Dopamine depletion shifts behavior from activity based reinforcers tomore sedentary ones and adenosine receptor antagonism reversesthat shift: Relation to ventral striatum DARPP32 phosphorylationpatterns

Abstract

The mesolimbic dopamine (DA) system plays a critical role in behavioral activation and effort-baseddecision-making. DA depletion produces anergia (shifts to low effort options) in animals tested oneffort-based decision-making tasks. Caffeine, the most consumed stimulant in the world, acts as anadenosine A1/A2Areceptor antagonist, and in striatal areas DA D1and D2receptors are co-localized withadenosine A1and A2Areceptors respectively. In the present work, we evaluated the effect of caffeine onanergia induced by the VMAT-2 inhibitor tetrabenazine (TBZ), which depletes DA. Anergia was evaluatedin 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 inventral striatum were evaluated using DARPP-32 phosphorylation patterns as an intracellular marker ofDA-adenosine receptor interaction. In the T-maze, control mice spent more time running and much lessconsuming sucrose or snif fi ng. TBZ (4.0 mg/kg) reduced ventral striatal DA tissue levels as measured byHPLC, and also shifted preferences in the T-maze, reducing selection of the reinforcer that involvedvigorous activity (RW), but increasing consumption of a reinforcer that required little effor t (sucrose), atdoses that had no effect on independent measures of appetite or locomotion in a RW. Caffeine at dosesthat had no effect on their own reversed the effects of TBZ on T-maze performance, and also suppressedTBZ-induced pDARPP-32(Thr34) expression as measured by western blot, suggesting a role for D2-A2Ainteractions. These results support the idea that DA depletion produces anergia, but does not affect theprimary motivational effects of sucrose. Caffeine, possibly by acting on A2Areceptors 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.