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BACKGROUND: Caffeine is frequently consumed with ethanol to reduce the impairing effects induced by ethanol, including psychomotor slowing or incoordination. Both drugs modulate dopamine (DA)-related markers in accumbens (Acb), and Acb DA is involved in voluntary locomotion and locomotor sensitization. The present study determined whether caffeine can affect locomotion induced by acute and repeated ethanol administration in adult male CD-1 mice. METHODS: Acute administration of caffeine (7.5 to 30.0 mg/kg) was evaluated for its effects on acute ethanol-induced (1.5 to 3.5 g/kg) changes in open-field horizontal locomotion, supported rearing, and rearing not supported by the wall. DA receptor-dependent phosphorylation markers were assessed: extracellular signal-regulated kinase (pERK), and dopamine-and cAMP-regulated phosphoprotein Mr32kDa phosphorylated at threonine 75 site (pDARPP-32-Thr75) in Acb core and shell. Acutely administered caffeine was also evaluated in ethanol-sensitized (1.5 g/kg) mice. RESULTS: Acute ethanol decreased both types of rearing. Caffeine increased supported rearing but did not block ethanol -induced decreases in rearing. Both substances increased horizontal locomotion in a biphasic manner, and caffeine potentiated ethanol-induced locomotion. Although ethanol administered repeatedly induced sensitization of locomotion and unsupported rearing, acute administration of caffeine to ethanol-sensitized mice in an ethanol-free state resulted in blunted stimulant effects compared with those seen in ethanol-naïve mice. Ethanol increased pERK immunoreactivity in both subregions of the Acb, but coadministration with caffeine blunted this increase. There were no effects on pDARPP-32(Thr75) immunoreactivity. CONCLUSIONS: The present results demonstrated that, after the first administration, caffeine potentiated the stimulating actions of ethanol, but did not counteract its suppressant or ataxic effects. Moreover, our results show that caffeine has less activating effects in ethanol-sensitized animals.
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Cafeína/administração & dosagem , Fosfoproteína 32 Regulada por cAMP e Dopamina/metabolismo , Etanol/administração & dosagem , Locomoção/fisiologia , Sistema de Sinalização das MAP Quinases/fisiologia , Núcleo Accumbens/metabolismo , Animais , Relação Dose-Resposta a Droga , Etanol/antagonistas & inibidores , Locomoção/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Núcleo Accumbens/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Fosforilação/fisiologiaRESUMO
Motivation has been defined as the process that allows organisms to regulate their internal and external environment, and control the probability, proximity and availability of stimuli. As such, motivation is a complex process that is critical for survival, which involves multiple behavioural functions mediated by a number of interacting neural circuits. Classical theories of motivation suggest that there are both directional and activational aspects of motivation, and activational aspects (i.e. speed and vigour of both the instigation and persistence of behaviour) are critical for enabling organisms to overcome work-related obstacles or constraints that separate them from significant stimuli. The present review discusses the role of brain dopamine and related circuits in behavioural activation, exertion of effort in instrumental behaviour, and effort-related decision-making, based upon both animal and human studies. Impairments in behavioural activation and effort-related aspects of motivation are associated with psychiatric symptoms such as anergia, fatigue, lassitude and psychomotor retardation, which cross multiple pathologies, including depression, schizophrenia, and Parkinson's disease. Therefore, this review also attempts to provide an interdisciplinary approach that integrates findings from basic behavioural neuroscience, behavioural economics, clinical neuropsychology, psychiatry, and neurology, to provide a coherent framework for future research and theory in this critical field. Although dopamine systems are a critical part of the brain circuitry regulating behavioural activation, exertion of effort, and effort-related decision-making, mesolimbic dopamine is only one part of a distributed circuitry that includes multiple neurotransmitters and brain areas. Overall, there is a striking similarity between the brain areas involved in behavioural activation and effort-related processes in rodents and in humans. Animal models of effort-related decision-making are highly translatable to humans, and an emerging body of evidence indicates that alterations in effort-based decision-making are evident in several psychiatric and neurological disorders. People with major depression, schizophrenia, and Parkinson's disease show evidence of decision-making biases towards a lower exertion of effort. Translational studies linking research with animal models, human volunteers, and clinical populations are greatly expanding our knowledge about the neural basis of effort-related motivational dysfunction, and it is hoped that this research will ultimately lead to improved treatment for motivational and psychomotor symptoms in psychiatry and neurology.
