect and potentiated LI.
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5,7-Dihidroxitriptamina/toxicidad , Condicionamiento Psicológico/fisiología , Núcleo Accumbens/lesiones , Núcleo Accumbens/fisiología , Serotoninérgicos/toxicidad , Ácido 3,4-Dihidroxifenilacético/metabolismo , Estimulación Acústica , Animales , Cromatografía Líquida de Alta Presión , Condicionamiento Psicológico/efectos de los fármacos , Dopamina/metabolismo , Inhibidores de Captación de Dopamina/farmacología , Electroquímica , Ácido Hidroxiindolacético/metabolismo , Inhibición Psicológica , Luz , Masculino , Piperazinas/farmacología , Ratas , Ratas Wistar , Serotonina/metabolismo , Privación de AguaRESUMEN
While knowing what to expect is important, it is equally important to know when to expect it and to respond accordingly. This is apparent even in simple Pavlovian training situations in which animals learn to respond more strongly closer to reward delivery. Here we report that the nucleus accumbens core, an area well-positioned to represent information about the timing of impending rewards, plays a critical role in this timing function.
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Condicionamiento Clásico/fisiología , Núcleo Accumbens/fisiología , Tiempo de Reacción/fisiología , Recompensa , Análisis de Varianza , Animales , Señales (Psicología) , Núcleo Accumbens/lesiones , RatasRESUMEN
We studied the role of nucleus accumbens shell (AcbSh) in Pavlovian fear conditioning. Rats were trained to fear conditioned stimulus A (CSA) in Stage I, which was then presented in compound with a neutral stimulus and paired with shock in Stage II. AcbSh lesions had no effect on fear-learning to CSA in Stage I, but selectively prevented learning about the neutral conditioned stimulus (CS) in Stage II. These results add to a growing body of evidence indicating an important role for the ventral striatum in fear-learning. They suggest that the ventral striatum and AcbSh, in particular, directs learning toward or away from a CS as a consequence of how well that CS predicts the shock unconditioned stimulus (US). AcbSh is required to reduce the processing of established predictors, thereby permitting neutral or less predictive stimuli to be learned about.
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Condicionamiento Clásico/fisiología , Miedo , Núcleo Accumbens/fisiología , Animales , Conducta Animal/efectos de los fármacos , Condicionamiento Clásico/efectos de los fármacos , Electrochoque/efectos adversos , Agonistas de Aminoácidos Excitadores/farmacología , Reacción Cataléptica de Congelación/efectos de los fármacos , Reacción Cataléptica de Congelación/fisiología , N-Metilaspartato/farmacología , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/lesiones , RatasRESUMEN
Considerable evidence suggests that dopamine in the core subregion of the nucleus accumbens is not only involved in Pavlovian conditioning but also supports instrumental performance. However, it is largely unknown whether NAc dopamine is required for outcome encoding which plays an important role both in Pavlovian stimulus-outcome learning and instrumental action-outcome learning. Therefore, we tested rats with 6-hydroxydopamine (6-OHDA) induced dopamine depletion of the NAc core for their sensitivity to outcome devaluation in a Pavlovian and an instrumental task. Results indicate that 6-OHDA-lesioned animals were sensitive to outcome devaluation in an instrumental task. This finding provides support to the notion that NAc core dopamine may not be crucial in encoding action-outcome associations. However, during instrumental conditioning lever pressing rates in 6-OHDA-lesioned animals were markedly lower which could reflect an impaired behavioral activation. By contrast, after outcome-specific devaluation in a Pavlovian task, performance in 6-OHDA-lesioned animals was impaired, i.e. their magazine-directed responding was non-selectively reduced. One possibility to explain non-selective responding is that NAc core DA depletion impaired the ability of conditioned stimuli to activate the memory of the current value of the reinforcer.
