Dopamine depletion shifts behavior from activity based reinforcers to more sedentary ones and adenosine receptor antagonism reverses that shift: Relation to ventral striatum DARPP32 phosphorylation patterns.

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 (4.0 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.

Ethanol and Caffeine Effects on Social Interaction and Recognition in Mice: Involvement of Adenosine A2A and A1 Receptors.

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.

Activational and effort-related aspects of motivation: neural mechanisms and implications for psychopathology.

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.

The pharmacology of effort-related choice behavior: Dopamine, depression, and individual differences.

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.

Choosing voluntary exercise over sucrose consumption depends upon dopamine transmission: effects of haloperidol in wild type and adenosine A2AKO mice.

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.

Selection of sucrose concentration depends on the effort required to obtain it: studies using tetrabenazine, D1, D2, and D3 receptor antagonists.

RATIONALE: Low doses of dopamine (DA) antagonists and accumbens DA depletions reduce food-reinforced instrumental behavior but do not impair primary food motivation, causing animals to reallocate behavior away from food-reinforced tasks with high response requirements and select less effortful alternatives. However, it is uncertain if this same pattern of effects would occur if sucrose was used as the reinforcer. OBJECTIVES: These experiments studied the impact of DA depletion and antagonism on performance of an effort-related choice task using sucrose as the reinforcer, as well as sucrose consumption, preference, and taste reactivity tests. METHODS: The effects of DA manipulations were assessed using a task in which rats chose between lever pressing on a fixed ratio 7 schedule for 5.0 % sucrose versus freely consuming a less concentrated solution (0.3 %). RESULTS: The DA depleting agent tetrabenazine shifted effort-related choice, decreasing lever pressing for 5.0 % sucrose but increasing intake of the concurrently available 0.3 % sucrose. Tetrabenazine did not affect sucrose appetitive taste reactivity, or sucrose consumption or preference, in free consumption tests. The D1 antagonist ecopipam and the D2 antagonist haloperidol also shifted choice behavior at doses that did not alter sucrose consumption or preference. In contrast, sucrose pre-exposure reduced consumption across all conditions. D3 antagonism had no effects. CONCLUSIONS: D1 and D2 receptor blockade and DA depletion reduce the tendency to work for sucrose under conditions that leave fundamental aspects of sucrose motivation (intake, preference, hedonic reactivity) intact. These findings have implications for studies employing sucrose intake or preference in animal models of depression.

Acetate as an active metabolite of ethanol: studies of locomotion, loss of righting reflex, and anxiety in rodents.

IT HAS BEEN POSTULATED THAT A NUMBER OF THE CENTRAL EFFECTS OF ETHANOL ARE MEDIATED VIA ETHANOL METABOLITES: acetaldehyde and acetate. Ethanol is known to produce a large variety of behavioral actions such anxiolysis, narcosis, and modulation of locomotion. Acetaldehyde contributes to some of those effects although the contribution of acetate is less known. In the present studies, rats and mice were used to assess the acute and chronic effects of acetate after central or peripheral administration. Male Sprague-Dawley rats were used for the comparison between central (intraventricular, ICV) and peripheral (intraperitoneal, IP) administration of acute doses of acetate on locomotion. CD1 male mice were used to study acute IP effects of acetate on locomotion, and also the effects of chronic oral consumption of acetate (0, 500, or 1000 mg/l, during 7, 15, 30, or 60 days) on ethanol- (1.0, 2.0, 4.0, or 4.5 g/kg, IP) induced locomotion, anxiolysis, and loss of righting reflex (LORR). In rats, ICV acetate (0.7-2.8 µmoles) reduced spontaneous locomotion at doses that, in the case of ethanol and acetaldehyde, had previously been shown to stimulate locomotion. Peripheral acute administration of acetate also suppressed locomotion in rats (25-100 mg/kg), but not in mice. In addition, although chronic administration of acetate during 15 days did not have an effect on spontaneous locomotion in an open field, it blocked ethanol-induced locomotion. However, ethanol-induced anxiolysis was not affected by chronic administration of acetate. Chronic consumption of acetate (up to 60 days) did not have an effect on latency to, or duration of LORR induced by ethanol, but significantly increased the number of mice that did not achieve LORR. The present work provides new evidence supporting the hypothesis that acetate should be considered a centrally-active metabolite of ethanol that contributes to some behavioral effects of this alcohol, such as motor suppression.