The timing of dopamine- and noradrenaline-mediated transmission reflects underlying differences in the extent of spillover and pooling.

Metabotropic transmission typically occurs through the spillover activation of extrasynaptic receptors. This study examined the mechanisms underlying somatodendritic dopamine and noradrenaline transmission and found that the extent of spillover and pooling varied dramatically between these two transmitters. In the mouse ventral tegmental area, the time course of D2-receptor-mediated IPSCs (D2-IPSCs) was consistent between cells and was unaffected by altering stimulation intensity, probability of release, or the extent of diffusion. Blocking dopamine reuptake with cocaine extended the time course of D2-IPSCs and suggested that transporters strongly limited spillover. As a result, individual release sites contributed independently to the duration of D2-IPSCs. In contrast, increasing the release of noradrenaline in the rat locus ceruleus prolonged the duration of α2-receptor-mediated IPSCs even when reuptake was intact. Spillover and subsequent pooling of noradrenaline activated distal α2-receptors, which prolonged the duration of α2-IPSCs when multiple release sites were activated synchronously. By using the rapid application of agonists onto large macropatches, we determined the concentration profile of agonists underlying the two IPSCs. Incorporating the results into a model simulating extracellular diffusion predicted that the functional range of noradrenaline diffusion was nearly fivefold greater in the locus ceruleus than dopamine in the midbrain. This study demonstrates that catecholamine synapses differentially regulate the extent of spillover and pooling to control the timing of local inhibition and suggests diversity in the roles of uptake and diffusion in governing metabotropic transmission.