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Condicionamiento Clásico/fisiología , Condicionamiento Operante/fisiología , Dopamina/metabolismo , Núcleo Accumbens/fisiología , Análisis de Varianza , Animales , Inmunohistoquímica , Masculino , Pruebas Neuropsicológicas , Neurotoxinas/toxicidad , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/lesiones , Oxidopamina/toxicidad , Ratas , Recompensa , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
How the subregions of the nucleus accumbens (NAc) shell and core and stress are involved in behavioral sensitization induced by psychostimulants remains unclear. The present study manipulated methamphetamine (MAMPH) injections, lesions of the NAc shell or core, and footshock-treatment-induced stress to address this issue. The present data showed that during the acquisition phase, MAMPH injections, lesions of the NAc shell, and footshock treatments induced hyperactivity for the NAc shell. For the NAc core, MAMPH injections induced hyperactivity; however, lesions of the NAc core did not affect locomotor activity. Footshock treatments disrupted hyperactivity of behavioral sensitization. During the testing phase, MAMPH injections, lesions of the NAc shell, and footshock-treatment-induced stress facilitated hyperactivity for the NAc shell. For the NAc core, MAMPH injections and footshock-treatment-induced stress increased hyperactivity. However, the lesion of the NAc core did not affect locomotor activity. In conclusion, MAMPH injections and footshock-treatment-induced stress play an excitatory role for the NAc shell in acquisition and testing. For the NAc core, footshock-treatment-induced stress plays an inhibitory role in acquisition but an excitatory role in testing. The NAc core was not involved in MAMPH-induced behavioral sensitization in acquisition and testing. The NAc shell plays an inhibitory role in acquisition and testing phases. The present data might provide some insights for drug addiction. The results should be discussed further.
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Conducta Animal , Sensibilización del Sistema Nervioso Central , Estimulantes del Sistema Nervioso Central/farmacología , Locomoción , Metanfetamina/farmacología , Núcleo Accumbens , Estrés Psicológico/fisiopatología , Animales , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Sensibilización del Sistema Nervioso Central/efectos de los fármacos , Sensibilización del Sistema Nervioso Central/fisiología , Estimulantes del Sistema Nervioso Central/administración & dosificación , Dopamina , Estimulación Eléctrica , Alimentos , Locomoción/efectos de los fármacos , Locomoción/fisiología , Masculino , Metanfetamina/administración & dosificación , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/lesiones , Núcleo Accumbens/fisiología , Ratas , Ratas WistarRESUMEN
Most mammalian infants vocalize when isolated. The vocalization promotes caregiver proximity, which is critical to survival. If, before isolation, a rat pup has contact with its dam, its isolation vocalization rate is increased (maternal potentiation) relative to isolation preceded only by littermate contact. Prior work showed that systemic administration of a D2 receptor agonist blocks maternal potentiation at doses that do not alter baseline vocalization. In this study, infusion of quinpirole (2 microg/side) into the nucleus accumbens also blocks maternal potentiation. Infusion of the accumbens with the D2 antagonist raclopride (4 microg/side) prevents systemic quinpirole from blocking potentiation. Quinpirole infusion in the dorsal striatum did not affect maternal potentiation and infusion of raclopride in the dorsal striatum did not reverse the block of maternal potentiation by systemic quinpirole. Vocalization results after a second vehicle infusion on a given day are no different than the results following an initial vehicle infusion, so experimental design can not account for the effects of drug infusions. Because activity level was increased by both dorsal and ventral striatum infusions, activity level can not account for the results.
