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Gary Aston JonesOrexin neurons in lateral hypothalamus: a role in drug and alcohol abuse

Abstract :

The lateral hypothalamus (LH) has been historically implicated in reward, but the neurotransmitters of LH neurons involved are unknown.
The orexins (also known as hypocretins) are neuropeptide transmitters in LH neurons. Although many studies have implicated orexin neurons in arousal, there is pronounced orexin innervation in reward-associated brain regions, including nucleus accumbens and ventral tegmental area (VTA). This indicates a possible role for these neurons in reward function and motivation, consistent with studies implicating them in feeding. We found that Fos expression in LH (but not in perifornical or dorsomedial hypothalamic) orexin neurons was strongly correlated with preferences for stimuli associated with morphine, cocaine or food reward (1, 2). In addition, chemical activation of LH orexin neurons reinstated an extinguished conditioned place preference (CPP) for morphine. This reinstatement effect was completely blocked by prior administration of the OxR1 antagonist, SB334867. Moreover, microinjection of orexin directly into VTA also reinstated an extinguished morphine CPP (1). The OxR1 antagonist also blocked stimulus-induced (but not cocaine-induced) reinstatement of extinguished cocaine-seeking in a self-administration paradigm (3). This effect was not seen for a selective OxR2 antagonist.
The OxR1 antagonist also decreased preference and consumption of alcohol in rats during a two-bottle choice paradigm. Thus, several results demonstrate a role for orexin projections to VTA and OxR1 in stimulus-reward associations. Studies by others showed that orexin potentiates glutamate responses of VTA dopamine (DA) neurons (4). This prompted us to to conduct neurophysiology studies, which revealed that orexin potentiates responses of VTA dopamine neurons to medial prefrontal cortex stimulation (5), a possible source of stimulus-reward information conveyed to VTA. Finally, we discovered that disruption of the LH orexin projection to VTA prevented learning a morphine CPP (6), consistent with previous findings that orexin is critical for drug-associated LTP in VTA DA neurons (4). These data reveal a novel role for LH orexin neurons in reward-seeking, drug relapse and addiction, and indicate that the VTA may be an important target site for these orexin actions. Supported by PHS grants R37 DA006214 and R01 DA017289.

Selected publications

Harris, G., Wimmer, M. and Aston-Jones, G., Nature 437: 556-559
Harris, G. and Aston-Jones, G., Trends Neurosci. 29: 571-57 (2006).
Smith, R., See, R. and Aston-Jones, G., Soc. Neurosci. Abstr. 33: Borgland et al., Neuron 49:589-601 (2006).

Moorman, D. and Aston-Jones, G., Soc. Neurosci. Abstr. 33: 916.3

Harris, G., Wimmer, M., Randall, J. and Aston-Jones, G., Behav.
Brain Res. 183: 43-51 (2007).