The first direct evidence for dendritic dopamine release came from experiments in brain slices directly

measuring release of 3H-dopamine in SN upon potassium-evoked cell depolarization (Geffen et al., 1976). These results were confirmed in vivo using push-pull canula, microdialysis, and voltammetry in the SN and ventral tegmental area (VTA) (Cheramy et al., 1981, Jaffe et al., 1998 and Kalivas and Duffy, 1988). Dopamine is also released from dendrites in more reduced preparations including dissociated culture (Fortin et al., 2006). Interestingly, when VMAT2 is exogenously expressed in dissociated hippocampal neurons, which don’t normally secrete selleck screening library dopamine from their dendrites or axons, robust dendritic dopamine release is observed HKI-272 chemical structure (Li et al., 2005). This experiment reveals that existing activity-dependent secretory pathways in nondopaminergic cells can be co-opted for dopamine release simply by expressing VMAT2, raising the question of what additional release factors might be required for dendritic release from SN dopamine neurons. The mechanism of dendritic dopamine release has been controversial. One study suggested

that dopamine release was not mediated by vesicular fusion, but by reversal of the dopamine transporter (DAT) upon activation of glutamatergic inputs (Falkenburger et al., 2001). However, other studies have shown that DAT inhibitors do not block dopamine release whereas Clostridial neurotoxins that cleave VAMP/synaptobrevin SNARE proteins ( Box 1) block exocytosis of dendritic dopamine, confirming a role for vesicular fusion in dendritic dopamine release ( Bergquist et al., 2002, Fortin et al., 2006 and John et al., 2006). As further evidence for a vesicular mechanism, quantal release events can be recorded from the somatodendritic

region of Rolziracetam dopamine neurons using carbon fiber amperometry ( Jaffe et al., 1998). Although dendritic dopamine appears to be released by vesicle fusion, the mechanisms are distinct from axonal dopamine release. Both dendritic and axonal dopamine release are dependent on Ca2+, but dendritic release is sustained in extracellular Ca2+ levels below those required for axonal release, suggesting different Ca2+ sensors for dendritic and axonal exocytosis (Fortin et al., 2006). The voltage-gated Ca2+ channel coupled to dendritic dopamine release appears to be different from the axonal channel, perhaps explaining the differential release properties of dendrites and axons. Unlike axonal exocytosis, dendritic dopamine release is not blocked by P/Q- or N-type Ca2+ channel blockers (Bergquist et al., 1998, Bergquist and Nissbrandt, 2003, Chen et al., 2006 and Chen and Rice, 2001).