Tolerance to hexobarbital and supersensitivity to pilocarpine after chronic barbital treatments in the rat.

Tolerance and physical dependence induced by chronic treatments with depressant drugs has been proposed as being due to denervation or disuse supersensitivity in the central nervous system. To illustrate this hypothesis, tolerance to barbiturates and the sensitivity to central cholinergic stimulation were recorded in the same male rats. Tolerance to barbiturates was recorded with a hexobarbital threshold. The dose needed to obtain an EEG criterion was measured. Sensitivity in central cholinergic structures was recorded by a temperature threshold method. A subthreshold dose of pilocarpine (3.5 mg/kg) was given s.c. together with 1.0 mg/kg methylscopolamine i.p. An increase in sensitivity to pilocarpine was recorded as a decrease in body temperature. In the abstinence period after 42 weeks of oral treatment with barbital, tolerance was recorded with the hexobarbital threshold method. The tolerance had two peaks, one after the end of the treatment and one approximately 3 weeks later. An increased sensitivity to pilocarpine was also recorded in the abstinence period. It had the same biphasic time pattern as the tolerance. Cholinergic neurones are thus probably involved in the changes induced by chronic barbital treatment. The denervation supersensitivity hypothesis of tolerance was not refuted by the present experiments.