Knockout of the vesicular monoamine transporter 2 gene results in neonatal death and supersensitivity to cocaine and amphetamine.
Vesicular monoamine transporters are known to transport monoamines from the cytoplasm into secretory vesicles. We have used homologous recombination to generate mutant mice lacking the vesicular monoamine transporter 2 (VMAT2), the predominant form expressed in the brain. Newborn homozygotes die within a few days after birth, manifesting severely impaired monoamine storage and vesicular release. In heterozygous adult mice, extracellular striatal dopamine levels, as well as K+- and amphetamine-evoked dopamine release, are diminished. The observed changes in presynaptic homeostasis are accompanied by a pronounced supersensitivity of the mice to the locomotor effects of the dopamine agonist apomorphine, the psychostimulants cocaine and amphetamine, and ethanol. Importantly, VMAT2 heterozygous mice do not develop further sensitization to repeated cocaine administration. These observations stress the importance of VMAT2 in the maintenance of presynaptic function and suggest that these mice may provide an animal model for delineating the mechanisms of vesicular release, monoamine function, and postsynaptic sensitization associated with drug abuse.
Wang
Y M
YM
Howard Hughes Medical Institute Laboratories, Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Gainetdinov
R R
RR
Fumagalli
F
F
Xu
F
F
Jones
S R
SR
Bock
C B
CB
Miller
G W
GW
Wightman
R M
RM
Caron
M G
MG
D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D001058:Apomorphine / Q000494:pharmacology; D001679:Biogenic Amines / Q000378:metabolism*; D001692:Biological Transport; D001921:Brain / Q000187:drug effects / Q000502:physiology*; D003042:Cocaine / Q000494:pharmacology*; D017931:DNA Primers; D003643:Death; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006706:Homeostasis; D006720:Homozygote; D007700:Kinetics; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D026901:Membrane Transport Proteins; D051379:Mice; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D009479:Neuropeptides; D018377:Neurotransmitter Agents / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011188:Potassium / Q000494:pharmacology; D011995:Recombination, Genetic; D013569:Synapses / Q000502:physiology; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins
D001679:Biogenic Amines; D017931:DNA Primers; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009479:Neuropeptides; D018377:Neurotransmitter Agents; C493453:Slc18a2 protein, mouse; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins; D000661:Amphetamine; D003042:Cocaine; D001058:Apomorphine; D011188:Potassium; D004298:Dopamine