Role of the central adrenergic system in mediating amitriptyline-induced alteration in the mammalian blood-brain barrier in vivo

All tricyclic antidepressants increase the degree of equilibration of [³H]water across the cerebral capillary (E(w)) as measured by a dual-label radioactive tracer technique. By using amitriptyline (AMI) as a prototype, a series of studies was conducted to determine the mechanism for this drug effect. The AMI-induced increase in E(w) was blocked by 6-hydroxydopamine ablation of central aminergic neurons and by pretreatment with phenoxybenzamine, an alpha adrenergic antagonist. Pretreatment with propranolol, a beta adrenergic antagonist, did not block the AMI-induced increase. Central serotonergic ablation by p-chloroamphetamine had no effect on the AMI-induced increase. Treatment with atropine and hydroxyzine separately also did not alter E(w). Based on these results, the AMI-induced increase in E(w) appears to be mediated by the effect of the drug on central adrenergic neurons. The serotonergic, anticholinergic and antihistaminergic actions of AMI, by themselves, do not appear to play a role in this phenomenon. The results are compatible with the concept that the central adrenergic system functions, in part, to regulate the cerebromicrocirculation.