RESUMO
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.
Assuntos
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
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
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.
Assuntos
Dopamina/metabolismo , Atividade Motora/fisiologia , Antagonistas de Receptores Purinérgicos P1/farmacologia , Receptores Purinérgicos P1/metabolismo , Reforço Psicológico , Inibidores da Captação Adrenérgica/farmacologia , Animais , Apetite/efeitos dos fármacos , Apetite/fisiologia , Tomada de Decisões/efeitos dos fármacos , Tomada de Decisões/fisiologia , Antagonistas de Dopamina/farmacologia , Fosfoproteína 32 Regulada por cAMP e Dopamina/metabolismo , Relação Dose-Resposta a Droga , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Receptores de Dopamina D2/metabolismo , Tetrabenazina/farmacologia , Estriado Ventral/efeitos dos fármacos , Estriado Ventral/metabolismo , Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores , Proteínas Vesiculares de Transporte de Monoamina/metabolismoRESUMO
Blockade of adenosine A2A receptors can potentiate motivation to work for natural reinforcers such as food. Conspecific interaction is a potent natural reinforcer in social animals that can be manifested as preference for social exploration versus other sources of novel stimulation. Deficiencies in this type of motivated behavior (social withdrawal) have been seen in several pathologies such as autism and depression. However, the role of A2A receptors in motivation for social interaction has not been widely explored. Social interaction paradigms evaluate the natural preference of animals for exploring other conspecifics, and the ability to differentiate between familiar versus novel ones. Anxiety is one of the factors that can induce avoidance of social interaction. In the present study, adenosine A2A knockout (A2AKO) and wild-type (WT) mice were assessed for social and anxiety-related behaviors. c-Fos immunoreactivity was evaluated as a measure of neuronal activation in brain areas involved in different aspects of motivation and emotional processes. Although A2AKO mice showed an anxious profile, they displayed higher levels of sociability and were less sensitive to social novelty. WT mice displayed a typical pattern of social recognition 24h later, but not A2AKO mice, which explored equally both conspecifics. There were no differences between strains in aggressiveness, perseverance or social odor preferences. c-Fos immunoreactivity in A2AKO mice was higher in anterior cingulate and amygdala compared to WT mice. Thus, A2A receptors appear to be potential targets for the improvement of pathologies related to social function.
Assuntos
Tonsila do Cerebelo/metabolismo , Ansiedade/metabolismo , Giro do Cíngulo/metabolismo , Receptor A2A de Adenosina/deficiência , Comportamento Social , Tonsila do Cerebelo/patologia , Animais , Giro do Cíngulo/patologia , Imuno-Histoquímica , Masculino , Camundongos Knockout , Neurônios/metabolismo , Neurônios/patologia , Percepção Olfatória/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Testes Psicológicos , Reconhecimento Psicológico/fisiologiaRESUMO
Ethanol and caffeine are frequently consumed in combination and have opposite effects on the adenosine system: ethanol metabolism leads to an increase in adenosine levels, while caffeine is a non-selective adenosine A1/A2A receptor antagonist. These receptors are highly expressed in striatum and olfactory tubercle, brain areas involved in exploration and social interaction in rodents. Ethanol modulates social interaction processes, but the role of adenosine in social behavior is still poorly understood. The present work was undertaken to study the impact of ethanol, caffeine and their combination on social behavior, and to explore the involvement of A1 and A2A receptors on those actions. Male CD1 mice were evaluated in a social interaction three-chamber paradigm, for preference of conspecific vs. object, and also for long-term recognition memory of familiar vs. novel conspecific. Ethanol showed a biphasic effect, with low doses (0.25 g/kg) increasing social contact and higher doses (1.0-1.5 g/kg) reducing social interaction. However, no dose changed social preference; mice always spent more time sniffing the conspecific than the object, independently of the ethanol dose. Ethanol, even at doses that did not change social exploration, produced amnestic effects on social recognition the following day. Caffeine reduced social contact (15.0-60.0 mg/kg), and even blocked social preference at higher doses (30.0-60.0 mg/kg). The A1 antagonist Cyclopentyltheophylline (CPT; 3-9 mg/kg) did not modify social contact or preference on its own, and the A2A antagonist MSX-3 (1.5-6 mg/kg) increased social interaction at all doses. Ethanol at intermediate doses (0.5-1.0 g/kg) was able to reverse the reduction in social exploration induced by caffeine (15.0-30.0 mg/kg). Although there was no interaction between ethanol and CPT or MSX-3 on social exploration in the first day, MSX-3 blocked the amnestic effects of ethanol observed on the following day. Thus, ethanol impairs the formation of social memories, and A2A adenosine antagonists can prevent the amnestic effects of ethanol, so that animals can recognize familiar conspecifics. On the other hand, ethanol can counteract the social withdrawal induced by caffeine, a non-selective adenosine A1/A2A receptor antagonist. These results show the complex set of interactions between ethanol and caffeine, some of which could be the result of the opposing effects they have in modulating the adenosine system.
