In addition to fast, excitatory glutamate-mediated synaptic transmission, dopamine neurons also express metabotropic glutamate receptors (mGluRs) which mediate slower, inhibitory synaptic transmission (Fiorillo and Williams 1998). The rapid rise and brief duration of synaptically released glutamate in the extracellular space mediates a rapid excitation through activation of ionotropic receptors, followed by inhibition through the mGluR1 receptor (Fiorillo and Williams 1998). CRF can enhance these mGluRs via a CRF2R-PKA pathway that stimulates release of calcium from intracellular stores (Riegel and Williams 2008). The CRF modulation of VTA synaptic activity is very complex because CRF has diverse actions on dopamine neurons that are excitatory and inhibitory. In summary, the excitatory effects of CRF on dopamine neurons appear to affect fast events (e.g. action potential firing rate and NMDAR-mediated synaptic transmission), whereas the inhibitory effects involve slow forms of synaptic transmission. Another important aspect is that CRF1R-mediated effects do not involve interactions with the CRF-BP, whereas CRF2R-mediated effects do.