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Cuerpo Estriado/metabolismo , Inhibición Psicológica , Privación Materna , Receptores de Dopamina D2/fisiología , Vocalización Animal/fisiología , Animales , Animales Recién Nacidos , Conducta Animal/efectos de los fármacos , Cuerpo Estriado/efectos de los fármacos , Agonistas de Dopamina/farmacología , Antagonistas de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Femenino , Masculino , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/lesiones , Núcleo Accumbens/fisiología , Embarazo , Quinpirol/farmacología , Racloprida/farmacología , Ratas , Ratas Wistar , Factores de Tiempo , Vocalización Animal/efectos de los fármacosRESUMEN
The nucleus accumbens core (NAc) has long been recognized as an important contributor to the computation of reward value that is critical for impulsive choice behavior. Impulsive choice refers to choosing a smaller-sooner (SS) over a larger-later (LL) reward when the LL is more optimal in terms of the rate of reward delivery. Two experiments examined the role of the NAc in impulsive choice and its component processes of delay and magnitude processing. Experiment 1 delivered an impulsive choice task with manipulations of LL reward magnitude, followed by a reward magnitude discrimination task. Experiment 2 tested impulsive choice under manipulations of LL delay, followed by temporal bisection and progressive interval tasks. NAc lesions, in comparison to sham control lesions, produced suboptimal preferences that resulted in lower reward earning rates, and led to reduced sensitivity to magnitude and delay within the impulsive choice task. The secondary tasks revealed intact reward magnitude and delay discrimination abilities, but the lesion rats persisted in responding more as the progressive interval increased during the session. The results suggest that the NAc is most critical for demonstrating good sensitivity to magnitude and delay, and adjusting behavior accordingly. Ultimately, the NAc lesions induced suboptimal choice behavior rather than simply promoting impulsive choice, suggesting that an intact NAc is necessary for optimal decision making.
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Conducta de Elección/fisiología , Descuento por Demora/fisiología , Conducta Impulsiva/fisiología , Núcleo Accumbens/lesiones , Animales , Conducta Animal/fisiología , Condicionamiento Operante/fisiología , Ratas Sprague-Dawley , RecompensaRESUMEN
Nuclear factor κ-light chain enhancer of activated B cells (NF-κB) is a transcription factor commonly associated with innate immunity and is activated by infection and inflammation. NF-κB has recently gained attention as a mediator of complex psychiatric phenomena such as stress and addiction. In regards to alcohol, most research on NF-κB has focused on neurotoxicity and few studies have explored the role of NF-κB in alcohol reward, reinforcement, or consumption. In these studies, we used conditioned place preference to assess the activity of NF-κB in response to rewarding doses of alcohol. To measure NF-κB activity we used a line of transgenic mice that express the LacZ gene under the control of an NF-κB-regulated promoter. In these animals, staining for ß-galactosidase (ß-gal) identifies cells in which NF-κB has been activated. We then used the Daun02 inactivation method to specifically silence NF-κB-expressing cells during place preference conditioning. Daun02 is an inactive prodrug that is converted to the inhibitory molecule daunorubicin by ß-gal. After alcohol place conditioning, we observed increased ß-gal staining in the nucleus accumbens (NAC) shell and dorsal raphe nucleus, and found that disruption of NF-κB-expressing cells using Daun02 attenuated the development of alcohol place preference when infused into the NAC shell following conditioning sessions. We found this effect to be regionally and temporally specific. These results suggest that, in addition to its role in alcohol-induced neurotoxicity, NF-κB mediates the development of alcohol place preference via its actions in the NAC shell.
