Target-specific glutamatergic regulation of dopamine neurons in the ventral tegmental area

Dopamine (DA) neurons in the ventral tegmental area (VTA) are thought to pl ay a critical role in affective, motivational, and cognitive functioning. T here are fundamental target-specific differences in the functional characte ristics of subsets of these neurons. For example, DA afferents to the prefr ontal cortex (PFC) have a higher firing and transmitter turnover rate and a re more responsive to some pharmacological and environmental stimuli than D A projections to the nucleus accumbens (NAc). These functional differences may be attributed in part to differences in tonic regulation by glutamate. The present study provides evidence for this mechanism: in freely moving an imals, blockade of basal glutamatergic activity in the VTA by the selective alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/kainate a ntagonist LY293558 produced an increase in DA release in the NAc while sign ificantly decreasing DA release in the PFC. These data support an AMPA rece ptor-mediated tonic inhibitory regulation of mesoaccumbens neurons and a to nic excitatory regulation of mesoprefrontal DA neurons. This differential r egulation may result in target-specific effects on the basal output of DA n eurons and on the regulatory influence of voltage-gated NMDA receptors in r esponse to phasic activation by behaviorally relevant stimuli.