RESUMO
This review paper is focused upon the involvement of mesolimbic dopamine (DA) and related brain systems in effort-based processes. Interference with DA transmission affects instrumental behavior in a manner that interacts with the response requirements of the task, such that rats with impaired DA transmission show a heightened sensitivity to ratio requirements. Impaired DA transmission also affects effort-related choice behavior, which is assessed by tasks that offer a choice between a preferred reinforcer that has a high work requirement vs. less preferred reinforcer that can be obtained with minimal effort. Rats and mice with impaired DA transmission reallocate instrumental behavior away from food-reinforced tasks with high response costs, and show increased selection of low reinforcement/low cost options. Tests of effort-related choice have been developed into models of pathological symptoms of motivation that are seen in disorders such as depression and schizophrenia. These models are being employed to explore the effects of conditions associated with various psychopathologies, and to assess drugs for their potential utility as treatments for effort-related symptoms. Studies of the pharmacology of effort-based choice may contribute to the development of treatments for symptoms such as psychomotor slowing, fatigue or anergia, which are seen in depression and other disorders.
Assuntos
Comportamento de Escolha/fisiologia , Condicionamento Operante/fisiologia , Depressão/fisiopatologia , Antagonistas de Dopamina/farmacologia , Dopamina/fisiologia , Individualidade , Animais , Comportamento de Escolha/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Modelos Animais de Doenças , Dopamina/deficiência , Humanos , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/fisiologia , Esquema de Reforço , RecompensaRESUMO
RATIONALE: Mesolimbic dopamine (DA) regulates behavioral activation and effort-related decision-making in motivated behaviors. Mesolimbic DA D2 receptors are co-localized with adenosine A2A receptors, and they interact in an antagonistic manner. OBJECTIVES: A T-maze task was developed to assess dopaminergic involvement in preference between a reinforcer that involves vigorous voluntary activity (running wheel) and a reinforcer that requires minimal behavioral activation (sucrose pellets). Haloperidol (D2 antagonist) was administered to adenosine A2A receptor knockout (A2AKO) and wild-type (WT) littermate controls to assess the involvement of these two receptors in the selection of running wheel activity versus sucrose consumption. RESULTS: Under control conditions, mice spent more time running and less time eating. In WT mice, haloperidol reduced time running but actually increased time-consuming sucrose. However, A2AKO mice did not show the haloperidol-induced shift from running wheel activity to sucrose intake. Prefeeding reduced sucrose consumption in the T-maze in both strains, indicating that this paradigm is sensitive to motivational devaluation. Haloperidol increased c-Fos immunoreactivity in anterior cingulate cortex (ACg) and nucleus accumbens (Acb) core of WT but not KO mice. CONCLUSIONS: These results indicate that after DA antagonism, the preference for vigorous physical activity is reduced, while palatable food selection increases. Adenosine A2A receptor deletion provides resistance to these effects of D2 receptor antagonism. These two receptors in Acb core and ACg seem to be involved in the regulation of the intrinsic reinforcing characteristics of voluntary exercise but not in the regulation of the primary reinforcing characteristics of palatable sedentary reinforcers.
