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The NIMH research domain criteria (RDoC) approach was instigated to refocus mental health research on the neural circuits that mediate psychological functions, with the idea that this would foster an understanding of the neural basis of specific psychiatric dysfunctions (i.e. ‘symptoms and circuits’) and ultimately facilitate treatment. As a general idea, this attempt to go beyond traditional diagnostic categories and focus on neural circuit dysfunctions related to specific symptoms spanning multiple disorders has many advantages. For example, motivational dysfunctions are present in multiple disorders, including depression, schizophrenia, Parkinson's disease, and other conditions. A critical aspect of motivation is effort valuation/willingness to work, and several clinical studies have identified alterations in effort-based decision making in various patient groups. In parallel, formal animal models focusing on the exertion of effort and effort-based decision making have been developed. This paper reviews the literature on models of effort-based motivational function in the context of a discussion of the RDoC approach, with an emphasis on the dissociable nature of distinct aspects of motivation. For example, conditions associated with depression and schizophrenia blunt the selection of high-effort activities as measured by several tasks in animal models (e.g. lever pressing, barrier climbing, wheel running). Nevertheless, these manipulations also leave fundamental aspects of hedonic reactivity, food motivation, and reinforcement intact. This pattern of effects demonstrates that the general emphasis of the RDoC on the specificity of the neural circuits mediating behavioral pathologies, and the dissociative nature of these dysfunctions, is a valid concept. Nevertheless, the specific placement of effort-related processes as simply a ‘sub-construct' of ‘reward processing' is empirically and conceptually problematic. Thus, while the RDoC is an excellent general framework for new ways to approach research and therapeutics, it still needs further refinement.

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. This research was supported by grants to JS from the NIH (R01MH121350) and the University of Connecticut Research Foundation, to MC from MINECO (PSI2015-68497-R) Spain, and to CC (FPI BES-2016-077177). JS has received grants from, and done consulting work for, Shire, Prexa, Chronos, Blackthorn, Lundbeck, NOEMA, and Acadia. On behalf of all authors, the corresponding author states that there is no conflict of interest.

Inflammation is linked to motivational deficits seen in depression and other disorders. Lipopolysaccharide (LPS) induces an inflammatory response and impairs motivated behavior in humans and rodents. It has been suggested that inflammation can shift metabolic needs to functions that warrant more response to the perceived threat (e.g., fighting infection), therefore altering aspects of motivation. Animal models have been developed to assess alterations in motivated behavior by giving the animal the option to work (i.e., lever press) for a highly palatable food reward vs. approaching and consuming a freely available, albeit less preferred, food. This model was used to determine if administration of 2-deoxy-D-glucose (2DG), a substance that inhibits glucose uptake and glycolysis, could reverse the motivational deficits induced by LPS in rats. A food preference/intake task was also conducted to see if LPS affected intake of the highly palatable vs. less palatable foods when both are freely available. It was hypothesized that 2-DG would reverse the motivational deficits caused by LPS and there would be no effect on food preference/intake of the highly palatable food. Results showed that 2-DG significantly reversed LPS effects at the lowest dose, while methylphenidate did not. The food intake/preference tests showed that LPS significantly decreased food intake of both foods but did not alter preference for the highly palatable food compared to vehicle. These results suggest that in addition to having effects on exertion of effort during instrumental behavior, LPS also has direct effects on primary food motivation.