The complex regulation of dopamine output: A review of current themes

Most studies of neurotransmission examine 'private' synapses where input from a presynaptic terminal is tightly coupled to a postsynaptic site. In contrast, dopamine release occurs via 'social' synapses where release of a quantum of neurotransmitter diffuses to tens to hundreds of postsynaptic sites. This overflow is controlled in part by the neuronal firing pattern and effects on vesicular mobilization and saturation of the dopamine uptake transporter (DAT). Presynaptic effects that mediate diffusion thus modulate social synapses, and dopaminergic terminals have evolved means to express a rich repertoire of presynaptic states. Addictive drugs enhance dopamine diffusion by a variety of mechanisms: cocaine blocks DAT, nicotine activates burst neuronal firing while depressing release at low firing rates, while amphetamine reduces quantal size, induces stimulation-independent DAT reverse transport, and depresses neuronal firing. Even at the level of a single terminal, social synapses seem adapted for complex modulation of neural circuits, and means to comprehend these interactions are only now beginning to be explored.