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Lobeline and nicotine evoke [3H]overflow from rat striatal slices preloaded with [3H]dopamine ([3H]DA). The lobeline-evoked overflow is calcium-independent and not antagonized by mecamylamine, suggesting a mechanism of action other than the stimulation of nicotinic receptors. Whereas nicotine stimulates nicotinic receptors, lobeline inhibits [3H]DA uptake into synaptic vesicles and striatal synaptosomes. The results suggest that different mechanisms are responsible for the increase in striatal DA release evoked by lobeline and nicotine. [3H]-Dihydrotetrabenazine [3H]DTBZ), used routinely to probe a high-affinity binding site-on the vesicular monoamine transporter (VMAT2) binds to vesicle membranes from rat striatum. Lobeline inhibits [3H]DTBZ binding with an IC50 of 0.90 μM, consistent with its IC50 of 0.88 μM for inhibition of [3H]DA uptake into vesicles. These results suggest that the action of lobeline is similar to that of amphetamine and that it specifically interacts with DTBZ sites on VMAT2 to inhibit DA uptake into synaptic vesicles. d-amphetamine inhibits [3H]DTBZ binding to vesicle membranes with an IC50 of 39.4 μM, a concentration 20 times greater than reported for inhibition of VMAT2 function, suggesting that d-amphetamine interacts with a different site than lobeline on VMAT2 to inhibit monoamine uptake. These results suggest the use of lobeline and analogs thereof in treating individuals for diseases and pathologies of the central nervous system.


University of Kentucky Research Foundation, Lexington, Ky.

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