Lobelane, a minor alkaloid of Lobelia inflata
and a synthetic, des
-oxy analog of lobeline, has enhanced affinity for the vesicular monoamine transporter and dopamine transporter compared to lobeline (Miller et al., 2004
). Both of these transporter proteins are considered therapeutic targets for the treatment of methamphetamine abuse (Baumann et al., 2002
; Miller et al., 2004
; Partilla et al., 2006
). The current experiments assessed the effect of lobelane pretreatment on methamphetamine self-administration, sucrose maintained responding, and locomotor activity in rats. Acute lobelane (5.6 or 10 mg/kg) administration decreased methamphetamine self-administration during the first 15 min of the session, with no change at later time points. This contrasts with the effect of lobeline, which has been shown previously to decrease methamphetamine self-administration during the first 25 min of the session, but then produces a compensatory increase in methamphetamine self-administration at the last time point (Harrod et al., 2001
). These findings suggest that lobelane has a shorter duration of action than does lobeline for decreasing methamphetamine self-administration. In the current report, acute pretreatment with lobelane (5.6 mg/kg) also resulted in a specific decrease in methamphetamine self-administration, i.e., without altering sucrose-maintained responding or locomotor activity.
In locomotor activity experiments, lobelane (0.1 – 10 mg/kg) did not significantly alter activity when analyzed across the entire 60-min session. However, analysis of the 15–30 min interval revealed a decrease in activity following the highest dose tested (10 mg/kg), which coincides with the time interval of interest in the methamphetamine self-administration and sucrose maintained responding experiments. Importantly, no effect on locomotor activity was observed following administration of a dose (5.6 mg/kg) of lobelane that decreased methamphetamine self-administration, demonstrating further that lobelane administration results in a behaviorally specific decrease in methamphetamine self-administration.
In the current study, tolerance developed to the effect of lobelane on methamphetamine self-administration across repeated pretreatments. These results contrast with those obtained previously with lobeline using similar procedures. Specifically, while Harrod et al. (2001)
found that acute lobeline decreased both methamphetamine self-administration and sucrose reinforced responding, tolerance developed to the lobeline-induced decrease in sucrose reinforced responding, but did not develop to the decrease in methamphetamine self-administration. In this respect, lobelane lacks affinity for α4β2* and α6-containing nicotinic acetylcholine receptors, in contrast to lobeline (Miller et al., 2004
). Thus, it is possible that tolerance does not develop to the effect of lobeline due to its action as an antagonist at these nicotinic acetylcholine receptor subtypes, suggesting that specific differences in pharmacodynamics between these two alkaloids may be responsible for the different behavioral effects observed. Significant differences in affinity between lobeline and lobelane have also been reported at the dopamine transporter and serotonin transporter (Miller et al., 2004
), suggesting that these targets may also be implicated in the differential behavioral effects of these alkaloids. Since lobeline and lobelane have similar affinities for α7* nicotinic acetylcholine receptors and for the norepinephrine transporter (Miller et al., 2004
), these targets are not likely responsible for the observed differential behavioral effects between these alkaloids. These results are intriguing and suggest the possibility that more than one target is required to produce the desired behavioral outcome, i.e., a potent decrease in methamphetamine self-administration in the absence of the development of tolerance. Future studies will need to investigate the relationship between tolerance and the ability to decrease methamphetamine self-administration using a small library of lobeline analogs with different activities at the relevant pharmacological targets.
An alternative explanation for the development of tolerance with lobelane, but not with lobeline, may involve pharmacokinetic differences because the des
-oxy lobelane molecule is likely a better substrate for hepatic metabolic oxidation reactions compared to lobeline, which already has two oxygen containing functionalities. These metabolic differences may also lead to differential distribution and elimination of these two drugs with repeated treatment. In this respect, a more rapid metabolism and elimination of lobelane compared with lobeline would suggest a shorter duration of action. Consistent with this, lobeline has been shown previously to decrease methamphetamine self-administration during the first 25 min of the session (Harrod et al., 2001
), whereas the current report showed that lobelane decreased methamphetamine self-administration only during the first 15 min of the session.
In summary, the current results demonstrate that lobelane, a molecule formed from deoxygenation of the lobeline molecule, selectively decreases operant responding for methamphetamine compared to sucrose-maintained responding, and has a shorter duration of action compared to lobeline. However, this deoxygenation of the lobeline molecule also resulted in an unexpected emergence of tolerance, suggesting that in addition to the critical interaction with the vesicular monoamine transporter, another pharmacodynamic or pharmacokinetic component(s) of lobeline’s action may be important for maintaining the decrease in methamphetamine self-administration upon repeated treatment.