Attention Deficit Hyperactivity Disorder (ADHD) is a neurobehavioral disorder that impairs the normal development of behavior, in particular of executive functioning. Three persistent symptoms characterize ADHD: inattention, impulsivity, and overactivity. A large body of evidence suggests that the Spontaneously Hypertensive rat (SHR) displays all three symptoms of ADHD, and may thus serve as a model for experimental research. The validity of SHR as a model of ADHD has, nonetheless, been challenged. A concern with animal models is that they never perfectly replicate the syndrome-they are at best models of symptoms of that syndrome. This application focuses on one symptom of ADHD, persistent overactivity. The primary aim of this research is to characterize SHR overactivity, grounded on state-of-the-art behavioral theory;its results will serve as foundation for the evaluation of this strain as a model of ADHD-related overactivity. In particular, this application s concerned with instrumental overactivity, the excessive emission of rewarded responses that is typical of the predominantly hyperactive-impulsive and combined subtypes of ADHD. The proposed methods are supported by empirically-validated models of instrumental behavior that indicate that rats engage in rewarded activities in bouts separated by pauses. Response rate may be thereby partitioned by 3 parameters: within-bout response rate, bout-initiation rate, and bout duration. Past research has shown the differential sensitivity of each parameter to motor, motivational, and schedule manipulations: Each is controlled by a distinct mechanism linked with motor capacity, motivational status, and the maintenance of response-reward associations ("coupling"). Preliminary research suggests that young-adult SHR produce shorter but more frequent response bouts than its normoactive control, the Wistar-Kyoto (WKY) rat. Those results indicated that a reduced response-reward coupling was responsible for the differences between strains. This important finding is compromised by the age of the rats and the use of multiple interacting schedules. Exp. 1 will seek to replicate the results from the preliminary study, but exposing adolescent (instead of adult) SHR and WKY to separate schedules (instead of multiple schedules), in which rewards will be programmed every 12 or 192 s. Exp. 2 will validate the interpretation of strain differences by "resynthesis": in this case, by experimentally reversing their main trait difference. For instance, if Exp. 1 verifies a response-reward coupling deficit in SHR on the basis of short-but-frequent bouts of responses, coupling would be increased and bouts "normalized" by rewarding longer response sequences. It will be verified whether such normalization generalizes to extinction performance. Taken together, these experiments will qualify our confidence in the preliminary findings (Exp. 1) and their interpretation (Exp. 2). Establishing the source of SHR overactivity is a fundamental step to its validation as a model of ADHD-related overactivity. The development on such model is critical for the progress of neurobiological research on ADHD and for the formulation of treatment alternatives.

Public Health Relevance

This project will use state-of-the-art behavioral theory to determine why the Spontaneously Hypertensive rat (SHR) emits excessive responses that yield rewards, whether it is because of physical capacity to produce such responses, stronger motivation for rewards, or abnormal response-reward association. Establishing the source of SHR overactivity is a critical first step to validate the SHR as an animal model of overactivity in Attention Deficit Hyperactivity Disorder (ADHD). An animal model of this symptom of ADHD will support future experimental work aimed at determining the neurobiological basis of ADHD, one of the most prevalent neurobehavioral disorders among children.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Small Research Grants (R03)
Project #
5R03MH094562-02
Application #
8458531
Study Section
Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
Program Officer
Friedman-Hill, Stacia
Project Start
2012-04-11
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2015-01-31
Support Year
2
Fiscal Year
2013
Total Cost
$66,757
Indirect Cost
$18,757
Name
Arizona State University-Tempe Campus
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
943360412
City
Tempe
State
AZ
Country
United States
Zip Code
85287
Íbias, Javier; Pellón, Ricardo; Sanabria, Federico (2015) A microstructural analysis of schedule-induced polydipsia reveals incentive-induced hyperactivity in an animal model of ADHD. Behav Brain Res 278:417-23
Sanabria, Federico; Oldenburg, Liliana (2014) Adaptation of timing behavior to a regular change in criterion. Behav Processes 101:58-71
Hoffman, Ann N; Lorson, Nickolaus G; Sanabria, Federico et al. (2014) Chronic stress disrupts fear extinction and enhances amygdala and hippocampal Fos expression in an animal model of post-traumatic stress disorder. Neurobiol Learn Mem 112:139-47
Mazur, Gabriel J; Wood-Isenberg, Gabriel; Watterson, Elizabeth et al. (2014) Detrimental effects of acute nicotine on the response-withholding performance of spontaneously hypertensive and Wistar Kyoto rats. Psychopharmacology (Berl) 231:2471-82