VMAT2 Knockout Mice: Heterozygotes Display Reduced Amphetamine-Conditioned Reward, Enhanced Amphetamine Locomotion, and Enhanced MPTP Toxicity
The brain vesicular monoamine transporter (VMAT2) pumps monoamine neurotransmitters and Parkinsonism-inducing dopamine neurotoxins such as 1-methyl-4-phenyl-phenypyridinium (MPP+) from neuronal cytoplasm into synaptic vesicles, from which amphetamines cause their release. Amphetamines and MPP+each a...
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Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 94; no. 18; pp. 9938 - 9943 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
National Academy of Sciences of the United States of America
02.09.1997
National Acad Sciences National Academy of Sciences The National Academy of Sciences of the USA |
Subjects | |
Online Access | Get full text |
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Summary: | The brain vesicular monoamine transporter (VMAT2) pumps monoamine neurotransmitters and Parkinsonism-inducing dopamine neurotoxins such as 1-methyl-4-phenyl-phenypyridinium (MPP+) from neuronal cytoplasm into synaptic vesicles, from which amphetamines cause their release. Amphetamines and MPP+each also act at nonvesicular sites, providing current uncertainties about the contributions of vesicular actions to their in vivo effects. To assess vesicular contributions to amphetamine-induced locomotion, amphetamine-induced reward, and sequestration and resistance to dopaminergic neurotoxins, we have constructed transgenic VMAT2 knockout mice. Heterozygous VMAT2 knockouts are viable into adult life and display VMAT2 levels one-half that of wild-type values, accompanied by smaller changes in monoaminergic markers, heart rate, and blood pressure. Weight gain, fertility, habituation, passive avoidance, and locomotor activities are similar to wild-type littermates. In these heterozygotes, amphetamine produces enhanced locomotion but diminished behavioral reward, as measured by conditioned place preference. Administration of the MPP+precursor N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine to heterozygotes produces more than twice the dopamine cell losses found in wild-type mice. These mice provide novel information about the contributions of synaptic vesicular actions of monoaminergic drugs and neurotoxins and suggest that intact synaptic vesicle function may contribute more to amphetamine-conditioned reward than to amphetamine-induced locomotion. |
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Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 To whom reprint requests should be addressed at: Molecular Neurobiology, Box 5180, Baltimore, MD 21224. e-mail guhl@irp.nida.nih.gov. Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved June 2, 1997 |
ISSN: | 0027-8424 1091-6490 |
DOI: | 10.1073/pnas.94.18.9938 |