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

• Published in: Neuropharmacology 2018-08, Vol.138, p.349-359
• Main Authors: López-Cruz, Laura, San Miguel, Noemí, Carratalá-Ros, Carla, Monferrer, Lidón, Salamone, John D., Correa, Mercè
• Format: Article
• Language: English
• Subjects: Adenosine; Adrenergic Uptake Inhibitors - pharmacology; Animals; Appetite - drug effects; Appetite - physiology; Behavioral activation; Caffeine; Decision Making - drug effects; Decision Making - physiology; Decision-making; Dopamine; Dopamine - metabolism; Dopamine and cAMP-Regulated Phosphoprotein 32 - metabolism; Dopamine Antagonists - pharmacology; Dose-Response Relationship, Drug; Intracellular Space - drug effects; Intracellular Space - metabolism; Male; Mice; Motivation; Motor Activity - drug effects; Motor Activity - physiology; Phosphorylation - drug effects; Purinergic P1 Receptor Antagonists - pharmacology; Receptors, Dopamine D2 - metabolism; Receptors, Purinergic P1 - metabolism; Reinforcement (Psychology); Running-wheel; Sucrose; Tetrabenazine - pharmacology; Ventral Striatum - drug effects; Ventral Striatum - metabolism; Vesicular Monoamine Transport Proteins - antagonists & inhibitors; Vesicular Monoamine Transport Proteins - metabolism
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2018.01.034

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. •DA-adenosine interaction modulates the activational component of motivation in a novel three chamber T-maze task.•Physical exercise acts as a reinforcer sensitive to DA-adenosine manipulations in a context of effort-based decision-making.•Caffeine reduces anergia-like effects induced by pharmacological DA depletion.•Behavioral results are parallel to changes in DA-adenosine receptor interactions on pDARPP32(Thr34).•The therapeutic effect of caffeine on TBZ-induced anergia