An Investigation of Motivational Dysfunctions in a Rat Model of Effort-Related Choice Behavior: Behavioral and Neurochemical Evidence for Possible Novel Pharmacological Treatments

Motivational symptoms such as fatigue, anergia, and amotivation are seen in depression, Parkinson’s disease, schizophrenia, and other disorders. These symptoms are often left untreated by the most frequently prescribed antidepressants, which typically block serotonin transport. Considerable evidence implicates brain dopamine (DA) in the regulation of behavioral activation and effort-related aspects of motivation. Animal studies of effort-based choice are being used to provide formal models of motivational dysfunctions in humans. Drugs that block DA transport (DAT) are able to reverse the effort-related effects of the vesicular monoamine transport inhibitor tetrabenazine, a drug that blocks DA storage and depletes DA. Many of the existing DAT inhibitor drugs are either classic DA blockers such as cocaine, or drugs that also stimulate release of DA. These drugs can produce a number of undesirable side effects, including psychotic symptoms and abuse liability. Thus, there is a need to develop and characterize novel atypical DAT inhibitors that are relatively selective and have unique binding profiles. The completed studies discussed here focus on the behavioral and neurochemical characterization of several recently synthesized atypical DAT inhibitors, with the aim of identifying a novel family of drugs that may be useful for the treatment of motivational dysfunctions in humans, and the development of physiological markers of the selection of high-effort instrumental behavior. In recent years, human imaging and neurophysiological studies have had sought to identify the neural processes involved in motivation, psychomotor retardation, anergia, and lassitude in depression and other disorders. Human studies have suggested that there is frontal electroencephalography (EEG) asymmetry in depressed patients, but physiological correlates of effort-related motivational dysfunction have not been identified in animals. To complement the investigation of effort-related impairments using pharmacological approaches, the final experiment involved the measurement of frontal cortex EEG activity of animals under pharmacological manipulation of DA transmission. Ultimately, the development of a physiological marker of effort-related dysfunction in a preclinical model may be critical for identifying the brain circuits involved in regulating these behaviors that can be readily translated to human studies. Together, results from these experiments may contribute to the identification of novel treatment options for motivational dysfunctions