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Transtorno Depressivo Maior/fisiopatologia , Motivação/fisiologia , Vias Neurais/fisiologia , Doença de Parkinson/fisiopatologia , Esforço Físico/fisiologia , Esquizofrenia/fisiopatologia , Animais , Tomada de Decisões/fisiologia , Dopamina/fisiologia , HumanosRESUMO
Motivated behaviors are often characterized by a high degree of behavioral activation, and work output and organisms frequently make effort-related decisions based upon cost/benefit analyses. Moreover, people with major depression and other disorders often show effort-related motivational symptoms such as anergia, psychomotor retardation, and fatigue. It has been suggested that tasks measuring effort-related choice behavior could be used as animal models of the motivational symptoms of depression, and the present studies characterized the effort-related effects of the vesicular monoamine transport (VMAT) inhibitor tetrabenazine. Tetrabenazine produces depressive symptoms in humans and, because of its selective inhibition of VMAT-2, it preferentially depletes dopamine (DA). Rats were assessed using a concurrent fixed-ratio 5/chow feeding choice task that is known to be sensitive to dopaminergic manipulations. Tetrabenazine shifted response choice in rats, producing a dose-related decrease in lever pressing and a concomitant increase in chow intake. However, it did not alter food intake or preference in parallel free-feeding choice studies. The effects of tetrabenazine on effort-related choice were reversed by the adenosine A2A antagonist MSX-3 and the antidepressant bupropion. A behaviorally active dose of tetrabenazine decreased extracellular DA in nucleus accumbens and increased expression of DARPP-32 in accumbens medium spiny neurons in a pattern indicative of reduced transmission at both D1 and D2 DA receptors. These experiments demonstrate that tetrabenazine, which is used in animal models to produce depression-like effects, can alter effort-related choice behavior. These studies have implications for the development of animal models of the motivational symptoms of depression and related disorders.
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Inibidores da Captação Adrenérgica/farmacologia , Depressão/psicologia , Motivação/efeitos dos fármacos , Tetrabenazina/farmacologia , Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores , Antagonistas do Receptor A2 de Adenosina/farmacologia , Inibidores da Captação Adrenérgica/antagonistas & inibidores , Animais , Antidepressivos de Segunda Geração/farmacologia , Comportamento Animal/efeitos dos fármacos , Bupropiona/farmacologia , Condicionamento Operante/efeitos dos fármacos , Modelos Animais de Doenças , Dopamina/metabolismo , Fosfoproteína 32 Regulada por cAMP e Dopamina/metabolismo , Encefalinas/metabolismo , Comportamento Alimentar/efeitos dos fármacos , Imuno-Histoquímica , Masculino , Microdiálise , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Sprague-Dawley , Substância P/metabolismo , Tetrabenazina/antagonistas & inibidores , Xantinas/farmacologiaRESUMO
BACKGROUND: Depression and related disorders are characterized by deficits in behavioral activation, exertion of effort, and other psychomotor/motivational dysfunctions. Depressed patients show alterations in effort-related decision making and a bias towards selection of low effort activities. It has been suggested that animal tests of effort-related decision making could be useful as models of motivational dysfunctions seen in psychopathology. METHODS: Because clinical studies have suggested that inhibition of catecholamine uptake may be a useful strategy for treatment of effort-related motivational symptoms, the present research assessed the ability of bupropion to increase work output in rats responding on a test of effort-related decision-making (ie, a progressive ratio/chow feeding choice task). With this task, rats can choose between working for a preferred food (high-carbohydrate pellets) by lever pressing on a progressive ratio schedule vs obtaining a less preferred laboratory chow that is freely available in the chamber. RESULTS: Bupropion (10.0-40.0 mg/kg intraperitoneal) significantly increased all measures of progressive ratio lever pressing, but decreased chow intake. These effects were greatest in animals with low baseline levels of work output on the progressive ratio schedule. Because accumbens dopamine is implicated in effort-related processes, the effects of bupropion on markers of accumbens dopamine transmission were examined. Bupropion elevated extracellular dopamine levels in accumbens core as measured by microdialysis and increased phosphorylated dopamine and cyclic-AMP related phosphoprotein 32 kDaltons (pDARPP-32) immunoreactivity in a manner consistent with D1 and D2 receptor stimulation. CONCLUSION: The ability of bupropion to increase exertion of effort in instrumental behavior may have implications for the pathophysiology and treatment of effort-related motivational symptoms in humans.
