Potential therapeutics for effort-related motivational dysfunction: assessing novel atypical dopamine transport inhibitors.

People with depression and other neuropsychiatric disorders can experience motivational dysfunctions such as fatigue and anergia, which involve reduced exertion of effort in goal-directed activity. To model effort-related motivational dysfunction, effort-based choice tasks can be used, in which rats can select between obtaining a preferred reinforcer by high exertion of effort vs. a low effort/less preferred option. Preclinical data indicate that dopamine transport (DAT) inhibitors can reverse pharmacologically-induced low-effort biases and increase selection of high-effort options in effort-based choice tasks. Although classical DAT blockers like cocaine can produce undesirable effects such as liability for misuse and psychotic reactions, not all DAT inhibitors have the same neurochemical profile. The current study characterized the effort-related effects of novel DAT inhibitors that are modafinil analogs and have a range of binding profiles and neurochemical actions (JJC8-088, JJC8-089, RDS3-094, and JJC8-091) by using two different effort-related choice behavior tasks in male Sprague-Dawley rats. JJC8-088, JJC8-089, and RDS3-094 significantly reversed the low-effort bias induced by the VMAT-2 inhibitor tetrabenazine, increasing selection of high-effort fixed ratio 5 lever pressing vs. chow intake. In addition, JJC8-089 reversed the effects of tetrabenazine in female rats. JJC8-088 and JJC8-089 also increased selection of high-effort progressive ratio responding in a choice task. However, JJC8-091 failed to produce these outcomes, potentially due to its unique pharmacological profile (i.e., binding to an occluded conformation of DAT). Assessment of a broad range of DAT inhibitors with different neurochemical characteristics may lead to the identification of compounds that are useful for treating motivational dysfunction in humans.

Complexities and paradoxes in understanding the role of dopamine in incentive motivation and instrumental action: Exertion of effort vs. anhedonia.

Instrumental behavior is a very complex and multifaceted process. Behavioral output during instrumental performance is influenced by a variety of factors, including associative conditioning, directional and activational aspects of motivation, affect, action selection and execution, and decision-making functions. Detailed assessments of instrumental behavior can focus on the temporal characteristics of instrumental behavior such as local frequency and response duration, and biophysical measures of response topography such as force output over time. Furthermore, engaging in motivated behavior can require exertion of effort and effort-based decision making. The present review provides an overview of research on the specific deficits in operant behavior induced by dopamine antagonism and depletion. Furthermore, it discusses research on effort-based decision making, and highlights the complexities and seeming paradoxes that are revealed when detailed analyses of operant behavior are conducted, and instrumental behavior is put in the context of factors such as primary or unconditioned food reinforcement, appetite, binge-like eating, and response choice. Although impairments in mesolimbic dopamine are sometimes labeled as being due to "anhedonia", a detailed deconstruction of the findings in this area of research point to a much more complex and nuanced picture of the role that dopamine plays in regulating instrumental behavior. Low doses of DA antagonists and accumbens dopamine depletions blunt the exertion of physical effort as measured by several different challenges in animal studies (e.g., lever pressing, barrier climbing, wheel running), and yet leave fundamental aspects of hedonic reactivity, food motivation, and reinforcement intact. Continued research on the specific features of instrumental behaviors that regulate the sensitivity to impaired dopamine transmission across a number of contexts is important for resolving some of the complexities that are evident in this area of inquiry. These investigations can also provide insights into psychomotor and motivational dysfunctions that are seen in neuropsychiatric conditions such as depression, schizophrenia, and Parkinson's disease.