Darragh P. Devine - US grants

DESCRIPTION: (Adapted from the applicant's Description) Self-injurious behavior (SIB) is a devastating dysfunction that is expressed in highly stereotyped manners by individuals with a variety of genetic and developmental disorders (e.g., Lesch-Nyhan syndrome, autism, intellectual handicaps). The most severe expression of SIB generally occurs in Lesch-Nyhan syndrome, a disorder of purine metabolism that results in altered adenosine and dopamine neurotransmission. A variety of animal models exist in which developmental and neurochemical manipulations result in SIB. One model is the chronic methylxanthine model, in which caffeine (an adenosine receptor antagonist) is administered to rats for 10 to 12 days. A second model consists of chronic administration of pemoline (an indirect dopamine agonist) for four to eight days. Both of these manipulations result in self-injury, but the phenomenology of the behavior that is expressed is very different between these two animal models. Pemoline-treated rats exhibit profound stereotypy (repetitive, apparently purposeless behavior) prior to onset of SIB, and the principle expression of SIB is stereotyped paw-biting. Caffeine-treated rats do not express high levels of stereotypy prior to onset of SIB, and the predominant form of SIB expressed by these rats is stereotypic gnawing on the tail until it is pink and raw. The differences in etiology and expression of SIB during chronic administration of caffeine and pemoline suggest that differing neurochemical adaptations may underlie these phenomenologically-distinct behavioral outcomes. The present experiments are designed to characterize adaptations in adenosinergic and dopaminergic neurotransmission that develop during chronic administration of caffeine and pemoline. Caffeine and pemoline will be administered to independent groups of rats until they exhibit SIB. Immediately upon the occurrence of SIB, the rats will be sacrificed, and the brains will be processed for in situ hybridization of mRNA for adenosine receptors and dopamine receptors. These experiments will identify whether adaptations occur in adenosine and dopamine systems that may be implicated in onset and expression of caffeine- and pemoline-induced SIB. Furthermore, these experiments will examine whether differing neuroadaptations occur within adenosine and dopamine systems in the phenomenologically different models of SIB, and they may lay a foundation for further exploration of the molecular biology of animal models of SIB.

Animals are frequently challenged by stressors in their environment, including changes in the availability of food and water, presence of reproductive opportunities or predators, and other demands. Survival depends upon the ability of the brain and body to respond to these challenges by altering behavior and bodily functions. For example, changes in availability of food and water, or presence of predators, will lead to changes in foraging behaviors, arousal states, and metabolic activities. These changes arise from the actions of neurotransmitters in the brain, and are coordinated by the actions of hormones in the brain and body.
The PI studies a neurotransmitter, called orphanin FQ or N/OFQ, that appears to be important in regulating responses to stressful challenges. N/OFQ is a member of the opioid family of molecules (that is, is related to opioid drugs). N/OFQ activates anxiety-related behaviors that increase vigilance and inhibit foraging, and it increases hormonal activities that affect bodily functions to enable the animal to cope with the stressors. The PI is studying various aspects of N/OFQ and its role in regulating behavior, particularly in response to stress. The PI is examining the regulation of expression of the N/OFQ gene, regulation of N/OFQ function during stressful challenges, regulation of behaviors and hormones by N/OFQ, and is assessing the role of hormones in the behavioral effects of N/OFQ. Because N/OFQ is found in all vertebrate animals, this research has the potential to shed light on the behavioral and biological regulation of organisms from fish to man. The consequences of stress are a challenge for humans, and so it is important to understand of the biological mechanisms that have evolved to cope with stress.
The research program includes the participation of 4 graduate and 5 undergraduate students, and thus includes a substantial teaching component. The laboratory at the University of Florida also has a long-standing collaboration with a researcher at Florida State University, which includes reciprocal training of students. This research should uncover important information about the basic regulation of organisms during stressful challenges to homeostasis.