METHYLATROPINE BLOCKS THE CENTRAL EFFECTS OF CHOLINERGIC ANTAGONISTS

These studies were conducted in order to establish the dose dependency and relative peripheral versus central activity of four prototypical cholinergic antagonists on the rodent passive avoidance response, a wi dely used animal model of retention. Subcutaneous administration of 0. 1 to 100 mg/kg revealed a potency profile of scopolamine > atropine >> methylscopolamine greater than or equal to methylatropine for the imp airment of passive avoidance responding. A series of neurological asse ssments of the doses used indicated that side effects alone were not s ufficient to impair passive avoidance responding. Although inactive wh en delivered peripherally, methylatropine was able to produce retentio n deficits at 10 nmol (3.66 mu g) when administered intracerebrally. T o further evaluate whether systemic methylatropine could enter the cen tral nervous system, either scopolamine or atropine was administered s ubcutaneously in mice and rats pretreated with 10-100 mg/kg methylatro pine. The deficit-producing effects of scopolamine and atropine were a bolished with methylatropine. Thus methylatropine is an exclusive peri pheral antagonist; its ability to block the deficit-producing effects of scopolamine and atropine may occur through a change in blood-brain barrier permeability or through uncharacterized pharmacokinetic proper ties.