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Condicionamiento Psicológico/efectos de los fármacos , Etanol/antagonistas & inhibidores , Etanol/farmacología , FN-kappa B/metabolismo , Núcleo Accumbens/lesiones , Núcleo Accumbens/patología , Animales , Daunorrubicina/análogos & derivados , Daunorrubicina/farmacología , Núcleo Dorsal del Rafe/metabolismo , Femenino , Masculino , Ratones , Ratones Transgénicos , Microinyecciones , beta-Galactosidasa/metabolismoRESUMEN
INTRODUCTION: To explore the effect of accumbens nucleus shell (ACbSh) lesioning on bitemporal lobe epilepsy. MATERIAL AND METHODS: Adult Wistar rats (male) were enrolled and randomly assigned into the control group and epilepsy groups with multiple time-points. Lithium-pilocarpine was used to establish the rat epilepsy model, while the control group received an equal amount of saline. Ibotenic acid stereotaxic injection was performed to cause accumbens nucleus shell lesioning for specific groups. Cascade software was used for electroencephalogram (EEG) examination. Fluoro-Jade C staining was performed to examine neuronal degeneration. RESULTS: Latency period of the epilepsy in epilepsy groups was 15.3 ± 1.1 min, and epilepsy intensity was 4.8 ± 0.5 events/ 12 h. ACbSh lesioning significantly reduced aggressive behavior. Compared with epilepsy groups without ACbSh lesioning, ACbSh lesioning significantly decreased epileptic seizures and reduced epileptic duration (p < 0.05). EEG showed that there were still sharp waves in the hippocampus and amygdala region after ACbSh lesioning, but epileptic discharge in prefrontal cortex was significantly decreased (p < 0.05), while epilepsy groups without ACbSh lesioning had more sharp waves in the prefrontal cortex, hippocampus and amygdala region. Fluoro-Jade C staining showed that ACbSh lesioning significantly decreased grades of neuronal degeneration (p < 0.05). CONCLUSIONS: Recurrent epilepsy caused neuronal degeneration via ACbSh region-related pathways, and ACbSh lesioning could mitigate epilepsy-caused neuronal degeneration by reducing epileptic discharge.
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Epilepsia/patología , Núcleo Accumbens/patología , Corteza Prefrontal/patología , Convulsiones/patología , Animales , Modelos Animales de Enfermedad , Hipocampo/patología , Hipocampo/fisiopatología , Masculino , Núcleo Accumbens/lesiones , Corteza Prefrontal/fisiopatología , Ratas WistarRESUMEN
The performance of conditioned responses (CRs) is diminished when trained subjects are tested in a novel context. This study tested the hypothesis that the flow of contextual information along the disynaptic "ESA" (entorhinal cortex-ventral subiculum-nucleus accumbens) pathway is responsible for context-related modulation of CRs. Rabbits received electrolytic or sham lesions of the ventral subiculum followed by discriminative avoidance conditioning and counterbalanced extinction sessions in the original training context, a novel context, and the original training context with a novel cue. Neuronal activity was recorded simultaneously in the nucleus accumbens, cingulate cortex, and basolateral amygdala. The lesions did not affect the acquisition of avoidance behavior or prevent the reduction of CRs in response to a novel cue. However, the lesions did reduce CR incidence during extinction, and they did eliminate a further novel-context-induced CR reduction found in controls. In addition, lesions disrupted context-dependent neuronal responses in the nucleus accumbens but not in the cingulate cortex or amygdala. These findings are interpreted as supportive of the hypothesis that the ESA pathway mediates contextual modulation of CRs during extinction.
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Condicionamiento Clásico/fisiología , Extinción Psicológica/fisiología , Hipocampo/fisiología , Núcleo Accumbens/fisiología , Potenciales de Acción/fisiología , Animales , Reacción de Prevención/fisiología , Conducta Animal/fisiología , Discriminación en Psicología/fisiología , Hipocampo/lesiones , Masculino , Núcleo Accumbens/lesiones , ConejosRESUMEN
Across different behavioural tasks, nucleus accumbens (n.acc) lesions have generated conflicting effects on locomotor activity and in particular, the relative roles of the n.acc shell and core subfields in this have been controversial. To date there is only one study examining effects of lesions to the medial n.acc on elevated plus-maze (EPM) behaviour; these lesions were shown to increase both locomotor and exploratory activity. Given the well-documented distinction between shell and core, the present study sought to extend previous research by testing lesions selective to each n.acc subfield in the EPM. Results showed no statistical differences between core lesioned and sham-operated animals on any measure. In contrast, shell lesions consistently reduced locomotion and exploratory activity. This direction of effects is opposite to that previously observed after medial n.acc. lesions. In conclusion, locomotion and exploratory activity were clearly reduced by shell but not core lesions, consistent with other evidence for the functional heterogeneity of n.acc shell and core.
