Hypocretin modulation of drug-induced synaptic plasticity

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. Hypocretin (hcrt), also known as orexin, is a lateral hypothalamic neuropeptide that can be released into the VTA. An increasing number of studies show that hcrt in the VTA exerts modulatory effects on a variety of behaviors produced by drugs of abuse. Importantly, at a cellular level, acute application of hcrt in the VTA potentiates N-methyl-D-aspartate receptors expressed in VTA neurons and facilitates the plasticity induced by drugs of abuse. In this review, we discuss evidence that hcrt directly targets dopamine neurons by modulating excitatory synaptic activity and that hcrt action at excitatory synapses onto VTA dopamine neurons plays a central role in motivated behaviors.