Development of tolerance to chronic barbital treatment in the cerebellar cyclic guanosine monophosphate system and its response to subsequent barbital abstinence.

Female Sprague-Dawley rats were placed on a 6-week barbital feeding regimen, previously documented to result in drug tolerance and dependence. Groups of animals were sacrificed on the 2nd and 5th day of each week, up to week 5, or at various time points following drug withdrawal. Cerebellae and cerebral cortices were collected for cyclic GMP (cGMP) measurements. Initial suppressions of cGMP were seen in both the cerebellum and cerebral cortex during early weeks of the feeding regimen. These gradually returned essentially to control levels by the end of 5 weeks, a finding consistent with the development of tolerance to chronic barbiturates in the cGMP system. Barbital was withdrawn after 6 weeks of chronic administration. Four hours after withdrawal, a dramatic elevation of cerebellar cGMP was seen. This elevation was coincident with a significant decline in serum barbital levels and preceded the onset of weight loss, spontaneous seizures and locomotor depression. The elevation of cGMP was less dramatic but still apparent at 72 hr postwithdrawal when all other evaluated parameters had returned to control values. Alterations of cGMP during chronic barbital treatment and subsequent to abrupt barbital withdrawal may reflect aberrations in the function of neurotransmitter pathways involved in regulating cGMP in the cerebellum. Further, the elevation of cGMP after barbiturate withdrawal may itself play a functional role in the manifestation of barbital abstinence.