Assessment of a glycine uptake inhibitor in animal models of effort-related choice behavior: implications for motivational dysfunctions

Abstract

Rationale Motivated behavior can be characterized by a substantial exertion of effort, and organisms often make effortrelated decisions based upon analyses of work-related response costs and reinforcement preference. Moreover, alterations in effort-based choice can be seen in people with major depression and schizophrenia. Effort-related decision making is studied using tasks offering choices between high effort options leading to highly valued reinforces vs low effort/low reward options. Interference with dopamine (DA) transmission by administration of the DA D2 family antagonist haloperidol biases behavior towards the lower effort option that can be obtained with minimal work, and previous research has shown that DA interacts with other transmitters, including adenosine and GABA, to regulate effort-based choice. Objectives The present studies focused upon the ability of the glycine transport inhibitor bitopertin to attenuate haloperidolinduced shifts in effort-related choice behavior. Methods Effort-based choice in rats was assessed using the concurrent fixed ratio (FR) 5/chow feeding choice task and the T-maze barrier choice procedure. Results Haloperidol shifted effort-based choice, biasing animals towards the low effort option in each task. Coadministration of bitopertin (1.0–10.0 mg/kg) significantly attenuated haloperidol-induced shifts in choice behavior, but the same doses of bitopertin had no effect when administered alone. Conclusions These results indicated that elevation of extracellular glycine via inhibition of glycine uptake was able to reverse the effects of D2 antagonism. Increases in extracellular glycine, possibly through actions on the glycine allosteric site on the NMDA receptor, may be a useful strategy for treating motivational dysfunctions in humans.