Lobelane decreases methamphetamine self-administration in rats

Abstract

Lobelane, a minor alkaloid of Lobelia inflata and a synthetic, des-oxy analog of lobeline, has good affinity for the vesicular monoamine transporter and the dopamine transporter. The current study examined the ability of lobelane to specifically decrease methamphetamine self-administration. Rats were trained on a fixed ratio 5 schedule of reinforcement to self-administer methamphetamine (0.05 mg/kg/infusion, i.v.) or to respond for sucrose pellets. Upon reaching stable responding, rats were pretreated with lobelane (0.1, 1, 3, 5.6, or 10 mg/kg, s.c.) or saline, 15 min prior to the operant session. To assess the effect of repeated lobelane on methamphetamine self-administration, rats were pretreated with lobelane (5.6 or 10 mg/kg, s.c.) for 7 sessions. Behavioral specificity was further investigated by assessing the effects of lobelane (0.1, 1, 3, 5, or 10 mg/kg, s.c.) or saline on locomotor activity. Within the dose range tested, lobelane dose-dependently decreased methamphetamine self-administration, while having no effect on sucrose-maintained responding. Locomotor activity was decreased following only the highest dose of lobelane (10 mg/kg). Across repeated pretreatments, tolerance developed to the effect of lobelane on methamphetamine self-administration, demonstrating that the ability of lobelane to specifically decrease methamphetamine self-administration is a transient effect. Thus, taken together, the results show that although lobelane interacts with the pharmacological targets believed to be responsible for its ability to decrease methamphetamine self-administration, removal of the oxygen functionalities from the lobeline molecule may have afforded a compound with an altered pharmacokinetic and/or pharmacodynamic profile.

Figure 1. Chemical Structures of Lobeline and Lobelane

Figure 2. Dose and Time Course Effects of Acute Lobelane Pretreatment on Methamphetamine Self-Administration

Data represent the mean number of infusions (± S.E.M.) obtained during each 5-min interval of the methamphetamine self-administration session following lobelane (5.6 or 10 mg/kg) or saline. * indicates a significant difference of both doses from saline control at the time point indicated (P < 0.05)

Figure 3. Dose Effect of Acute Lobelane on Methamphetamine Self-Administration and Sucrose-Maintained Responding

Data represent the mean number of sucrose pellets or methamphetamine infusions (± S.E.M.) earned during the first 15 min of the 60-min operant session following pretreatment with lobelane (0.1–10 mg/kg) or saline. *indicates a significant difference from saline control (P < 0.05)

Figure 4. Dose Effect of Acute Lobelane on Locomotor Activity

Data represent the mean total distance traveled (± S.E.M.) during the 15–30 min time interval, which corresponded to the first 15 min of the operant session in the operant conditioning experiments. *indicates a significant difference from saline control (P < 0.05, one-tailed).

Figure 5. Dose Effect of Repeated Lobelane (5.6 or 10 mg/kg) on Methamphetamine Self-Administration

Data represent the mean number of methamphetamine infusions (± S.E.M.) earned during the first 15 min of the session following repeated administration of lobelane (5.6 or 10 mg/kg) across 7 sessions. *indicates a significant difference from baseline infusions (P < 0.05).