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Aprendizaje por Laberinto/fisiología , Núcleo Accumbens/lesiones , Núcleo Accumbens/fisiología , Animales , Conducta Animal , Electrólisis/efectos adversos , Conducta Exploratoria/fisiología , Locomoción/fisiología , Masculino , Núcleo Accumbens/anatomía & histología , Ratas , Ratas WistarRESUMEN
Analysis of the nature of changes in the immune response in operated Wistar rats showed that electrolytic lesioning of the nucleus accumbens, the site of the greatest density of dopamine D1 and D2 receptors, led to suppression of the immune response in animals immunized with sheep erythrocytes. Administration of SKF 38393 (20 mg/kg) and quinpirol (1 mg/kg), selective agonists of dopamine D1 and D2 receptors respectively, to sham-operated rats induced significant increases in immune responses. However, no immunostimulation was seen on administration of the selective dopamine D2 agonist quinpirol to animals with lesions to the nucleus accumbens as compared with controls. At the same time, treatment of animals with nucleus accumbens lesions using the dopamine D1 receptor agonist SKF 38393 had no effect on the immune response as compared with that in sham-operated animals given the D1 receptor agonist. These data provide evidence that dopamine D2 receptors in the nucleus accumbens have a role in the mechanisms of immunostimulation, though D2 receptors in other brain structures may also make some contribution to this process; D1 receptors in the nucleus accumbens make no significant contribution to controlling the immune response.
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Inmunización , Núcleo Accumbens/inmunología , Receptores de Dopamina D1/fisiología , Receptores de Dopamina D2/fisiología , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/farmacología , Análisis de Varianza , Animales , Agonistas de Dopamina/farmacología , Eritrocitos/inmunología , Masculino , Núcleo Accumbens/lesiones , Quinpirol/farmacología , Ratas , Ratas Wistar , Formación de Roseta/métodos , OvinosRESUMEN
Drugs of abuse increase the frequency and magnitude of brief (1-3s), high concentration (phasic) dopamine release events in terminal regions. These are thought to be a critical part of drug reinforcement and ultimately the development of addiction. Recently, metabolic regulatory peptides, including the satiety signal glucagon-like peptide-1 (GLP-1), have been shown to modulate cocaine reward-driven behavior and sustained dopamine levels after cocaine administration. Here, we use fast-scan cyclic voltammetry (FSCV) to explore GLP-1 receptor (GLP-1R) modulation of dynamic dopamine release in the nucleus accumbens (NAc) during cocaine administration. We analyzed dopamine release events in both the NAc shell and core, as these two subregions are differentially affected by cocaine and uniquely contribute to motivated behavior. We found that central delivery of the GLP-1R agonist Exendin-4 suppressed the induction of phasic dopamine release events by intravenous cocaine. This effect was selective for dopamine signaling in the NAc core. Suppression of phasic signaling in the core by Exendin-4 could not be attributed to interference with cocaine binding to one of its major substrates, the dopamine transporter, as cocaine-induced increases in reuptake were unaffected. The results suggest that GLP-1R activation, instead, exerts its suppressive effects by altering dopamine release - possibly by suppressing the excitability of dopamine neurons. Given the role of NAc core dopamine in the generation of conditioned responses based on associative learning, suppression of cocaine-induced dopamine signaling in this subregion by GLP-1R agonism may decrease the reinforcing properties of cocaine. Thus, GLP-1Rs remain viable targets for the treatment and prevention of cocaine seeking, taking and relapse.
