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Orexin neurons, reward and addiction: It all comes together in the lateral hypothalamus
Gary Aston-Jones, Ph.D.
Department of NeurosciencesMedical University of South Carolina
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Orexin (hypocretin) neurons:
Peyron et al. J. Neurosci. 1998;18:9996-10015
- located only in hypothalamus- widespread projections- mutations produce narcolepsy symptoms- prominent hypothesis: arousal
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Not all orexin neurons are created equal
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Activity of orexin neurons in LH does not correspond to arousal rhythm
Estabrooke, I. V. et al. J. Neurosci. 2001;21:1656-1662
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LH orexin neurons: Possible role in reward processing
• Orexin administration increases feeding
• Orexin neurons send projections to brain areas involved in reward (e.g., PFC, Nac, VTA)
• Lateral hypothalamus long implicated in reward functions
• Q: Are LH orexin neurons important in reward processing and addiction?
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Place conditioning procedureConditioned place preference (CPP)
3 drug or food pairing days, balanced designPreference tested next day, drug-freeBrains taken 2 hr after preference test for Fos measurements
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Fos activation in orexin neurons with exposure to morphine environment
Non-conditionedMorphine-conditionedHarris, Wimmer and Aston-Jones, Nature 437: 556-9 (2005)
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Preference scores
correlate with percentage of LH orexin cells that are Fos+
Harris, Wimmer and Aston-Jones, Nature 437: 556-9 (2005)
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Conclusion: LH orexin neurons are potently activated in proportion to reward preference
Q: Could activation of LH orexin neurons be involved in drug-seeking and relapse?
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Orexin antagonist attenuates expression of CPP
Saline SB334867
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Drug-seeking during protracted withdrawal: Animal Model of Relapse
3 days of morphine CPP conditioning
Repeated testing for 1 to 3 weeks daily without drug to extinguish preference
Stimulate LH orexin neurons to test for reinstatement(rat pancreatic polypeptide, rPP, microinjection in LH)
CPP extinguished for 2 consecutive days
Brains taken for Fos staining2 h after test for reinstate.
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rPP in LH reinstates morphine preference
-effective
-ineffective
Harris, Wimmer and Aston-Jones, Nature 437: 556-9 (2005)
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Correlation: rPP-induced reinstatement and % LH orexin neurons with Fos
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% orexin neurons with Fos
Harris, Wimmer and Aston-Jones, Nature 437: 556-9 (2005)
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rPP-induced reinstatement is blocked by selective orexin antagonist
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Harris, Wimmer and Aston-Jones, Nature 437: 556-9 (2005)
- Test Day 1- Test Day 2
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Orexin injected into VTA reinstates morphine preference
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Harris, Wimmer and Aston-Jones, Nature 437: 556-9 (2005)
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Orexin is also involved in plasticity and learning
Narita et al, J. Neurosci 29 (2006)
Borgland et al, Neuron 49 (2006)
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LH orexin neurons are stimulated during drug pairing
QuickTime™ and aTIFF (LZW) decompressor
are needed to see this picture.
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Bilateral disconnection of LH orexin projections to VTA blocks acquisition of a morphine CPP
Unilateral excitotoxic lesion of LH + SB in contra VTA
Go see: Wimmer et al., poster 00-74 Monday PM
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SUMMARY
• LH orexin neurons (but not other orexin neurons) are stimulated in proportion to reward preference.
• Blockade of orexin receptors attenuates expression of drug preference.
• Exogenous stimulation of LH orexin neurons reinstates extinguished drug preference (relapse).
• Orexin in VTA dopamine neuron area reinstates extinguished drug preference (relapse).
• Orexin projections from LH to VTA are critical for learning stimulus-drug relationships.
Hypothesis: LH orexin neurons are involved in reward-based learning and memory
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LH
Reward-related inputs:
•Morphine
•Cocaine
•Food
Projections to forebrain and midbrain reward areas:•VTA•NAc•Amy
DMH/PFA
Arousal-related inputs:
•Waking
•Stress
Projections to brainstemarousal areas:•LC•TMN•PPT/LDT
Functionally distinct orexin neuron groups
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Collaborators
Glenda Harris
Toastmaster
Matt Wimmer
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Role of LH orexin neurons in reward-based learning and memory circuitry
Harris and Aston-Jones, TINS 29: 571-7 (2006)
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Bilateral neurotoxic lesions of LH orexin neurons blocks acquistion of a morphine CPP
QuickTime™ and aTIFF (LZW) decompressor
are needed to see this picture.