Convergent actions of orexin/hypocretin and CRF on dopamine neurons: Emerging players in addiction

The ventral tegmental area (VTA) is a brain region centrally involved in the development and expression of a variety of behaviors associated with drug use. Orexin/hypocretin (ox/hcrt) and corticotropin releasing factor (CRF) are both peptides released into the VTA, and an increasing number of studies show that both ox/hcrt and CRF in the VTA exert powerful modulatory effects on a variety of behaviors produced by drugs of abuse. Importantly, at a cellular and synaptic level, there is strong evidence supporting the hypothesis that these neuropeptides exert similar effects onto N-methyl-d-aspartate receptors (NMDARs) expressed in VTA neurons, suggesting a common molecular target in the actions of these peptides on this circuitry and ultimately on behaviors associated with drug use. In this review, we discuss emerging evidence that ox/hcrt and CRF directly target dopamine neurons by modulating excitatory synaptic activity, and that interaction of ox/hcrt and CRF may play a central role in addictive behaviors. Understanding these interactions in more detail may suggest new therapeutic targets in the treatment of relapse to substance abuse.