VMAT2 KNOCKOUT MICE - HETEROZYGOTES DISPLAY REDUCED AMPHETAMINE-CONDITIONED REWARD, ENHANCED AMPHETAMINE LOCOMOTION, AND ENHANCED MPTP TOXICITY

The brain vesicular monoamine transporter (VMAT2) pumps monoamine neur otransmitters and Parkinsonism-inducing dopamine neurotoxins such as 1 -methyl-4-phenyl-phenypyridinium (MPP+) from neuronal cytoplasm into s ynaptic vesicles, from which amphetamines cause their release. Ampheta mines 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-induce d locomotion, amphetamine-induced reward, and sequestration and resist ance to dopaminergic neurotoxins, we have constructed transgenic VMAT2 knockout mice. Heterozygous VMAT2 knockouts are viable into adult lif e and display VMAT2 levels one-half that of wild-type values, accompan ied 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 h eterozygotes, amphetamine produces enhanced locomotion but diminished behavioral reward, as measured by conditioned place preference. Admini stration of the MPP+ precursor N-methyl-4-phenyl-1,2,3,6-tetrahydropyr idine to heterozygotes produces more than twice the dopamine cell loss es found in wild-type mice. These mice provide novel information about the contributions of synaptic vesicular actions of monoaminergic drug s and neurotoxins and suggest that intact synaptic vesicle function ma y contribute more to amphetamine-conditioned reward than to amphetamin e-induced locomotion.