Control of Extracellular Dopamine at Dendrite and Axon Terminals

Abstract

Midbrain dopamine neurons release dopamine from both axons and dendrites. The mechanism underlying release at these different sites has been proposed to differ. This study used electrochemical and electrophysiological methods to compare the time course and calcium dependence of somatodendritic dopamine release in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) to that of axonal dopamine release in the dorsal striatum. The amount of dopamine released in the striatum was ϳ20-fold greater than in cell body regions of the VTA or SNc. However, the calcium dependence and time to peak of the dopamine transients were similar. These results illustrate an unexpected overall similarity in the mechanisms of dopamine release in the striatum and cell body regions. To examine how diffusion regulates the time course of dopamine following release, dextran was added to the extracellular solution to slow diffusion. In the VTA, dextran slowed the rate of rise and fall of the extracellular dopamine transient as measured by fast-scan cyclic voltammetry yet did not alter the kinetics of the dopamine-dependent IPSC. Dextran failed to significantly alter the time course of the rise and fall of the dopamine transient in the striatum, suggesting a more influential role for reuptake in the striatum. The conclusion is that the time course of dopamine within the extracellular space of the VTA is dependent on both diffusion and reuptake, whereas the activation of D 2 receptors on dopamine neurons is primarily limited by reuptake.

Somatodendritic dopamine release: recent mechanistic insights

“…This voltammetric method allows detection of evoked release of DA in discrete brain regions, including the SNc and VTA [17][18][19]21,25,26,32,38,[67][68][69]. Identification of DA can be confirmed by its characteristic voltammogram (figure 2) [18,22], as well as by amplification of the release response by inhibition of the DA transporter (DAT) [20,21], or suppression of release following inhibition of the vesicular monoamine transporter, VMAT2 [17].…”

“…Williams and co-workers pioneered the use of D2 DA autoreceptor-dependent currents as a 'biosensor' for evoked DA release in the SNc and VTA [23,24,26,55,69,72]. The detected currents arise from the DA-dependent activation of D2 autoreceptors, which are linked to G-protein-coupled inwardly rectifying K þ (GIRK) channels in DA neurons [73][74][75][76].…”

“…These are referred to as D2-dependent inhibitory postsynaptic currents (D2-IPSCs; figure 2b, right panel). Evoked D2-IPSCs are abolished by the D2 receptor antagonist sulpiride and by VMAT2 inhibitors, and are amplified by the DA precursor L-DOPA or inhibition of the DAT by cocaine [23,24,26,69,72]. Notably, consistent D2-IPSCs can be evoked repetitively by brief pulse-train stimulation (five pulses, 40 Hz).…”

“…It should be noted that the role of intracellular Ca 2þ stores in facilitating somatodendritic DA release is complex and appears to vary with experimental condition or species tested [26,63,69]; moreover, it has yet to be demonstrated in VTA. Another factor to consider is that somatodendritic DA release may require a very rapid elevation in [Ca 2þ ] i close to the releasing organelle to trigger release, whereas slower global increases in [Ca 2þ ] i could act to enhance priming, for example, as seen for the release of oxytocin from the dendrites of hypothalamic neurons [126].…”

“…Midbrain DA neurons in the SNc and VTA also release DA from their somata and dendrites [13][14][15][16][17][18][19][20][21][22][23][24][25][26]. The term 'somatodendritic' accurately describes evoked DA release in the SNc and VTA, in which somata and dendrites intermingle (figure 1), so that somatic and dendritic release cannot readily be distinguished.…”