title: Noradrenergic blockade prevents attacks in a model of episodic dysfunction caused by a channelopathy.
abstract: Episodic neurological dysfunction often results from ion channel gene mutations. Despite knowledge of the mutations, the factors that precipitate attacks in channelopathies are not clear. In humans, mutations of the calcium channel gene CACNA1A are associated with attacks of neurological dysfunction in familial hemiplegic migraine and episodic ataxia type-2. In tottering mice, a mutation in the same gene causes attacks resembling paroxysmal dyskinesia. Stress, a trigger associated with human episodic disorders, reliably elicits attacks in tottering mice. Because noradrenergic neurotransmission is critical to the stress response and because noradrenergic hyperinnervation is observed in tottering mice, the role of norepinephrine in stress-induced attacks was investigated. Drugs that act at alpha-adrenergic receptors to block noradrenergic transmission prevented attacks. However, agents that facilitate noradrenergic neurotransmission failed to induce attacks. These results suggest that, while noradrenergic neurotransmission may be necessary for attacks, an increase in norepinephrine is not sufficient to induce attacks.
authors.affiliation: Department of Neurology, Johns Hopkins University, Baltimore, MD 21152, USA.
authors.forename: Brandy E
authors.initials: BE
authors.lastname: Fureman
authors.forename: Ellen J
authors.initials: EJ
authors.lastname: Hess
mesh_terms: D000322:Adrenergic Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001342:Autonomic Nervous System Diseases / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D001928:Brain Diseases, Metabolic / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D015220:Calcium Channels / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D007473:Ion Channels / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008818:Mice, Neurologic Mutants; D009069:Movement Disorders / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control; D009154:Mutation / Q000235:genetics; D009638:Norepinephrine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000378:metabolism; D013312:Stress, Physiological / Q000378:metabolism / Q000503:physiopathology; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics; D016896:Treatment Outcome; D020864:Calcium Channels, N-Type
chemical_list: D000322:Adrenergic Agonists; D000317:Adrenergic alpha-Antagonists; D015220:Calcium Channels; D007473:Ion Channels; D009638:Norepinephrine; D011942:Receptors, Adrenergic, alpha; C105656:CACNA1A protein, human; D020864:Calcium Channels, N-Type