A novel mechanism of action and potential use for lobeline as a treatment for psychostimulant abuse

Linda P. Dwoskin, Peter A. Crooks

Research output: Contribution to journalComment/debate

178 Scopus citations


Lobeline, an alkaloidal constituent of Lobelia inflata LINN., has a long history of therapeutic usage ranging from emetic and respiratory stimulant to tobacco smoking cessation agent. Although classified as both an agonist and an antagonist at nicotinic receptors, lobeline has no structural resemblance to nicotine, and structure-function relationships do not suggest a common pharmacophore. Lobeline inhibits nicotine-evoked dopamine release and [3H]nicotine binding, thus acting as a potent antagonist at both α3β2* and α4β2* neuronal nicotinic receptor subtypes. However, lobeline does not release dopamine from its presynaptic terminal, but appears to induce the metabolism of dopamine intraneuronally. Reevaluation of the mechanism by which lobeline alters dopamine function reveals that its primary mechanism is inhibition of dopamine uptake and promotion of dopamine release from the storage vesicles within the presynaptic terminal, via an interaction with the tetrabenazine-binding site on the vesicular monoamine transporter (VMAT2). Thus, lobeline appears to perturb the fundamental mechanisms of dopamine storage and release. Based on its neurochemical mechanism, the ability of lobeline to functionally antagonize the neurochemical and behavioral effects of the psychostimulants amphetamine and methamphetamine was examined. Lobeline was found to inhibit the amphetamine-induced release of dopamine in vitro, and amphetamine-induced hyperactivity, drug discrimination, and self-administration. However, lobeline does not support self-administration in rats, suggesting a lack of addiction liability. Thus, lobeline may reduce the abuse liability of these psychostimulants. The development of lobeline and lobeline analogs with targeted selectivity at VMAT2 represents a novel class of therapeutic agents having good potential as efficacious treatments for methamphetamine abuse.

Original languageEnglish
Pages (from-to)89-98
Number of pages10
JournalBiochemical Pharmacology
Issue number2
StatePublished - Jan 15 2002

Bibliographical note

Funding Information:
The work of the authors discussed in this commentary was supported by NIH Grants DA00399 and DA13519. The authors would also like to thank Dr. Dennis Miller for technical assistance.


  • Dopamine transporter
  • Lobeline
  • Methamphetamine
  • Nicotine
  • Psychostimulants
  • Vesicular monoamine transporter

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology


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