Activation of locus coeruleus neurons in the rat by a benzazocine derivative (UM 1046) that mimics opiate withdrawal.

The drug UM 1046 (N-cyclopropylmethyl-1,2,3,4,5,6-hexahydro-8-hydroxy-6-methyl-3-benzazoc ine), administered to opiate-naive monkeys, produces certain behavioral responses resembling antagonist-precipitated morphine withdrawal (Swain and Seevers, 1975). In the present study, UM 1046 (5.6 mg/kg, i.v.), administered to naive rats, produced a syndrome that consisted primarily of retching, chewing, teeth chattering, shaking and abnormal postures. It was of interest to determine whether UM 1046 had an effect on noradrenergic neurons of the locus coeruleus (NE-LC) since increased activity of these cells has been reported to occur during antagonist-precipitated opiate withdrawal (Aghajanian, 1978) and after the administration of drugs that mimic this syndrome in normal animals. (i.e. methylxanthine phosphodiesterase inhibitors, Grant and Redmond, 1981). In the present study, UM 1046 (1.0-5.6 mg/kg, i.v.) caused a dose-dependent increase (of up to 200%) in the spontaneous discharge rate of noradrenergic neurons of the locus coeruleus in rats anesthetized with halothane. The time-course of this effect was similar to the time-course of the behavioral syndrome described above. Stimulation of central muscarinic receptors is integrally involved in the response to this drug since the effects of UM 1046 (5.6 mg/kg) were antagonized by scopolamine (0.5 mg/kg, i.v.), but not by methylscopolamine (1.0 mg/kg, i.v.). Unlike systemic administration, iontophoretic application of UM 1046 did not consistently increase the spontaneous discharge rate of these cells, indicating that the site of action of the drug may be outside the nucleus locus coeruleus. This study complements previous findings of increased activity in noradrenergic neurons of the locus coeruleus during withdrawal-like behavior. In addition, the results are compatible with others which suggest that a cholinergic link is essential for the withdrawal-like actions of the benzazocine.