Substantial preclinical evidence indicates that glutamatergic activity mediates natural as well as alcohol- and drug-associated reward through direct and indirect interactions with other neurotransmitter/neuromodulatory systems within the mesocorticolimbic, extended amygdala, and associated reward neurocircuitry (Fig. 1).95–102 A key hypothesis that has received considerable attention postulates that the mesocorticolimbic and extended amygdala reward circuits, in the presence of alcohol, lose homeostasis between excitatory and inhibitory transmission and revert to a hyperglutamatergic/hyper-excitatory state resulting in the development and expression of alcohol/drug dependence.37,98,102–107
