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 fro m the cytoplasm into secretory vesicles. We have used homologous recom bination to generate mutant mice lacking the vesicular monoamine trans porter 2 (VMAT2), the predominant form expressed in the brain. Newborn homozygotes die within a few days after birth, manifesting severely i mpaired monoamine storage and vesicular release. In heterozygous adult mice, extracellular striatal dopamine levels, as well as K+- and amph etamine-evoked dopamine release, are diminished. The observed changes in presynaptic homeostasis are accompanied by a pronounced supersensit ivity of the mice to the locomotor effects of the dopamine agonist apo morphine, the psychostimulants cocaine and amphetamine, and ethanol. I mportantly, VMAT2 heterozygous mice do not develop further sensitizati on to repeated cocaine administration. These observations stress the i mportance of VMAT2 in the maintenance of presynaptic function and sugg est that these mice may provide an animal model for delineating the me chanisms of vesicular release, monoamine function, and postsynaptic se nsitization associated with drug abuse.