The posterior subdivision of the medial orbitofrontal cortex (mOFC-p) mediates the willingness to expend effort to reach a selected goal. However, the neural circuitry through which the mOFC-p modulates effort-related function is as yet unknown. The mOFC-p projects prominently to the posterior ventral tegmental area (pVTA). Therefore, we analyzed the role of the mOFC-p and interactions with the pVTA in effort-related responding using a combination of behavioral, pharmacological and neural circuit analysis methods in rats. Pharmacological inhibition of the mOFC-p was found to increase lever pressing for food under a progressive ratio (PR) schedule of reinforcement. These findings provide further support for a modulation of effort-related function by the mOFC-p. Then, we investigated effects of disconnecting the mOFC-p and pVTA on PR responding using unilateral pharmacological inhibition of both areas. This asymmetric intervention was also found to increase PR responding suggesting that the mOFC-p controls effort-related function through interactions with the pVTA. Possibly, a reduced excitatory mOFC-p drive on pVTA GABAergic relays disinhibits VTA dopamine neurons which are known to support PR responding. Collectively, our findings suggest that the mOFC-p and pVTA are key components of a neural circuit mediating the willingness to expend effort to reach a goal.

Here we tested in rats effects of the procognitive drugs modafinil and methylphenidate on post-acquisition performance in an object -location paired-associates learning (PAL) task. Modafinil (32; 64 mg/kg) was without effect, while higher (9 mg/ kg) but not lower (4.5 mg/kg) doses of methylphenidate impaired PAL performance. Likewise, higher but not lower doses of amphetamine (0.4; 0.8 mg/kg) and MK-801 (0.08; 0.12 mg/kg) decreased PAL performance. Impaired PAL performance induced by methylphenidate, amphetamine, and MK801 most likely reflects compromised cognitive function, e.g., retrieval of learned paired associates. Our data suggest that stimulant drugs such as methylphenidate and modafinil might not facilitate performance in hippocampus-related cognitive tasks.[Supplemental material is available for this article.]Touchscreen equipped operant boxes represent a powerful tool to study cognition in rats. This methodology provides superior translational potential because a number of different cognitive tasks can be run that mirror touchscreen methods being part of the Cambridge Neuropsychological Test Automated Battery (CANTAB) used to test human subjects. For instance, the pairedassociates learning task (PAL) allows to investigate learning of object-location associations in rodents and humans Mar et al. 2013;Talpos and Steckler 2013;Josey and Brigman 2015). In rats, post-acquisition performance on the PAL task is sensitive to hippocampal dysfunction. For instance, intrahippocampal microinfusions of lidocaine or NMDA and AMPA receptor antagonists impaired PAL performance in animals that acquired the task before (Talpos et al. 2009). Likewise, in mice, post-acquisition intrahippocampal microinfusions of muscimol impaired PAL performance (Kim et al. 2015). In humans, PAL task performance is predictive of the conversion from mild cognitive dysfunction to Alzheimer's disease (Blackwell et al. 2004). Furthermore, in mild cognitive impairment, PAL performance was correlated with hippocampal volume (Keri et al. 2012).To date, little is known about effects of procognitive drugs on PAL performance. The few available data show that, in mice, the cholinesterase inhibitor donezepil (0.3 mg/kg, i.p.) facilitated PAL performance (Bartko et al. 2011). In contrast, the effects of two other prominent procognitive drugs, methylphenidate and modafinil, in PAL have not been tested yet. Modafinil facilitated performance in a number of rodent cognitive tasks (Beracochea et al. 2001(Beracochea et al. , 2002(Beracochea et al. , 2003Shuman et al. 2009), e.g., enhanced visual discrimination and visual sustained attention (Morgan et al. 2007). Likewise, methylphenidate improved acquisition and retention of spatial memory in maze tasks (Carmack et al. 2014). Both drugs seem to be used as cognitive enhancers for nonmedical purposes (McCabe et al. 2005). However, for both drugs, evidence in favor of cognitive enhancement in humans is mixed (Repantis et al. 2010). For instance, in healthy individuals, methylphenidate and modafinil did not imp...