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Cocaína/farmacología , Inhibidores de Captación de Dopamina/farmacología , Dopamina/metabolismo , Receptor del Péptido 2 Similar al Glucagón/metabolismo , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Análisis de Varianza , Animales , Electrólisis/métodos , Exenatida , Receptor del Péptido 2 Similar al Glucagón/agonistas , Hipoglucemiantes/farmacología , Masculino , Núcleo Accumbens/lesiones , Péptidos/farmacología , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Factores de Tiempo , Ponzoñas/farmacologíaRESUMEN
Repeated exposure to cocaine leads to behavioral sensitization, which is the augmentation of the locomotor response to a subsequent exposure to the drug. The nucleus accumbens (NAc), a major termination site of dopaminergic neurons, is believed to be involved in behavioral sensitization and studies have demonstrated that the NAc shell can be split into five zones of analysis; the vertex, arch, cone, intermediate and ventrolateral zones [Todtenkopf MS, Stellar JR. Assessment of tyrosine hydroxylase immunoreactive innervation in five subregions of the nucleus accumbens shell in rats treated with repeated cocaine. Synapse 2000;38:261-70]. Several reports show cocaine-induced c-fos expression particularly in the intermediate zone after 14, but not 2, drug-free days following repeated cocaine administration, suggesting that this region may be involved in sensitization and particularly in the later phase of expression, versus the earlier phase of sensitization. Bilateral electrolytic lesions of the intermediate zone were made in two groups of rats, which were then repeatedly exposed to cocaine (15 mg/kg, twice/day for 5 days). One group was subsequently given a single cocaine challenge injection (15 mg/kg) after 14 drug-free days, while the other group was challenged after only 2 drug-free days. Two sham surgery groups in which an electrode was lowered but no current was passed served as controls. Results show that lesioned animals as well as sham controls exhibited behavioral sensitization to the drug. However, following a 14-day drug-free period, the lesioned animals showed significant reduction in sensitization, compared to sham controls. Together these findings suggest that the intermediate zone of the NAc shell is indeed involved in the expression phase of behavioral sensitization to cocaine.
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Conducta Animal/efectos de los fármacos , Cocaína/administración & dosificación , Inhibidores de Captación de Dopamina/administración & dosificación , Electrólisis , Núcleo Accumbens/lesiones , Núcleo Accumbens/fisiopatología , Análisis de Varianza , Animales , Inmunohistoquímica/métodos , Masculino , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Núcleo Accumbens/metabolismo , Núcleo Accumbens/patología , Ratas , Ratas Sprague-Dawley , Síndrome de Abstinencia a Sustancias/psicología , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Both humans and non-humans discount the value of rewards that are delayed or uncertain, and individuals that discount delayed rewards at a relatively high rate are considered impulsive. To investigate the neural mechanisms that mediate delay discounting, the present study examined the effects of excitotoxic lesions of the nucleus accumbens (NAC) on discounting of reward value by delay and probability. Rats were trained on delay (n=24) or probability discounting (n=24) tasks. Following training, excitotoxic lesions of the NAC were made by intracranial injections of 0.5 microl 0.15 M quinolinic acid (n=12) or vehicle (n=12) aimed at the NAC (AP +1.6, ML +/-1.5, DV -7.1). NAC lesions did not alter performance in animals tested with a constant delay (4s) or probability (0.4) of reinforcement. However, when tested with between session changes in the delay (0, 1, 2, 4, and 8s) of reinforcement, the lesioned rats had flatter discount curves than the sham group, indicating that they were less sensitive to frequent changes in the delay to reward. In contrast, the NAC lesions did not affect discounting of probabilistic rewards. NAC lesions impaired the ability to adapt to frequent between session changes in the delay to reward but did not increase or decrease discounting when the delay was held constant across sessions. NAC lesions may disrupt the ability of the animals to predict the timing of delayed rewards when the delay to reward is changed frequently.
