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 selfadministration, 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 selfadministration 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.

Novel N-1,2-Dihydroxypropyl Analogs of Lobelane Inhibit Vesicular Monoamine Transporter-2 Function and Methamphetamine-Evoked Dopamine Release

“…Through an interaction with VMAT2, lobeline inhibits the neurochemical and behavioral effects of methamphetamine (Teng et al, 1997(Teng et al, , 1998Harrod et al, 2001;Miller et al, 2001;Dwoskin and Crooks, 2002;Nickell et al, 2010). Lobelane, a lobeline analog with greater selectivity for VMAT2, decreased both methamphetamineevoked DA release (IC 50 ϭ 0.65 M; I max ϭ 73.2%; same experimental conditions as the current work) and methamphetamine self-administration (Zheng et al, 2005a;Neugebauer et al, 2007;Beckmann et al, 2010;Nickell et al, 2010Nickell et al, , 2011. Unfortunately, further development of lobelane as an effective pharmacotherapy was hindered by unacceptable drug-likeness properties.…”

“…1), a chemically defunctionalized, saturated analog of lobeline, competitively inhibited DA uptake at VMAT2 and exhibited increased affinity and selectivity for VMAT2 compared with lobeline (Miller et al, 2001;. Lobelane inhibited methamphetamine-evoked DA release and decreased methamphetamine self-administration; however, tolerance developed to the latter behavior effects (Neugebauer et al, 2007;Nickell et al, 2010). Unfortunately, lobelane exhibits decreased water solubility and diminished drug-likeness properties caused by its decreased polarity resulting from removal of the keto and hydroxyl functionalities of lobeline.…”

Phenyl Ring-Substituted Lobelane Analogs: Inhibition of [3H]Dopamine Uptake at the Vesicular Monoamine Transporter-2

“…These studies revealed that removal of the oxygen-containing functional groups of lobeline, such as with lobelane, diminished affinity for [ 3 H]nicotine and [ 3 H]methyllycaconitine binding sites (␣4␤2* and ␣7* nAChRs, respectively, where * indicates the putative nAChR subtype assignment) (Miller et al, 2004) and retained affinity for VMAT2 at the [ 3 H]DTBZ binding site on VMAT2 (Zheng et al, 2005a). Furthermore, lobelane retained the ability to decrease methamphetamine self-administration (Neugebauer et al, 2007). Thus, the findings that methamphetamine interacts with VMAT2 to increase extracellular DA and ultimately methamphetamine-induced reward, the selective interaction of lobelane with VMAT2, and the observations that lobelane inhibits the effects of methamphetamine provide support for VMAT2 as a pharmacological target for the development of novel treatments for methamphetamine abuse.…”

meso-Transdiene Analogs Inhibit Vesicular Monoamine Transporter-2 Function and Methamphetamine-Evoked Dopamine Release

“…Behavioral experiments were conducted as described previously (Neugebauer et al, 2007). Operant conditioning chambers (ENV-008; MED Associates, St. Albans, VT) were enclosed within sound-attenuating compartments (ENV-018M; MED Associates).…”