To assess the relative sensitivity of Manduca sexta central nervous system (CNS) to nicotine and other cholinergic agonists, global electrophysiological recording techniques were used. Comparisons were made between the tobacco hornworm and Periplaneta americana. Cords were tested in intact and partially desheathed conditions using two different recording methods (differential recording of activity in interganglionic connectives and non-electrolyte gap recording of potentials developed in the ganglion). Both recording methods indicate that the Manduca tissue is about 100-fold less sensitive to nicotine than Periplaneta, suggesting that mechanisms local to the CNS contribute to Manduca's ability to subsist on a nicotine-rich diet. The threshold for response of desheathed Manduca cords to nicotine (during 5-min exposures) is 5 × 10−5 M nicotine. Desheathing increases the sensitivity of the Manduca CNS to nicotine but does not make the tissue equally as responsive as the Periplaneta CNS. The cholinergic agonists acetylcholine, muscarine, lobeline, and tetramethylammonium and the anticholinesterase, eserine, all induce neural activity in Manduca, indicating that the tissue is not intrinsically insensitive to cholinergic agents. The tertiary amide N'-methylnicotinamide potentiates the toxicity of nicotine to the Manduca CNS.