Hypocretin receptor 1 involvement in cocaine-associated behavior: Therapeutic potential and novel mechanistic insights

Abstract Since its discovery in 1998, the hypocretin/orexin system has been identified as a critical modulator of behavior. Through interactions with dopamine neurons of the ventral tegmental area, this system is poised to regulate motivation for drug rewards by impacting dopamine neurotransmission in target structures including the nucleus accumbens. Across numerous experiments, we and others have identified a critical influence of hypocretin receptor 1 in mediating the behavioral and physiological effects of cocaine which positions this receptor as a potential target for the treatment of cocaine addiction. Here we discuss evidence for hypocretin receptor 1 involvement in driving cocaine-associated behavior and how hypocretin receptor 1 in the ventral tegmental area are critical for supporting dopamine neuron activity and dopamine neurotransmission. We then present new data supporting the novel hypothesis that in addition to exerting acute actions on dopamine systems, pharmacological hypocretin manipulations also produce lasting adaptations to dopamine terminals that impact sensitivity to cocaine, and ultimately, future behavior.