VESICULAR TRANSPORT REGULATES MONOAMINE STORAGE AND RELEASE BUT IS NOT ESSENTIAL FOR AMPHETAMINE ACTION

To assess the role of exocytotic release in signaling by monoamines, w e have disrupted the neuronal vesicular monoamine transporter 2 (VMAT2 ) gene. VMAT2(-/-) mice move little, feed poorly, and die within a few days after birth. Monoamine cell groups and their projections are ind istinguishable from those of wild-type littermates, but the brains of mutant mice show a drastic reduction in monoamines. Using midbrain cul tures from the mutant animals, amphetamine but not depolarization indu ces dopamine release. In vivo, amphetamine increases movement, promote s feeding, and prolongs the survival of VMAT2(-/-) animals, indicating that precise, temporally regulated exocytotic release of monoamine is not required for certain complex behaviors. In addition, the brains o f VMAT2 heterozygotes contain substantially lower monoamine levels tha n those of wild-type littermates, and depolarization induces less dopa mine release from heterozygous than from wild-type cultures, suggestin g that VMAT2 expression regulates monoamine storage and release.