A subset of motoric symptoms associated with autism includes mild, stereotypic to intense, self-injurious behaviors. In the past, these behaviors have been linked to dysfunction of brain dopamine but, unfortunately, clinical trials with dopamine antagonists have met with poor results. The accepted rodent model of self-injurious behavior relies on neonatal dopamine lesions followed by L-dopa administration to the adult. This model works well in rats but not in mice. In a series of studies using in situ hybridization as well as knockout and transgenic mice to explore the development of the topographic projections of brain dopaminergic neurons, it was observed that brain serotinergic systems are activated following neonatal damage to dopaminergic neurons. That is, it appeared that early dopamine lesions activated brain serotinergic systems. This observation was then linked to the induction of stereotypic and self-injurious behaviors in adult mice treated with high doses of amphetamine, doses which induced the release of both dopamine and serotonin. On the basis of these and other observations, a new animal model of self-injurious behaviors centering on the dual activation of brain dopamine and serotonin is proposed. In addition, based on this new model, the possible beneficial effects of risperidone, an antagonist of these transmitter systems, will be explored.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-SSS-C (01))
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Hirtz, Deborah G
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Rutgers University
Schools of Arts and Sciences
New Brunswick
United States
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Wagner, George C; Reuhl, Kenneth R; Ming, Xue et al. (2007) Behavioral and neurochemical sensitization to amphetamine following early postnatal administration of methylmercury (MeHg). Neurotoxicology 28:59-66
Wagner, George C; Reuhl, Kenneth R; Cheh, Michelle et al. (2006) A new neurobehavioral model of autism in mice: pre- and postnatal exposure to sodium valproate. J Autism Dev Disord 36:779-93
Carlson, Kirsten M; Wagner, George C (2006) Voluntary exercise and tail shock have differential effects on amphetamine-induced dopaminergic toxicity in adult BALB/c mice. Behav Pharmacol 17:475-84
Carlson, Kirsten M; Wagner, George C (2006) Shock stress protects mice against amphetamine-induced dopaminergic toxicity. Brain Res 1087:186-9
Cheh, Michelle A; Millonig, James H; Roselli, Lauren M et al. (2006) En2 knockout mice display neurobehavioral and neurochemical alterations relevant to autism spectrum disorder. Brain Res 1116:166-76
Halladay, A K; Wagner, G C; Sekowski, A et al. (2006) Alterations in alcohol consumption, withdrawal seizures, and monoamine transmission in rats treated with phentermine and 5-hydroxy-L-tryptophan. Synapse 59:277-89
Ming, X; Stein, T P; Brimacombe, M et al. (2005) Increased excretion of a lipid peroxidation biomarker in autism. Prostaglandins Leukot Essent Fatty Acids 73:379-84
Wagner, George C; Avena, Nicole; Kita, Taizo et al. (2004) Risperidone reduction of amphetamine-induced self-injurious behavior in mice. Neuropharmacology 46:700-8
Halladay, A K; Tessarollo, L; Zhou, R et al. (2004) Neurochemical and behavioral deficits consequent to expression of a dominant negative EphA5 receptor. Brain Res Mol Brain Res 123:104-11
Halladay, Alycia K; Kusnecov, Alexander; Michna, Lauri et al. (2003) Relationship between methamphetamine-induced dopamine release, hyperthermia, self-injurious behaviour and long term dopamine depletion in BALB/c and C57BL/6 mice. Pharmacol Toxicol 93:33-41

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