Dopamine (DA), the most abundant human brain catecholaminergic neurotransmitter, modulates key behavioral and neurological processes in young and senescent brains, including motricity, sleep, attention, emotion, learning and memory, and social and reward-seeking behaviors. The DA transporter (DAT) regulates transsynaptic DA levels, influencing all these processes. Compounds targeting DAT (e.g., cocaine and amphetamines) were historically used to shape mood and cognition, but these substances typically lead to severe negative side effects (tolerance, abuse, addiction, and dependence). DA/DAT signaling dysfunctions are associated with neuropsychiatric and progressive brain disorders, including Parkinson’s and Alzheimer diseases, drug addiction and dementia, resulting in devastating personal and familial concerns and high socioeconomic costs worldwide. The development of low-side-effect, new/selective medicaments with reduced abuse-liability and which ameliorate DA/DAT-related dysfunctions is therefore crucial in the fields of medicine and healthcare. Using the rat as experimental animal model, the present work describes the synthesis and pharmacological profile of (S)-MK-26, a new modafinil analogue with markedly improved potency and selectivity for DAT over parent drug. Ex vivo electrophysiology revealed significantly augmented hippocampal long-term synaptic potentiation upon acute, intraperitoneally delivered (S)-MK-26 treatment, whereas in vivo experiments in the hole-board test showed only lesser effects on reference memory performance in aged rats. However, in effort-related FR5/chow and PROG/chow feeding choice experiments, (S)-MK-26 treatment reversed the depression-like behavior induced by the dopamine-depleting drug tetrabenazine (TBZ) and increased the selection of high-effort alternatives. Moreover, in in vivo microdialysis experiments, (S)-MK-26 significantly increased extracellular DA levels in the prefrontal cortex and in nucleus accumbens core and shell. These studies highlight (S)-MK-26 as a potent enhancer of transsynaptic DA and promoter of synaptic plasticity, with predominant beneficial effects on effort-related behaviors, thus proposing therapeutic potentials for (S)-MK-26 in the treatment of low-effort exertion and motivational dysfunctions characteristic of depression and aging-related disorders.

During operant behavior, oscillatory activity is coordinated across multiple brain regions and can change under different task conditions. In this study, we use a decoding approach to characterize these patterns and predict lever pressing behavior in rats from local field potentials (LFP) recorded bilaterally in the hippocampus, nucleus accumbens, and prefrontal cortex. We extract LFP features for band power and peak frequency and predict behavior across animals and conditions with a Poisson Generalized Linear Model (GLM). We use data from both male and female rats performing either fixed-ratio (FR40) or progressive (PROG) operant lever-pressing tasks, under vehicle (VEH) or tetrabenazine (TBZ), a vesicular monoamine transport (VMAT-2) inhibitor that depletes dopamine and induces depressive-like motivation dysfunction. We find that we can accurately predict lever pressing from multi-region LFP within-animals on a timescale of seconds with >30% variance explained. Although within-animal and within-condition predictions are highest, we also find, interestingly, that these decoders generalize across animals and across drug, sex, and task conditions, suggesting a stable association between LFP and behavior. We then evaluate whether LFP features can be used to decode long-term task variables, such as the number of presses since or until the next reinforcer. We find that LFP features can predict these long-term task variables, but that decoding relies on different LFP features for prediction than those used for immediate lever pressing. Altogether these results suggest that there are robust distributed patterns of LFP associated with lever-pressing behavior under multiple drug, task, and sex conditions. Significance Statement: Although patterns of neural activity related to many observable behaviors, such as sleep and locomotion, have been well described, identifying stable neural patterns related to other states, such as motivation and effort, is an ongoing challenge. Here we use a decoding approach and aim to predict effort-based lever pressing from neural activity for a wide range of conditions, with rats of different sexes performing different tasks with and without a drug, tetrabenazine. We find that there is a stable pattern of neural features that allows us to robustly predict lever-pressing across these many conditions. This pattern may serve as a general indicator of effortful behavior, and deviations from the pattern could potentially indicate motivational dysfunction.