Abstract
Lobeline interacts with the dopamine transporter and vesicular monoamine transporter, presynaptic proteins involved in dopamine storage and release. This study used rodent models to assess lobeline-induced inhibition of the neurochemical and behavioral effects of amphetamine. Rat striatal slices were preloaded with [3H]dopamine and superfused with lobeline for 30 min, and then with d-amphetamine (0.03–3.00 μM) plus lobeline for 60 min. As predicted, lobeline (1–3 μM) intrinsically increased3H overflow but did not inhibitd-amphetamine-evoked 3H overflow. Consequently, the effect of lobeline ond-amphetamine-evoked endogenous dopamine and dihydroxyphenylacetic acid overflow was assessed. Lobeline (0.1–1 μM) inhibited d-amphetamine (1 μM)-evoked dopamine overflow but did not inhibit electrically evoked 3H overflow, indicating a selective inhibition of this effect ofd-amphetamine. To determine whether the in vitro results translated into in vivo inhibition, the effect of lobeline (0.3–10.0 mg/kg) pretreatment on d-amphetamine (0.1–1.0 mg/kg)-induced hyperactivity in rats and ond-methamphetamine (0.1–3.0 mg/kg)-induced hyperactivity in mice was determined. Doses of lobeline that produced no effect alone attenuated the stimulant-induced hyperactivity. Lobeline also attenuated the discriminative stimulus properties ofd-methamphetamine in rats. Acute, intermittent, or continuous in vivo administration of lobeline (1–30 mg/kg) did not deplete striatal dopamine content. Thus, lobeline inhibits amphetamine-induced neurochemical and behavioral effects, and is not toxic to dopamine neurons. These results support the hypothesis that lobeline redistributes dopamine pools within the presynaptic terminal, reducing pools available for amphetamine-induced release. Collectively, the results support a role for lobeline as a potential pharmacotherapy for psychostimulant abuse.
Footnotes
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Send reprint requests to: Linda Dwoskin, Ph.D., College of Pharmacy, University of Kentucky, Lexington, KY 40536-0082. E-mail:ldwoskin{at}pop.uky.edu
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This study was supported by National Institutes of Health Grants DA13519, DA00399, and DA06043, National Institute on Environmental Health Sciences Training Grant ES07266, and by a grant from the Tobacco and Health Research Institute, Lexington, KY.
- Abbreviations:
- DA
- dopamine
- [3H]DA
- 3,4-ethyl-2-[N-3H]dihydroxyphenylethylamine
- DAT
- dopamine transporter
- VMAT2
- vesicular monoamine transporter
- MAO
- monoamine oxidase
- DOPAC
- dihydroxyphenylacetic acid
- ANOVA
- analysis of variance
- Received September 12, 2000.
- Accepted October 31, 2000.
- U.S. Government
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