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Bupropiona/farmacologia , Comportamento de Escolha/efeitos dos fármacos , Inibidores da Captação de Dopamina/farmacologia , Motivação/efeitos dos fármacos , Psicotrópicos/farmacologia , Esquema de Reforço , Animais , Comportamento de Escolha/fisiologia , Cromatografia Líquida de Alta Pressão , Dopamina/metabolismo , Fosfoproteína 32 Regulada por cAMP e Dopamina/metabolismo , Relação Dose-Resposta a Droga , Alimentos , Imuno-Histoquímica , Masculino , Microdiálise , Motivação/fisiologia , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/fisiologia , Fosforilação/efeitos dos fármacos , Ratos Sprague-DawleyRESUMO
Effort-based decision-making is impaired in multiple psychopathologies leading to significant impacts on the daily life of patients. Preclinical studies of this important transdiagnostic symptom in rodents are hampered, however, by limitations present in currently available decision-making tests, including the presence of delayed reinforcement and off-target cognitive demands. Such possible confounding factors can complicate the interpretation of results in terms of decision-making per se. In this study we addressed this problem using a novel touchscreen Rearing-Effort Discounting (RED) task in which mice choose between two single-touch responses: rearing up to touch an increasingly higher positioned stimulus to obtain a High Reward (HR) or touching a lower stimulus to obtain a Low Reward (LR). To explore the putative advantages of this new approach, RED was compared with a touchscreen version of the well-studied Fixed Ratio-based Effort Discounting (FRED) task, in which multiple touches are required to obtain an HR, and a single response is required to obtain an LR. Results from dopaminergic (haloperidol and d-amphetamine), behavioral (changes in the order of effort demand; fixed-ratio schedule in FRED or response height in RED), and dietary manipulations (reward devaluation by pre-feeding) were consistent with the presence of variables that may complicate interpretation of conventional decision-making tasks, and demonstrate how RED appears to minimize such variables.
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Dextroanfetamina , Haloperidol , Humanos , Camundongos , Animais , Haloperidol/farmacologia , Dextroanfetamina/farmacologia , Reforço Psicológico , Recompensa , Antagonistas de Dopamina/farmacologia , Tomada de Decisões/fisiologia , MotivaçãoRESUMO
Metformin, a primary anti-diabetic medication, has been anticipated to provide benefits for Alzheimer's disease (AD), also known as "type 3 diabetes". Nevertheless, some studies have demonstrated that metformin may trigger AD pathology and even elevate AD risk in humans. Despite this, limited research has elucidated the behavioral outcomes of metformin treatment, which would hold significant translational value. Thus, we aimed to perform thorough behavioral research on the prolonged administration of metformin to mice: We administered metformin (300 mg/kg/day) to transgenic 3xTg-AD and non-transgenic (NT) C57BL/6 mice over 1 and 2 years, respectively, and evaluated their behaviors across multiple domains via touchscreen operant chambers, including motivation, attention, memory, visual discrimination, and cognitive flexibility. We found metformin enhanced attention, inhibitory control, and associative learning in younger NT mice (≤16 months). However, chronic treatment led to impairments in memory retention and discrimination learning at older age. Furthermore, metformin caused learning and memory impairment and increased levels of AMPKα1-subunit, ß-amyloid oligomers, plaques, phosphorylated tau, and GSK3ß expression in AD mice. No changes in potential confounding factors on cognition, including levels of motivation, locomotion, appetite, body weight, blood glucose, and serum vitamin B12, were observed in metformin-treated AD mice. We also identified an enhanced amyloidogenic pathway in db/db mice, as well as in Neuro2a-APP695 cells and a decrease in synaptic markers, such as PSD-95 and synaptophysin in primary neurons, upon metformin treatment. Our findings collectively suggest that the repurposing of metformin should be carefully reconsidered when this drug is used for individuals with AD.
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Doença de Alzheimer , Metformina , Humanos , Camundongos , Animais , Doença de Alzheimer/metabolismo , Metformina/farmacologia , Metformina/uso terapêutico , Proteínas tau/metabolismo , Reposicionamento de Medicamentos , Camundongos Endogâmicos C57BL , Peptídeos beta-Amiloides/metabolismo , Camundongos Transgênicos , Cognição , Modelos Animais de Doenças , Precursor de Proteína beta-Amiloide/genéticaRESUMO
In the mouse embryonic forebrain, developmentally distinct oligodendrocyte progenitor cell populations and their progeny, oligodendrocytes, emerge from three distinct regions in a spatiotemporal gradient from ventral to dorsal. However, the functional importance of this oligodendrocyte developmental heterogeneity is unknown. Using a genetic strategy to ablate dorsally derived oligodendrocyte lineage cells (OLCs), we show here that the areas in which dorsally derived OLCs normally reside in the adult central nervous system become populated and myelinated by OLCs of ventral origin. These ectopic oligodendrocytes (eOLs) have a distinctive gene expression profile as well as subtle myelination abnormalities. The failure of eOLs to fully assume the role of the original dorsally derived cells results in locomotor and cognitive deficits in the adult animal. This study reveals the importance of developmental heterogeneity within the oligodendrocyte lineage and its importance for homeostatic brain function.
