Tubocurarine reduced the neurally evoked [3H]acetylcholine release in the absence of nicotine, indicating positive nicotinic feedback. Tubocurarine, however, enhanced [3H]acetylcholine release after pretreatment with nicotine, a condition which causes desensitization of nicotine autoreceptors. After a nicotine-free period (15-60 min) during which the facilitatory autoreceptors could recover from desensitization, tubocurarine again reduced [3H]acetylcholine release. Protection of facilitatory nicotine autoreceptors from desensitization could explain the tubocurarine-induced increase in transmitter release.