Pharmacology of Lobeline, A Nicotinic Receptor Ligand1

Abstract

In this study we investigated the pharmacology of lobeline, a high affinity nicotinic ligand with a unique pharmacological profile, in different in vitro and in vivo tests. Although lobeline displaced [³H]-nicotine binding sites in the rat brain with a K_i of 4.4 nM, it did not activate α4β2 expressed receptors in frog oocytes. The in vivopharmacological effects of lobeline were highly complex. Lobeline, at the time of maximal effect, dose-dependently produced motor impairment and decreased locomotor activity and body temperature in mice after s.c. treatment. However, antinociception was present after intrathecal but not after s.c. administration of lobeline in the tail-flick tests. The behavioral effects of lobeline were not blocked by pretreatment with either mecamylamine or dihydro-β-erythroidine. In addition, lobeline given s.c. enhanced nicotine-induced antinociception in a dose-related manner. No acute tolerance developed to either lobeline’s behavioral or antinociceptive effect after s.c. or intrathecal administration, respectively. However, tolerance developed to lobeline’s pharmacological effects after chronic treatment with the drug for 10 days (15 mg/kg, s.c. twice a day). Furthermore, cross-tolerance between lobeline and nicotine developed after chronic treatment with either drug. Although the α4β2 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.