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Encéfalo , Linhagem da Célula , Oligodendroglia , Animais , Oligodendroglia/fisiologia , Camundongos , Encéfalo/citologia , Encéfalo/embriologia , Linhagem da Célula/fisiologia , Diferenciação Celular/fisiologia , Camundongos Transgênicos , Bainha de Mielina/metabolismo , Bainha de Mielina/fisiologiaRESUMO
Major depressive disorder (MDD) is a stress-related condition hypothesized to involve aberrant reinforcement learning (RL) with positive and negative stimuli. The present study investigated whether repeated early maternal separation (REMS) stress, a procedure widely recognized to cause depression-like behaviour, affects how subjects learn from positive and negative feedback. The REMS procedure was implemented by separating male and female rats from their dam for 6 h each day from post-natal day 5-19. Control rat offspring were left undisturbed during this period. Rats were tested as adults for behavioral flexibility and feedback sensitivity on a probabilistic reversal learning task. A computational approach based on RL theory was used to derive latent behavioral variables related to reward learning and flexibility. To assess underlying brain substrates, a seed-based functional MRI connectivity analysis was applied both before and after an additional adulthood stressor in control and REMS rats. Female but not male rats exposed to REMS stress showed increased response 'stickiness' (repeated responses regardless of reward outcome). Following repeated adulthood stress, reduced functional connectivity from the basolateral amygdala (BLA) to the dorsolateral striatum (DLS), cingulate cortex (Cg), and anterior insula (AI) cortex was observed in females. By contrast, control male rats exposed to the second stressor showed impaired learning from negative feedback (i.e., non-reward) and reduced functional connectivity from the BLA to the DLS and AI compared to maternally separated males. RL in male rats exposed to REMS was unaffected. The fMRI data further revealed that connectivity between the mOFC and other prefrontal cortical and subcortical structures was positively correlated with response 'stickiness'. These findings reveal differences in how females and males respond to early life adversity and subsequent stress. These effects may be mediated by functional divergence in resting-state connectivity between the basolateral amygdala and fronto-striatal brain regions.
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Early-life stress (ELS) or adversity, particularly in the form of childhood neglect and abuse, is associated with poor mental and physical health outcomes in adulthood. However, whether these relationships are mediated by the consequences of ELS itself or by other exposures that frequently co-occur with ELS is unclear. To address this question, we carried out a longitudinal study in rats to isolate the effects of ELS on regional brain volumes and behavioral phenotypes relevant to anxiety and depression. We used the repeated maternal separation (RMS) model of chronic ELS, and conducted behavioral measurements throughout adulthood, including of probabilistic reversal learning (PRL), responding on a progressive ratio task, sucrose preference, novelty preference, novelty reactivity, and putative anxiety-like behavior on the elevated plus maze. Our behavioral assessment was combined with magnetic resonance imaging (MRI) for quantitation of regional brain volumes at three time points: immediately following RMS, young adulthood without further stress, and late adulthood with further stress. We found that RMS caused long-lasting, sexually dimorphic biased responding to negative feedback on the PRL task. RMS also slowed response time on the PRL task, but without this directly impacting task performance. RMS animals were also uniquely sensitive to a second stressor, which disproportionately impaired their performance and slowed their responding on the PRL task. MRI at the time of the adult stress revealed a larger amygdala volume in RMS animals compared with controls. These behavioral and neurobiological effects persisted well into adulthood despite a lack of effects on conventional tests of 'depression-like' and 'anxiety-like' behavior, and a lack of any evidence of anhedonia. Our findings indicate that ELS has long-lasting cognitive and neurobehavioral effects that interact with stress in adulthood and may have relevance for understanding the etiology of anxiety and depression in humans.
Assuntos
Experiências Adversas da Infância , Adulto , Humanos , Animais , Ratos , Adulto Jovem , Retroalimentação , Estudos Longitudinais , Privação Materna , Estresse Psicológico/diagnóstico por imagem , Tonsila do Cerebelo/diagnóstico por imagem , ViésRESUMO
Despite considerable advances in both in silico and in vitro approaches, in vivo studies that involve animal model systems remain necessary in many research disciplines. Neuroscience is one such area, with studies often requiring access to a complete nervous system capable of dynamically selecting between and then executing a full range of cognitive and behavioral outputs in response to a given stimulus or other manipulation. The involvement of animals in research studies is an issue of active public debate and concern and is therefore carefully regulated. Such regulations are based on the principles of the 3Rs of Replacement, Reduction and Refinement. In the sub-specialty of behavioral neuroscience, Full/Absolute Replacement remains a major challenge, as the complete ex vivo recapitulation of a system as complex and dynamic as the nervous system has yet to be achieved. However, a number of very positive developments have occurred in this area with respect to Relative Replacement and to both Refinement and Reduction. In this review, we discuss the Refinement- and Reduction-related benefits yielded by the introduction of touchscreen-based behavioral assessment apparatus. We also discuss how data generated by a specific panel of behavioral tasks developed for this platform might substantially enhance monitoring of laboratory animal welfare and provide robust, quantitative comparisons of husbandry techniques to define and ensure maintenance of best practice.
