Tourette Syndrome (TS) is a neurodevelopmental disorder characterized by vocal and motor tics, as well as premonitory urges, obsessions, compulsions and attention deficits. Current medications for TS reduce tic severity in some patients, but are ineffective against the most impairing TS symptoms and are associated with significant adverse effects. Thus, new medications that effectively target TS symptoms, but are less prone to produce deleterious side effects are critically needed. The etiology of TS remains unknown, but new evidence from genetic and neuropathological studies has led to plausible hypotheses for the etiology of some forms of this disorder. The discovery of novel medications for TS, and the assessment of new hypotheses for its causes, has been limited by the paucity of animal models for TS. Existing animal models are based primarily on decades-old measures of """"""""tic-like"""""""" or stereotyped behaviors in rats that may have little neurobiological relevance to the most functionally impairing TS symptoms. Most of these antiquated models are limited in their ability to predict efficacy for compounds other than dopamine D2-receptor antagonists, which have only limited efficacy in treating TS. Novel TS models are needed that are sensitive to neurobiological substrates of the most impairing cognitive and sensorimotor deficits in this disorder. The goal of the present application is to develop and apply a novel predictive animal model for TS based on visuospatial priming (VSP) deficits in TS patients. The VSP paradigm is a quantitative psychophysiological measure of response inhibition and facilitation in which TS patients exhibit excessive facilitation and deficient inhibition, relative to healthy controls. VSP deficits in TS patients correlate significantly with the therapeutic outcome of habit reversal therapy, an effective controlled treatment for TS. This suggests that an animal model of VSP deficits may be a valuable and predictive model for novel TS therapeutics. A rat operant model of VSP is being developed that reproduces the patterns of normal VSP exhibited by humans. Rats are trained to respond to a target stimulus, but to inhibit responding to a simultaneously presented distracter stimulus. This discrimination task is then extended to model a full human VSP task, with prime and probe trials and measurements of reaction times to detect levels of facilitatory and inhibitory priming. Normal VSP performance will then be challenged pharmacologically, using drugs that are conceptually linked to neurochemical abnormalities in TS patients. The predictive validity of this novel model will first be assessed using """"""""known"""""""" anti-tic medications to normalize VSP deficits, and a potential new medication for TS will then be tested that is believed to function via a novel therapeutic mechanism. Future studies will investigate the neural mechanisms regulating VSP in rats, and will use this measure to test novel genetic and neurodevelopmental hypotheses of TS etiology. If successful, the present application may provide a critical tool to bridge a significant gap in TS research, and ultimately advance our understanding and treatment of this disorder.

Public Health Relevance

The goal of the present application is to develop and apply a novel predictive animal model for Tourette Syndrome (TS) that is based on visuospatial priming (VSP) deficits in TS patients. VSP deficits in TS patients correlate strongly, and highly significantly, with the therapeutic outcome of habit reversal therapy (HRT), an emerging and clinically controlled treatment form for TS. This suggests that a model of VSP deficits in rats may be valuable in predicting therapeutic success in TS, and ultimately help bridge the translational gap from preclinical studies to novel therapeutics for TS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21MH091571-02
Application #
8115079
Study Section
Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
Program Officer
Grabb, Margaret C
Project Start
2010-07-21
Project End
2013-04-30
Budget Start
2011-05-01
Budget End
2013-04-30
Support Year
2
Fiscal Year
2011
Total Cost
$191,194
Indirect Cost
Name
University of California San Diego
Department
Psychiatry
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Amitai, Nurith; Powell, Susan; Weber, Martin et al. (2015) Negative visuospatial priming in isolation-reared rats: Evidence of resistance to the disruptive effects of amphetamine. Cogn Affect Behav Neurosci 15:901-14
van Enkhuizen, Jordy; Acheson, Dean; Risbrough, Victoria et al. (2014) Sleep deprivation impairs performance in the 5-choice continuous performance test: similarities between humans and mice. Behav Brain Res 261:40-8
Amitai, Nurith; Young, Jared W; Higa, Kerin et al. (2014) Isolation rearing effects on probabilistic learning and cognitive flexibility in rats. Cogn Affect Behav Neurosci 14:388-406
Young, Jared W; Meves, Jessica M; Geyer, Mark A (2013) Nicotinic agonist-induced improvement of vigilance in mice in the 5-choice continuous performance test. Behav Brain Res 240:119-33
Young, Jared W; Jentsch, J David; Bussey, Timothy J et al. (2013) Consideration of species differences in developing novel molecules as cognition enhancers. Neurosci Biobehav Rev 37:2181-93
Amitai, Nurith; Weber, Martin; Swerdlow, Neal R et al. (2013) A novel visuospatial priming task for rats with relevance to Tourette syndrome and modulation of dopamine levels. Neurosci Biobehav Rev 37:1139-49
Gilmour, Gary; Arguello, Alexander; Bari, Andrea et al. (2013) Measuring the construct of executive control in schizophrenia: defining and validating translational animal paradigms for discovery research. Neurosci Biobehav Rev 37:2125-40
van Enkhuizen, Jordy; Geyer, Mark A; Young, Jared W (2013) Differential effects of dopamine transporter inhibitors in the rodent Iowa gambling task: relevance to mania. Psychopharmacology (Berl) 225:661-74
van Enkhuizen, Jordy; Geyer, Mark A; Kooistra, Klaas et al. (2013) Chronic valproate attenuates some, but not all, facets of mania-like behaviour in mice. Int J Neuropsychopharmacol 16:1021-31
Young, Jared W; Powell, Susan B; Geyer, Mark A (2012) Mouse pharmacological models of cognitive disruption relevant to schizophrenia. Neuropharmacology 62:1381-90

Showing the most recent 10 out of 13 publications