Abstract
This study evaluated whether the caudate-putamen dopamine response that has been observed after deprenyl administration could be attributed exclusively to metabolically generated l-methamphetamine (l-MeAmp). Brain and plasma levels of deprenyl andl-MeAmp were measured after deprenyl (10 mg/kg s.c.) from 10 to 60 min in conscious rats. Peak caudate-putamen levels were observed for deprenyl (15 nmol/g) at 10 min and forl-MeAmp (3 nmol/g) at 30 min. In a parallel study,l-MeAmp metabolism was evaluated. Afterl-MeAmp (20 mg/kg s.c.), metabolite levels remained low relative to those of the parent compound: l-amphetamine, ∼5 to 12%; andpara-hydroxy-l-methamphetamine (OH-MeAmp), ∼0.25%. Accordingly, l-MeAmp was considered to be the primary pharmacologically active deprenyl metabolite. A pharmacokinetic-pharmacodynamic analysis was then used to relate these pharmacokinetic data to the results of previous microdialysis studies in which increases in extracellular dopamine were measured in the caudate-putamen after l-MeAmp (3–18 mg/kg) and after deprenyl (10 mg/kg). Dopamine response-area under curve versus dose plots were generated and used to show that an administered dose of 4 mg/kg l-MeAmp would be necessary to effect a dopamine response-area under curve comparable to that observed after the deprenyl dose. However, the present pharmacokinetic results indicated that l-MeAmp brain levels after deprenyl corresponded to those that would be obtained from 0.4 mg/kgl-MeAmp (i.e., one tenth of the required dose). Collectively, these results suggest that the acute increases in extracellular dopamine observed after deprenyl are not due uniquely to metabolically generated l-MeAmp but also to other actions of deprenyl at the dopamine terminal.
Footnotes
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Send reprint requests to: William P. Melega, Ph.D., Department of Molecular and Medical Pharmacology, 23-120 CHS, UCLA School of Medicine, Box 951735, Los Angeles, CA 90095-1735. E-mail:wmelega{at}mednet.ucla.edu
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↵1 This work was supported in part by U.S. Department of Energy Grant DE-FC03–87ER60615 and Intra-agency Agreement 1-YO1-DA500038-00.
- Abbreviations:
- d-Amp
- d-amphetamine
- d-MeAmp
- d-methamphetamine
- l-MeAmp
- l-methamphetamine
- MAO
- monoamine oxidase
- DA
- dopamine
- DOPAC
- 3,4-dihydroxyphenylacetic acid
- HVA
- homovanillic acid
- 5-HIAA
- 5-hydroxyindoleacetic acid
- OH-MeAmp
- para-hydroxymethamphetamine
- HPLC
- high-pressure liquid chromatography
- GC/MS
- gas chromatography-mass spectrometry
- AUC
- area under the curve
- Received May 26, 1998.
- Accepted September 4, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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