Role of orexin/hypocretin in dependence and addiction

Abstract

The orexins (or hypocretins) are hypothalamic neuropeptides that have been implicated in a variety of behaviors ranging from feeding to sleep and arousal. Evidence from animal models suggests a role for orexins in reward processing and drug addiction. In this review, we discuss orexin's interaction with the mesocorticolimbic reward pathway and the effects of drugs of abuse on the orexin system. We further review models of drug dependence and addiction and describe behavioral alterations that are seen when the orexin system is manipulated both pharmacologically and genetically. Based on the findings reported in the literature thus far, we posit that orexin functioning contributes to both drug reward and drug-related stress/aversive responsiveness; however, diverse anatomical substrates, and perhaps receptor specificity, contribute differentially to reward and stress components.

Figure 1

Schematic representation of the orexin system and its interactions with the mesocorticolimbic reward pathway. Orexin projections (blue arrows) activate the ventral tegmental area (VTA), amygdala (Amy), and prefrontal cortex (PFC). Conflicting data suggest both activation and inhibition of the nucleus accumbens (NAc) by orexin. In the VTA, orexin activates both dopamine and GABA neurons. Orexin’s activation of the VTA results in increased dopamine (DA) in via projections (green arrows) to the NAc and PFC. Orexin’s action in the PFC is due to stimulation of Ox1rs. Orexin’s action in the NAc and amygdala is due to stimulation of Ox2rs.

Figure 2

Effects of acute or chronic drug adminsitration on orexin cells in the LH. Abbr: DMH-dorsal medial hypothalamus; PFA-perifornical area; LLH-lateral portion of lateral hypothalamus; 3V-third ventricle; f-fornix. Data derived from (Estabrooke et al., 2001; Fadel and Deutch, 2002; Georgescu et al., 2003; Kane et al., 2000; Morshedi and Meredith, 2008; Pasumarthi et al., 2006; Pasumarthi and Fadel, 2008; Sharf et al., 2008; Zhang et al., 2007; Zhou et al., 2006; Zhou et al., 2008)