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Bem-Estar do Animal , Ciências do Comportamento , Animais , Animais de Laboratório , Cognição , Modelos Animais de DoençasRESUMO
Impaired behavioral activation and effort-related motivational dysfunctions like fatigue and anergia are debilitating treatment-resistant symptoms of depression. Depressed people show a bias towards the selection of low effort activities. To determine if the broadly used antidepressant fluoxetine can improve behavioral activation and reverse dopamine (DA) depletion-induced anergia, male CD1 mice were evaluated for vigorous escape behaviors in an aversive context (forced swim test, FST), and also with an exercise preference choice task [running wheel (RW)-T-maze choice task]. In the FST, fluoxetine increased active behaviors (swimming, climbing) while reducing passive ones (immobility). However, fluoxetine was not effective at reducing anergia induced by the DA-depleting agent tetrabenazine, further decreasing vigorous climbing and increasing immobility. In the T-maze, fluoxetine alone produced the same pattern of effects as tetrabenazine. Moreover, fluoxetine did not reverse tetrabenazine-induced suppression of RW time but it reduced sucrose intake duration. This pattern of effects produced by fluoxetine in DA-depleted mice was dissimilar from devaluing food reinforcement by pre-feeding or making the food bitter since in both cases sucrose intake time was reduced but animals compensated by increasing time in the RW. Thus, fluoxetine improved escape in an aversive context but decreased relative preference for active reinforcement. Moreover, fluoxetine did not reverse the anergic effects of DA depletion. These results have implications for the use of fluoxetine for treating motivational symptoms such as anergia in depressed patients.
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Perseveration and apathy are two of the most common behavioural and psychological symptoms of dementia (BPSDs) in amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD). Availability of a validated and behaviourally characterised animal model is crucial for translational research into BPSD in the FTD context. We behaviourally evaluated the male TDP-43Q331K mouse, an ALS-FTD model with a human-equivalent mutation (TDP-43Q331K) knocked into the endogenous Tardbp gene. We utilised a panel of behavioural tasks delivered using the rodent touchscreen apparatus, including progressive ratio (PR), extinction and visual discrimination/reversal learning (VDR) assays to examine motivation, response inhibition and cognitive flexibility, respectively. Relative to WT littermates, TDP-43Q331K mice exhibited increased responding under a PR schedule. While elevated PR responding is typically an indication of increased motivation for reward, a trial-by-trial response rate analysis revealed that TDP-43Q331K mice exhibited decreased maximal response rate and slower response decay rate, suggestive of reduced motivation and a perseverative behavioural phenotype, respectively. In the extinction assay, TDP-43Q331K mice displayed increased omissions during the early phase of each session, consistent with a deficit in activational motivation. Finally, the VDR task revealed cognitive inflexibility, manifesting as stimulus-bound perseveration. Together, our data indicate that male TDP-43Q331K mice exhibit a perseverative phenotype with some evidence of apathy-like behaviour, similar to BPSDs observed in human ALS-FTD patients. The TDP-43Q331K knock-in mouse therefore has features that recommend it as a useful platform to facilitate translational research into behavioural symptoms in the context of ALS-FTD.
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Esclerose Lateral Amiotrófica , Apatia , Demência Frontotemporal , Idoso , Esclerose Lateral Amiotrófica/genética , Animais , Proteínas de Ligação a DNA/genética , Demência Frontotemporal/genética , Humanos , Masculino , Camundongos , MutaçãoRESUMO
Drug-associated contexts and discrete cues can trigger motivational states responsible for drug-seeking behavior and relapse. In preclinical research, drug-free conditioned hyperactivity has been used to investigate the expression of memories associated with psychostimulant drug effects. Addictive drugs can produce long-lasting sensitization to their psychomotor actions, a phenomenon known as behavioral sensitization. The neuroplasticity underlying behavioral sensitization appears to be involved in pathological drug pursuit and abuse. In the present study we evaluated drug-free, context-dependent hyperactivity in DBA/2â¯J mice previously treated with cocaine and we explored whether this conditioned effect was related to behavioral sensitization. Given the role of noradrenergic (NA) neurotransmission in memory retrieval, consolidation and reconsolidation processes, we also investigated whether conditioned hyperactivity in a drug-free state was mediated by NA receptors. Animals underwent a sensitization protocol with six cocaine injections (0, 5, 10 or 20â¯mg/kg) paired to a particular floor cue. Three days after this sensitization phase, all animals were exposed to the same familiar floor environment without drug treatment. A second test with an unfamiliar floor was conducted 24â¯h later. Conditioned hyperactivity was also explored after one or three cocaine pairings and was evaluated for its duration (with repeated familiar vs. unfamiliar floor tests). In a series of pharmacological experiments, we evaluated the effects propranolol (a non-selective antagonist of ß1- and ß2-receptors) and prazosin (α1-receptor antagonist) on conditioned hyperactivity. Cocaine treatment produced both robust sensitization and drug-free conditioned hyperactivity, an effect that lasted up to 17â¯days (with cocaine 20â¯mg/kg). A significant correlation between the magnitude of cocaine sensitization and the level of conditioned hyperactivity was found. Propranolol, but not prazosin, blocked context-dependent hyperlocomotion in a drug-free state. Our data, together with a vast body of literature, indicate that the NA system plays a key role in the retrieval and behavioral expression of drug-associated memories.
