Some aspects of the changes induced by chronic barbital treatments in the male rat.

Oral barbital treatments consisting of average daily doses of 200 mg/kg with durations of 15-50 weeks have been used to induce functional tolerance and physical dependence. Tolerance is usually studied with a hexobarbital threshold while increased excitation has been studied by various means, such as induction of convulsions with pilocarpine or choline. After barbital treatments for 30 weeks brain weights are reduced by approximately 10 per cent. This reduction is not due to changes in body weight or water content of the brain. The decrease is still found 30 days after the end of the barbital treatment. Supersensitivity to pilocarpine and reduced acetylcholine content in the brain are some earlier published indications that cholinergic mechanisms are involved in abstinence. Further studies have shown that atropine (8 mg/kg given intraperitoneally on the third day of abstinence) can reduce the tolerance to hexobarbital. An atropine treatment (4 mg/kg per day for 2 weeks) given late in the period of abstinence following a barbital treatment can induce a tolerance to hexobarbital. A prerequisite for this tolerance is the earlier barbital treatment. A steric selectivity in the action of hexobarbital is indicated by the interaction between atropine (8 mg/kg) and the isomers of hexobarbital. In normal rats only the potent isomer of hexobarbital is influenced by atropine. If the convulsive effect of choline is utilized in a threshold test, an increased sensitivity indicating increased excitation is found on day 10-11 of the period of abstinence when other signs of excitation are returning to normal. When these signs are maximal, on day 3, no increased sensitivity to choline is found. Choline seems to act on a selective mechanism which is revealed only late in the abstinence period. Hexobarbital thresholds performed on two phases of the blood ethanol concentration curve were used to study the interaction between ethanol and hexobarbital during abstinence following a barbital treatment. Immediately after the end of the barbital treatment, a general tolerance was present. A week later, ethanol eliminated the tolerance to hexobarbital. On day 15 of abstinence, no tolerance to hexobarbital was found, but there was a tolerance to ethanol on the increasing portion of the blood ethanol concentration curve. Thus, it is unlikely that physical dependence and functional tolerance constitute a single phenomenon in abstinence after barbital treatments. Cholinergic mechanisms seem to be involved in the presumably adaptive changes that can be recorded.