Abstract

A centrally mediated hypothermic response to muscarine-type drugs was employed to demonstrate central nervous system supersensitivity. Scopolamine was administered chronically to mature male mice and was withdrawn abruptly after intervals ranging from 8 hr to 4 weeks. After preinjecting methscopolamine (to block peripheral muscarinic effects), test doses of pilocarpine were administered to determine whether the response of the central nervous system had been altered by the long exposure to scopolamine. An increased sensitivity of the thermoregulatory system to pilocarpine developed after withdrawal of scopolamine which gradually declined over a period of several days. This was indicated by a leftward shift (P < .001) of the dose-response curve. The minimum period of chronic scopolamine intoxication required to produce a detectable effect of this kind was about 48 hr (with i. p. administration). Longer periods of chronic scopolamine intoxication produced greater and longer lasting effects. A slight, but statistically significant, spontaneous hypothermia was also observed during the withdrawal period. During this period, too, it was possible to demonstrate "tolerance" to scopolamine, in the sense that a higher dose was required to block pilocarpine-induced hypothermia; this "tolerance" waned concurrently with the supersensitivity. These changes resemble the "disuse" after "pharmacologic denervation" supersensitivity observed in peripheral autonomic effectors.