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Comportamento Animal/efeitos dos fármacos , Cocaína/efeitos adversos , Locomoção/efeitos dos fármacos , Agitação Psicomotora/etiologia , Receptores Adrenérgicos/fisiologia , Antagonistas de Receptores Adrenérgicos alfa 1/administração & dosagem , Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Antagonistas Adrenérgicos beta/administração & dosagem , Antagonistas Adrenérgicos beta/farmacologia , Animais , Associação , Cocaína/administração & dosagem , Cocaína/farmacologia , Condicionamento Psicológico/efeitos dos fármacos , Comportamento de Procura de Droga , Injeções Intraperitoneais , Masculino , Memória/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos DBA , Norepinefrina/metabolismo , Prazosina/administração & dosagem , Prazosina/farmacologia , Propranolol/administração & dosagem , Propranolol/farmacologiaRESUMO
This review is concerned with methods for assessing the processing of unrewarded responses in experimental animals and the mechanisms underlying performance of these tasks. A number of clinical populations, including Parkinson's disease, depression, compulsive disorders, and schizophrenia demonstrate either abnormal processing or learning from non-rewarded responses in laboratory-based reinforcement learning tasks. These effects are hypothesized to result from disturbances in modulatory neurotransmitter systems, including dopamine and serotonin. Parallel work in experimental animals has revealed consistent behavioral patterns associated with non-reward and, consistent with the human literature, modulatory roles for specific neurotransmitters. Classical tests involving an important reward omission component include appetitive extinction, ratio schedules of responding, reversal learning, and delay and probability discounting procedures. In addition, innovative behavioral tests have recently been developed leverage probabilistic feedback to specifically assay accommodation of, and learning from, non-rewarded responses. These procedures will be described and reviewed with discussion of the behavioral and neural determinants of performance. A final section focusses specifically on the benefits of trial-by-trial analysis of responding during such tasks, and the implications of such analyses for the translation of findings to clinical studies.
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Encéfalo/fisiologia , Modelos Animais de Doenças , Neurotransmissores/metabolismo , Recompensa , Pesquisa Translacional Biomédica , Animais , Aprendizagem por Associação/fisiologia , Condicionamento Clássico/fisiologia , Condicionamento Operante/fisiologia , Desvalorização pelo Atraso/fisiologia , Dopamina/metabolismo , Humanos , Masculino , Motivação/fisiologia , Reforço Psicológico , Reversão de Aprendizagem/fisiologia , Esquizofrenia/fisiopatologia , Psicologia do Esquizofrênico , Serotonina/metabolismoRESUMO
Physical activities can have intrinsic motivational or reinforcing properties. The choice to engage in voluntary physical activity is undertaken in relation to the selection of other alternatives, such as sedentary behaviors, drugs, or food intake. The mesolimbic dopamine (DA) system plays a critical role in behavioral activation or exertion of effort, and DA antagonism or depletion induces anergia in effort-based decision-making tasks. However, little is known about the neural mechanisms underlying the decision-making processes that establish preferences for sedentary vs. activity-based reinforcers. In the present work with male CD1 mice, we evaluated the effect of tetrabenazine (TBZ), a DA-depleting agent, on a three-choice T-maze task developed to assess preference between reinforcers with different behavioral activation requirements and sensory properties [i.e., a running wheel (RW) vs. sweet pellets or a neutral nonsocial odor]. We also studied the effects of TBZ on the forced swim test (FST), which measures climbing and swimming in a stressful setting, and on anxiety tests [dark-light (DL) box and elevated plus maze (EPM)]. In the three-choice task, TBZ reduced time running in the wheel but increased time spent consuming sucrose, thus indicating reduced activation but relatively intact sucrose reinforcement. The effect of TBZ was not mimicked by motivational manipulations that change the value of the reinforcers, such as making the RW aversive or harder to move, food-restricting the animals, inducing a binge-like eating pattern, or introducing social odors. In the FST, TBZ decreased time climbing (most active behavior) and increased immobility but did not affect anxiety in the DL or EPM. These results indicate that the three-choice T-maze task could be useful for assessing DA modulation of preferences for exercise based on activation and effort requirements, differentiating those effects from changes in preference produced by altering physical requirements, food restriction state, and stress during testing.