Assuntos
Antagonistas de Dopamina/farmacologia , Dopamina/fisiologia , Haloperidol/farmacologia , Condicionamento Físico Animal/psicologia , Receptor A2A de Adenosina/genética , Sacarose/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/genética , Animais , Comportamento Animal/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Antagonistas dos Receptores de Dopamina D2/farmacologia , Giro do Cíngulo/efeitos dos fármacos , Giro do Cíngulo/metabolismo , Camundongos , Camundongos Knockout , Motivação/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Proteínas Proto-Oncogênicas c-fos/biossíntese , Receptores de Dopamina D2/efeitos dos fármacosRESUMO
RATIONALE: Caffeine and theophylline are methylxanthines that are broadly consumed, sometimes at high doses, and act as minor psychostimulants. Both are nonselective adenosine antagonists for A1 and A2A receptors, which are colocalized with dopamine D1 and D2 receptors in striatal areas. Adenosine antagonists generally have opposite actions to those of dopamine antagonists. Although the effects of caffeine are widely known, theophylline has been much less well characterized, especially at high doses. METHODS: Adult male CD1 mice were used to study the effect of a broad range of doses (25.0, 50.0 or 100.0mg/kg) of caffeine and theophylline on measures of spontaneous locomotion and coordination, as well as the pattern of c-Fos immunoreactivity in brain areas rich in adenosine and dopamine receptors. In addition, we evaluated possible anxiety and stress effects of these doses. RESULTS: Caffeine, at these doses, impaired or suppressed locomotion in several paradigms. However, theophylline was less potent than caffeine at suppressing motor parameters, and even stimulated locomotion. Both drugs induced corticosterone release, however caffeine was more efficacious at intermediate doses. While caffeine showed an anxiogenic profile at all doses, theophylline only did so at the highest dose used (50mg/kg). Only theophylline increased c-Fos immunoreactivity in cortical areas. CONCLUSION: Theophylline has fewer disruptive effects than caffeine on motor parameters and produces less stress and anxiety effects. These results are relevant for understanding the potential side effects of methylxanthines when consumed at high doses.
Assuntos
Afeto/efeitos dos fármacos , Cafeína/farmacologia , Atividade Motora/efeitos dos fármacos , Antagonistas de Receptores Purinérgicos P1/farmacologia , Teofilina/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Cafeína/administração & dosagem , Relação Dose-Resposta a Droga , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Desempenho Psicomotor/efeitos dos fármacos , Antagonistas de Receptores Purinérgicos P1/administração & dosagem , Teofilina/administração & dosagemRESUMO
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.
Assuntos
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
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.
Assuntos
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
The impact of caffeine on the behavioral effects of ethanol, including ethanol consumption and abuse, has become a topic of great interest due to the rise in popularity of the so-called energy drinks. Energy drinks high in caffeine are frequently taken in combination with ethanol under the popular belief that caffeine can offset some of the intoxicating effects of ethanol. However, scientific research has not universally supported the idea that caffeine can reduce the effects of ethanol in humans or in rodents, and the mechanisms mediating the caffeine-ethanol interactions are not well understood. Caffeine and ethanol have a common biological substrate; both act on neurochemical processes related to the neuromodulator adenosine. Caffeine acts as a nonselective adenosine A1 and A2A receptor antagonist, while ethanol has been demonstrated to increase the basal adenosinergic tone via multiple mechanisms. Since adenosine transmission modulates multiple behavioral processes, the interaction of both drugs can regulate a wide range of effects related to alcohol consumption and the development of ethanol addiction. In the present review, we discuss the relatively small number of animal studies that have assessed the interactions between caffeine and ethanol, as well as the interactions between ethanol and subtype-selective adenosine receptor antagonists, to understand the basic findings and determine the possible mechanisms of action underlying the caffeine-ethanol interactions.
