It is well-documented that midbrain dopamine neurons express D2 autoreceptors. These receptors are Gi-coupled, resulting in hyperpolarizing potassium currents when activated. Furthermore, these receptors are endogenously active in vivo: pharmacological inhibition causes increased firing rates of VTA dopamine neurons, and selective genetic knockout of D2 autoreceptors results in hyperactive mice. Despite these observations, the source of dopamine that activates these autoreceptors is not understood. Golgi stains have revealed that the VTA does not contain robust dopaminergic axon collaterals, which would suggest an alternative source rather than local classical synaptic release. The consensus view within the field is that the dopamine that activates D2 autoreceptors comes from dendritic release of neurotransmitter. However, a major problem with this theory is that electron microscopic studies have noted an absence of dopamine-containing synaptic vesicles in dendrites within the VTA. We are currently using a combination of electrophysiological, optogenetic, pharmacological, and genetic techniques to explore alternative possible sources of dopamine onto these receptors.
