title: PET imaging for attention deficit preclinical drug testing in neurofibromatosis-1 mice.
abstract: Attention system abnormalities represent a significant barrier to scholastic achievement in children with neurofibromatosis-1 (NF1). Using a novel mouse model of NF1-associated attention deficit (ADD), we demonstrate a presynaptic defect in striatal dopaminergic homeostasis and leverage this finding to apply [(11)C]-raclopride positron-emission tomography (PET) in the intact animal. While methylphenidate and l-Deprenyl correct both striatal dopamine levels on PET imaging and defective attention system function in Nf1 mutant mice, pharmacologic agents that target de-regulated cyclic AMP and RAS signaling in these mice do not. These studies establish a robust preclinical model to evaluate promising agents for NF1-associated ADD.
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Jacquelyn A
authors.initials: JA
authors.lastname: Brown
authors.forename: Jinbin
authors.initials: J
authors.lastname: Xu
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Diggs-Andrews
authors.forename: David F
authors.initials: DF
authors.lastname: Wozniak
authors.forename: Robert H
authors.initials: RH
authors.lastname: Mach
authors.forename: David H
authors.initials: DH
authors.lastname: Gutmann
mesh_terms: D000818:Animals; D001288:Attention / Q000502:physiology; D001289:Attention Deficit Disorder with Hyperactivity / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000209:etiology; D002250:Carbon Radioisotopes; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000502:physiology; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000502:physiology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D008774:Methylphenidate / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D009456:Neurofibromatosis 1 / Q000150:complications / Q000000981:diagnostic imaging / Q000235:genetics; D018696:Neuroprotective Agents / Q000494:pharmacology; D049268:Positron-Emission Tomography / Q000379:methods*; D017729:Presynaptic Terminals / Q000187:drug effects / Q000502:physiology; D020891:Raclopride; D012642:Selegiline / Q000494:pharmacology*
chemical_list: D002250:Carbon Radioisotopes; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D018696:Neuroprotective Agents; D008774:Methylphenidate; D012642:Selegiline; D020891:Raclopride