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RATIONALE: Dopamine D2-like receptors (D2R) are important drug targets in schizophrenia and Parkinson's disease, but D2R ligands also cause cognitive inflexibility such as poor reversal learning. The specific role of D2R in reversal learning remains unclear. OBJECTIVES: We tested the hypotheses that D2R agonism impairs reversal learning by blocking negative feedback and that antagonism of D1-like receptors (D1R) impairs learning from positive feedback. METHODS: Male Lister Hooded rats were trained on a novel visual reversal learning task. Performance on "probe trials", during which the correct or incorrect stimulus was presented with a third, probabilistically rewarded (50% of trials) and therefore intermediate stimulus, revealed individual learning curves for the processes of positive and negative feedback. The effects of D2R and D1R agonists and antagonists were evaluated. A separate cohort was tested on a spatial probabilistic reversal learning (PRL) task after D2R agonism. Computational reinforcement learning modelling was applied to choice data from the PRL task to evaluate the contribution of latent factors. RESULTS: D2R agonism with quinpirole dose-dependently impaired both visual reversal and PRL. Analysis of the probe trials on the visual task revealed a complete blockade of learning from negative feedback at the 0.25 mg/kg dose, while learning from positive feedback was intact. Estimated parameters from the model that best described the PRL choice data revealed a steep and selective decrease in learning rate from losses. D1R antagonism had a transient effect on the positive probe trials. CONCLUSIONS: D2R stimulation impairs reversal learning by blocking the impact of negative feedback.
Assuntos
Retroalimentação Fisiológica/fisiologia , Estimulação Luminosa/métodos , Receptores de Dopamina D2/metabolismo , Reversão de Aprendizagem/fisiologia , Percepção Espacial/fisiologia , Animais , Dopamina/farmacologia , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Antagonistas dos Receptores de Dopamina D2/farmacologia , Retroalimentação Fisiológica/efeitos dos fármacos , Masculino , Ratos , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/antagonistas & inibidores , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/agonistas , Reversão de Aprendizagem/efeitos dos fármacos , Percepção Espacial/efeitos dos fármacos , Percepção Visual/efeitos dos fármacos , Percepção Visual/fisiologiaRESUMO
Major depressive disorder is one of the most common and debilitating psychiatric disorders. Some of the motivational symptoms of depression, such anergia (lack of self-reported energy) and fatigue are relatively resistant to traditional treatments such as serotonin uptake inhibitors. Thus, new pharmacological targets are being investigated. Epidemiological data suggest that caffeine consumption can have an impact on aspects of depressive symptomatology. Caffeine is a non-selective adenosine antagonist for A1/A2A receptors, and has been demonstrated to modulate behavior in classical animal models of depression. Moreover, selective adenosine receptor antagonists are being assessed for their antidepressant effects in animal studies. This review focuses on how caffeine and selective adenosine antagonists can improve different aspects of depression in humans, as well as in animal models. The effects on motivational symptoms of depression such as anergia, fatigue, and psychomotor slowing receive particular attention. Thus, the ability of adenosine receptor antagonists to reverse the anergia induced by dopamine antagonism or depletion is of special interest. In conclusion, although further studies are needed, it appears that caffeine and selective adenosine receptor antagonists could be therapeutic agents for the treatment of motivational dysfunction in depression.
RESUMO
Caffeine is a methylxanthine consumed in different contexts to potentiate alertness and reduce fatigue. However, caffeine can induce anxiety at high doses. Caffeine is also a minor psychostimulant that seems to act as an appetite suppressant, but there are also reports indicating that it could stimulate appetite. Dopamine also is involved in food motivation and in behavioral activation. In the present series of experiments, we evaluated the effects of acute administration of caffeine on food consumption under different access conditions. CD1 male adult mice had access to highly palatable food (50% sucrose) in a restricted but habitual context, under continuous or intermittent access as well as under anxiogenic, or effortful conditions. Caffeine (2.5-20.0 mg/kg) increased intake at the highest dose under familiar continuous and intermittent access. However, this high dose reduced food intake in the dark-light paradigm. In contrast, a dopamine-depleting agent, tetrabenazine (TBZ; 1.0-8.0 mg/kg) did not affect food intake in any of those experimental conditions. In the T-maze-barrier task that evaluates seeking and taking of food under effortful conditions, caffeine (10.0 mg/kg) decreased latency to reach the food, but did not affect selection of the high-food density arm that required more effort, or the total amount of food consumed. In contrast, TBZ (4.0 mg/kg) reduced selection of the high food density arm with the barrier, thus affecting amount of food consumed. Interestingly, a small dose of caffeine (5.0 mg/kg) was able to reverse the anergia-inducing effects produced by TBZ in the T-maze. These results suggest that caffeine can potentiate or suppress food consumption depending on the context. Moreover, caffeine did not change appetite, and did not impair orientation toward food under effortful conditions, but it rather helped to achieve the goal by improving speed and by reversing performance to normal levels when fatigue was induced by dopamine depletion.
