Norepinephrine regulates locomotor hyperactivity in the mouse mutant coloboma.
An imbalance between dopaminergic and noradrenergic systems is implicated in hyperactivity disorders such as attention deficit hyperactivity disorder (ADHD) and Tourette syndrome. We have identified the mouse mutant coloboma as an animal model for examining the neurological basis of hyperactivity. Coloboma mice exhibit spontaneous locomotor hyperactivity that is a result of a reduction in SNAP-25, a presynaptic protein that regulates exocytotic release. These mice exhibit an imbalance in catecholamine regulation whereby brain dopamine (DA) utilization is reduced while norepinephrine (NE) concentrations are significantly increased. Further, calcium-dependent NE release was also increased in these hyperactive mice, despite the reduction in SNAP-25. To determine the role of NE in the expression of hyperactivity, brain NE concentrations were reduced using the specific noradrenergic neurotoxin DSP-4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride]. DSP-4 treatment specifically decreased NE concentrations, but had no effect on brain DA or serotonin. Depletion of NE by DSP-4 through either systemic or central administration significantly reduced the locomotor activity in coloboma mice. These results suggest that NE regulation in the CNS plays an important role in the expression of hyperactivity in this mouse model, consistent with results of human studies and current models of ADHD.
Jones
Michelle D
MD
Department of Neurology, Johns Hopkins University School of Medicine, Meyer 6-181, 600 North Wolfe Street, Baltimore, MD 21287, USA.
Hess
Ellen J
EJ
D000818:Animals; D001369:Axons / Q000187:drug effects; D001596:Benzylamines / Q000494:pharmacology; D001923:Brain Chemistry / Q000187:drug effects / Q000235:genetics; D002851:Chromatography, High Pressure Liquid; D003103:Coloboma / Q000235:genetics* / Q000523:psychology*; D004298:Dopamine / Q000378:metabolism; D006948:Hyperkinesis / Q000235:genetics* / Q000523:psychology*; D007276:Injections, Intraventricular; D008125:Locus Coeruleus / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008809:Mice, Inbred C3H; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D009498:Neurotoxins / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism / Q000502:physiology*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D011188:Potassium / Q000494:pharmacology
D001596:Benzylamines; D009498:Neurotoxins; C012102:DSP 4; D011188:Potassium; D004298:Dopamine; D009638:Norepinephrine