Both corticotropin releasing factor (CRF) and orexin A/hypocretin-1 (oxA/hcrt-1) can modulate drug-evoked synaptic plasticity, presumably through their effect on firing rates of VTA DA neurons and potentiation of NMDAR-mediated synaptic transmission (for a recent review see Borgland et al., 2010). While either neuropeptide, when administered in the VTA, can lead to dopamine release in target regions of the VTA, distinct subpopulations of DA neurons seem to be the target for these substances. Cells that synthesize orexin are located in lateral hypothalamus and project to VTA DA neurons, where they release OxA/hcrt-1 and OxB/hcrt-2. DA neurons in turn express both orexin 1 and orexin 2 receptors and are generally excited by their activation. It has been suggested that orexin preferentially activates caudomedial VTA neurons that primarily project to the PFC and NAc shell (Vittoz et al., 2008) and that this effect contributes to the behaviors elicited by drugs of abuse as well as natural rewards. Indeed, the increase in the AMPAR/NMDAR ratio following in vivo cocaine administration was blocked when an OXR1 antagonist was administered systemically before the cocaine injection (Borgland et al., 2006).