RESUMO
Motivated behavior is characterized by activation and high work output. Nucleus accumbens (Nacb) modulates behavioral activation and effort-based decision-making. Caffeine is widely consumed because of its energizing properties. This methylxanthine is a non-selective adenosine A1/A2A receptor antagonist. Adenosine receptors are highly concentrated in Nacb. Adenosine agonists injected into Nacb, shift preference towards low effort alternatives. The present studies characterized effort-related effects of caffeine in a concurrent progressive ratio (PROG)/free reinforcer choice procedure that requires high levels of work output, and generates great variability among different animals. Male Sprague-Dawley rats received an acute dose of caffeine (2.5-20.0â¯mg/kg, IP) and 30â¯min later were tested in operant boxes. One group was food-restricted and had to lever pressed for high carbohydrate pellets, another group was non-food-restricted and lever pressed for a high sucrose solution. Caffeine (2.5 and 5.0â¯mg/kg) increased lever pressing in food-restricted animals that were already high responders. However, in non-restricted animals, caffeine (5.0 and 10.0â¯mg/kg) increased work output only among low responders. In fact, caffeine (10.0 and 20.0â¯mg/kg) in non-restricted animals, reduced lever pressing among high responders in the PROG task, and also in a different group of animals lever pressing in an easy task (fixed ratio 7 schedule) that uniformly generates high levels of responding. Caffeine did not modify sucrose preference or consumption under free access conditions. Thus, when animals do not have a homeostatic need, caffeine can help those not very intrinsically motivated to work harder for a more palatable reward. However, caffeine can disrupt performance of animals intrinsically motivated to work hard for a better reward.
Assuntos
Comportamento Animal/efeitos dos fármacos , Cafeína/farmacologia , Tomada de Decisões/efeitos dos fármacos , Antagonistas do Receptor A1 de Adenosina/administração & dosagem , Antagonistas do Receptor A1 de Adenosina/farmacologia , Antagonistas do Receptor A2 de Adenosina/administração & dosagem , Antagonistas do Receptor A2 de Adenosina/farmacologia , Animais , Cafeína/administração & dosagem , Relação Dose-Resposta a Droga , Masculino , Motivação , Ratos Sprague-Dawley , Sacarose/administração & dosagemRESUMO
The mesolimbic dopamine (DA) system plays a critical role in behavioral activation and effort-based decision-making. DA depletion produces anergia (shifts to low effort options) in animals tested on effort-based decision-making tasks. Caffeine, the most consumed stimulant in the world, acts as an adenosine A1/A2A receptor antagonist, and in striatal areas DA D1 and D2 receptors are co-localized with adenosine A1 and A2A receptors respectively. In the present work, we evaluated the effect of caffeine on anergia induced by the VMAT-2 inhibitor tetrabenazine (TBZ), which depletes DA. Anergia was evaluated in a three-chamber T-maze task in which animals can chose between running on a wheel (RW) vs. sedentary activities such as consuming sucrose or sniffing a neutral odor. TBZ-caffeine interactions in ventral striatum were evaluated using DARPP-32 phosphorylation patterns as an intracellular marker of DA-adenosine receptor interaction. In the T-maze, control mice spent more time running and much less consuming sucrose or sniffing. TBZ (4.0â¯mg/kg) reduced ventral striatal DA tissue levels as measured by HPLC, and also shifted preferences in the T-maze, reducing selection of the reinforcer that involved vigorous activity (RW), but increasing consumption of a reinforcer that required little effort (sucrose), at doses that had no effect on independent measures of appetite or locomotion in a RW. Caffeine at doses that had no effect on their own reversed the effects of TBZ on T-maze performance, and also suppressed TBZ-induced pDARPP-32(Thr34) expression as measured by western blot, suggesting a role for D2-A2A interactions. These results support the idea that DA depletion produces anergia, but does not affect the primary motivational effects of sucrose. Caffeine, possibly by acting on A2A receptors in ventral striatum, reversed the DA depletion effects. It is possible that caffeine, like selective adenosine A2A antagonists, could have some therapeutic benefit for treating effort-related symptoms.