Abnormal presynaptic catecholamine regulation in a hyperactive SNAP-25-deficient mouse mutant.
The consequences of a reduction in the presynaptic protein, SNAP-25, were investigated to determine the neurochemical basis of the marked hyperlocomotor activity in coloboma (Cm/+) mice. SNAP-25 is part of the minimal presynaptic machinery necessary for exocytotic neurotransmitter release. Reserpine treatment was used to deplete vesicular stores of catecholamines. Coloboma mice were more sensitive to the effects of reserpine than control mice. However, presynaptic regulation of dopamine (DA) release, as assessed by low-dose apomorphine challenge, was intact. There were region-specific reductions in in vivo tyrosine hydroxylation and the DA metabolites homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum and nucleus accumbens of Cm/+ mice. While hyperactivity is often associated with changes in DA concentration, norepinephrine (NE) concentration was significantly increased in the striatum and nucleus accumbens of the hyperactive mutant. The increase in NE may regulate the hyperactivity in these mice, as suggested by current hypotheses of the mechanisms underlying attention-deficit hyperactivity disorder (ADHD) and Tourette's syndrome.
Jones
M D
MD
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Williams
M E
ME
Hess
E J
EJ
D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D002395:Catecholamines / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006948:Hyperkinesis / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics*; D051379:Mice; D008809:Mice, Inbred C3H; D008817:Mice, Mutant Strains; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics*; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism*; D050825:Synaptosomal-Associated Protein 25; D014443:Tyrosine / Q000378:metabolism
D002395:Catecholamines; D018491:Dopamine Agonists; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C494209:Snap25 protein, mouse; D050825:Synaptosomal-Associated Protein 25; D014443:Tyrosine; D001058:Apomorphine