RESUMO
Mesolimbic dopamine (DA) is involved in behavioral activation and effort-related processes. Rats with impaired DA transmission reallocate their instrumental behavior away from food-reinforced tasks with high response requirements, and instead select less effortful food-seeking behaviors. In the present study, the effects of several drug treatments were assessed using a progressive ratio (PROG)/chow feeding concurrent choice task. With this task, rats can lever press on a PROG schedule reinforced by a preferred high-carbohydrate food pellet, or alternatively approach and consume the less-preferred but concurrently available laboratory chow. Rats pass through each ratio level 15 times, after which the ratio requirement is incremented by one additional response. The DA D(2) antagonist haloperidol (0.025-0.1 mg/kg) reduced number of lever presses and highest ratio achieved but did not reduce chow intake. In contrast, the adenosine A(2A) antagonist MSX-3 increased lever presses and highest ratio achieved, but decreased chow consumption. The cannabinoid CB1 inverse agonist and putative appetite suppressant AM251 decreased lever presses, highest ratio achieved, and chow intake; this effect was similar to that produced by pre-feeding. Furthermore, DA-related signal transduction activity (pDARPP-32(Thr34) expression) was greater in nucleus accumbens core of high responders (rats with high lever pressing output) compared to low responders. Thus, the effects of DA antagonism differed greatly from those produced by pre-feeding or reduced CB1 transmission, and it appears unlikely that haloperidol reduces PROG responding because of a general reduction in primary food motivation or the unconditioned reinforcing properties of food. Furthermore, accumbens core signal transduction activity is related to individual differences in work output.
Assuntos
Fenômenos Fisiológicos da Nutrição Animal/fisiologia , Comportamento de Escolha/fisiologia , Dopamina/metabolismo , Comportamento Alimentar/efeitos dos fármacos , Individualidade , 3,3'-Diaminobenzidina , Antagonistas do Receptor A2 de Adenosina/farmacologia , Análise de Variância , Ração Animal/análise , Animais , Antagonistas de Dopamina/farmacologia , Fosfoproteína 32 Regulada por cAMP e Dopamina/metabolismo , Haloperidol/farmacologia , Imuno-Histoquímica , Masculino , Piperidinas , Pirazóis , Ratos , Ratos Sprague-Dawley , Xantinas/farmacologiaRESUMO
Adenosine A(2A) and dopamine D2 receptors interact to regulate diverse aspects of ventral and dorsal striatal functions related to motivational and motor processes, and it has been suggested that adenosine A(2A) antagonists could be useful for the treatment of depression, parkinsonism and other disorders. The present experiments were performed to characterize the effects of MSX-4, which is an amino acid ester prodrug of the potent and selective adenosine A(2A) receptor antagonist MSX-2, by assessing its ability to reverse pharmacologically induced motivational and motor impairments. In the first group of studies, MSX-4 reversed the effects of the D2 antagonist eticlopride on a concurrent lever pressing/chow feeding task that is used as a measure of effort-related choice behavior. MSX-4 was less potent after intraperitoneal administration than the comparison compound, MSX-3, though both were equally efficacious. With this task, MSX-4 was orally active in the same dose range as MSX-3. MSX-4 also reversed the locomotor suppression induced by eticlopride in the open field, but did not induce anxiogenic effects as measured by the relative amount of interior activity. Behaviorally active doses of MSX-4 also attenuated the increase in c-Fos and pDARPP-32(Thr34) expression in nucleus accumbens core that was induced by injections of eticlopride. In addition, MSX-4 suppressed the oral tremor induced by the anticholinesterase galantamine, which is consistent with an antiparkinsonian profile. These actions of MSX-4 indicate that this compound could have potential utility as a treatment for parkinsonism, as well as some of the motivational symptoms of depression and other disorders.