Dopamine D1 receptors in the medial orbitofrontal cortex support effort-related responding in rats

Rodent studies on effort-related responding provide a tool to analyze basal aspects of motivation and to model psychiatric motivational dysfunctions reflecting low exertion of effort or reduced behavioral activation. It turned out that dopamine (DA) signaling in brain areas such as nucleus accumbens are essential in regulating effort-related motivational function and could play a major role in motivational dysfunction in psychiatric disorders. Recent rodent studies revealed that the medial orbitofrontal cortex (mOFC) is another key component of the neural circuitry regulating effort-related motivational function. The mOFC receives prominent DA input, however, the behavioral role of mOFC DA signaling is unknown. Here, we investigated whether DA signaling in the mOFC supports effort-related responding in rats. Results demonstrate that an intra-mOFC D1 receptor blockade markedly reduced effort-related responding in a progressive ratio task. Notably, the magnitude of this effect was comparable to the one caused by a systemic DA depletion induced by the VMAT-2 inhibitor tetrabenazine or by a satiety-induced motivational downshift. Collectively, our data show for the first time that D1 receptor activity in the mOFC plays a critical role in high effort responding. These results support findings in humans pointing to a role of the mOFC in effort-related responding. It is well known that the mOFC becomes dysfunctional in depression and schizophrenia. Our data point to the possibility that reduced mOFC DA activity could contribute to effort-related motivational symptoms in these disorders and support the notion that the DA system may be a drug target to treat effort-related motivational symptoms.