PHARMACOLOGY OF LOBELINE, A NICOTINIC RECEPTOR-LIGAND

In this study we investigated the pharmacology of lobeline, a high aff inity nicotinic ligand with a unique pharmacological profile, in diffe rent in vitro and in vivo tests. Although lobeline displaced [H-3]-nic otine binding sites in the rat brain with a K-I of 4.4 nM, it did not activate alpha 4 beta 2 expressed receptors in frog oocytes. The in vi vo pharmacological effects of lobeline were highly complex. Lobeline, at the time of maximal effect, dose-dependently produced motor impairm ent and decreased locomotor activity and body temperature in mice afte r s.c. treatment. However, antinociception was present after intrathec al but not after s.c. administration of lobeline in the tail-flick tes ts. The behavioral effects of lobeline were not blocked by pretreatmen t with either mecamylamine or dihydro-beta-erythroidine. in addition, lobeline given s.c. enhanced nicotine-induced antinociception in a dos e-related manner. No acute tolerance developed to either lobeline's be havioral or antinociceptive effect after s.c. or intrathecal administr ation, respectively. However, tolerance developed to lobeline's pharma cological effects after chronic treatment with the drug for 10 days (1 5 mg/kg, s.c. twice a day). Furthermore, cross-tolerance between lobel ine and nicotine developed after chronic treatment with either drug. A lthough the alpha 4 beta 2 receptor is unlikely to mediate the agonist effects of lobeline, our results indicate that lobeline does interact with the nicotinic receptor in a novel fashion.