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Lesiones Encefálicas/patología , Núcleo Accumbens/fisiopatología , Tiempo de Reacción/fisiología , Refuerzo en Psicología , Animales , Conducta Animal , Peso Corporal/efectos de los fármacos , Peso Corporal/fisiología , Lesiones Encefálicas/inducido químicamente , Condicionamiento Operante/efectos de los fármacos , Condicionamiento Operante/fisiología , Inmunohistoquímica/métodos , Masculino , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Núcleo Accumbens/lesiones , Fosfopiruvato Hidratasa/metabolismo , Probabilidad , Ácido Quinolínico/toxicidad , Ratas , Ratas Sprague-Dawley , Esquema de Refuerzo , Factores de TiempoRESUMEN
Neurotensin (NT) modulates ventral tegmental area (VTA) signaling in a manner relevant to psychostimulant drug actions, thus inviting evaluation of psychostimulant effects in conditions of reduced or absent VTA NT. However, in a preliminary study, NT immunoreactivity (-ir) in the VTA was unaffected following destruction of the main concentration of forebrain neurotensinergic VTA afferents in the lateral preoptic-rostral lateral hypothalamic continuum (LPH) and adjacent lateral part of the medial preoptic area (MPOA). This study attempted to determine what measures are necessary to obtain a significant reduction of VTA NT-ir. Large unilateral ibotenic acid lesions were made in several structures containing NTergic, VTA-projecting neurons, including the LPH-MPOA, nucleus accumbens, VTA itself and dorsal raphe. None of these was associated with substantial ipsilateral loss of NT-ir in the VTA, lateral hypothalamus or lateral habenula. Combinations of lesions, such as LPH-MPOA plus VTA and LPH-MPOA plus dorsal raphe, also failed to substantially reduce NT-ir in these structures. Transections of the medial forebrain bundle (mfb) likewise failed to produce a substantial loss of VTA NT-ir measured with immunohistochemistry and radioimmunoassay. Transections of the mfb were carried out in combination with infusions of retrograde and anterograde axonal tract-tracers, revealing that the routes taken by some forebrain NT-ir VTA afferents circumvent mfb transections. All of these results together are consistent with the hypothesis that the connectional organization of forebrain and brainstem, potentially in combination with limited adaptive synaptogenesis, renders the VTA relatively insensitive to moderate losses of neurotensinergic and, perhaps, other peptidergic afferents.
Asunto(s)
Vías Eferentes/fisiología , Neurotensina/metabolismo , Prosencéfalo/anatomía & histología , Área Tegmental Ventral/metabolismo , Adrenérgicos/toxicidad , Animales , Vías Eferentes/efectos de los fármacos , Vías Eferentes/lesiones , Agonistas de Aminoácidos Excitadores/toxicidad , Lateralidad Funcional , Ácido Iboténico/toxicidad , Inmunohistoquímica/métodos , Hibridación in Situ/métodos , Masculino , Haz Prosencefálico Medial/efectos de los fármacos , Haz Prosencefálico Medial/lesiones , Haz Prosencefálico Medial/fisiología , Neurotensina/genética , Núcleo Accumbens/lesiones , Núcleo Accumbens/fisiología , Oxidopamina/toxicidad , Fitohemaglutininas/metabolismo , Prosencéfalo/metabolismo , Radioinmunoensayo/métodos , Ratas , Ratas Sprague-Dawley , Factores de Tiempo , Aglutinina del Germen de Trigo-Peroxidasa de Rábano Silvestre Conjugada/metabolismoRESUMEN
This study examined the effects of sexual experience in female hamsters (Mesocricetus auratus) on copulatory interactions with male hamsters. Female sexual experience improved the copulatory efficiency of sexually naive males, an effect that persisted for at least 6 weeks without further sexual behavior testing. In a 2nd study, dopamine lesions made in the region of the nucleus accumbens prior to sexual experience specifically blocked the effects of the female's sexual experience on the hit rate of naive males. These results suggest that sexual experience in female hamsters increases the efficiency of copulatory interactions with males, that these effects persist in the absence of further sexual experience, and that dopamine neurotransmission in the basal forebrain underlies this effect of sexual experience.