Self-injurious behavior is a common problem among several neurodevelopmental and psychiatric disorders. There are currently few safe and reliable treatments for the behavior, in part because of our limited understanding of its neurobiological basis. Recently, we demonstrated that administration of the L-type calcium channel agonist Bay K 8644 can acutely provoke self-injury in weanling mice, providing a new animal model that can be exploited to study the neurobiology of this unusual behavior.
Specific Aim 1 addresses the neuroanatomical substrates for self-injurious behavior provoked by Bay K 8644 with two functional histochemical mapping methods, induction of the mRNA encoding the immediate-early gene c-fos and 2-deoxyglucose autoradiography. Our hypothesis for this aim is that Bay K 8644 causes self-injurious behavior by influencing the functions of the caudoputamen, the region most often implicated in the expression of self-injurious behavior in other studies.
Specific Aims 2 -3 address the neuropharmacological basis for self-injurious behavior provoked by Bay K 8644, and in particular the involvement of dopaminergic and serotonergic systems, the two neurotransmitter systems most often implicated as mediators of the behavior in prior studies. Our hypothesis for these aims is that Bay K 8644 causes self-injurious behavior by activating specific dopaminergic and serotonergic receptor subtypes.
Specific Aim 4 addresses the role of L-type calcium channels in another well-characterized model for self-injurious behavior, the administration of dopaminergic or serotonergic agonists to rats that had received 6-hydroxydopamine lesions during the neonatal period. We will test the ability of calcium channel antagonists to prevent the expression of self-injurious behavior in this model. Our hypothesis for this aim is that the L-type calcium channels may provide a """"""""final common pathway"""""""" for the expression of self-injury. These studies have direct relevance for understanding the neuroanatomical and neurochemical basis for self-injurious behavior and direct implications for a potential novel treatment strategy.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD039795-04
Application #
6873756
Study Section
Integrative, Functional and Cognitive Neuroscience 8 (IFCN)
Program Officer
Oster-Granite, Mary Lou
Project Start
2002-04-01
Project End
2007-03-31
Budget Start
2005-04-01
Budget End
2007-03-31
Support Year
4
Fiscal Year
2005
Total Cost
$294,300
Indirect Cost
Name
Johns Hopkins University
Department
Neurology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Zizzo, Maria G; Frinchi, Monica; Nuzzo, Domenico et al. (2018) Altered gastrointestinal motility in an animal model of Lesch-Nyhan disease. Auton Neurosci 210:55-64
Blake, Bonita L; Muehlmann, Amber M; Egami, Kiyoshi et al. (2007) Nifedipine suppresses self-injurious behaviors in animals. Dev Neurosci 29:241-50
Shirley, Thomas L; Lewers, J Chris; Egami, Kiyoshi et al. (2007) A human neuronal tissue culture model for Lesch-Nyhan disease. J Neurochem 101:841-53
Kasim, Suhail; Blake, Bonita L; Fan, Xueliang et al. (2006) The role of dopamine receptors in the neurobehavioral syndrome provoked by activation of L-type calcium channels in rodents. Dev Neurosci 28:505-17
Papadeas, Sophia T; Blake, Bonita L; Knapp, Darin J et al. (2004) Sustained extracellular signal-regulated kinase 1/2 phosphorylation in neonate 6-hydroxydopamine-lesioned rats after repeated D1-dopamine receptor agonist administration: implications for NMDA receptor involvement. J Neurosci 24:5863-76
Kasim, Suhail; Jinnah, H A (2003) Self-biting induced by activation of L-type calcium channels in mice: dopaminergic influences. Dev Neurosci 25:20-5
Jinnah, H A; Egami, Kiyoshi; Rao, Lekha et al. (2003) Expression of c-FOS in the brain after activation of L-type calcium channels. Dev Neurosci 25:403-11
Kasim, Suhail; Egami, Kiyoshi; Jinnah, H A (2002) Self-biting induced by activation of L-type calcium channels in mice: serotonergic influences. Dev Neurosci 24:322-7
Kasim, Suhail; Jinnah, H A (2002) Pharmacologic thresholds for self-injurious behavior in a genetic mouse model of Lesch-Nyhan disease. Pharmacol Biochem Behav 73:583-92