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Neurotransmitter orexin associated with pleasure and reward pathways in the brain

Newly discovered role could be basis for novel drug addiction treatments

University of Pennsylvania School of Medicine

(Philadelphia, PA) - Researchers at the University of Pennsylvania School of Medicine have discovered that the recently identified neurotransmitter orexin (also known as hypocretin) influences reward processing by activating neurons in the lateral hypothalamus region of the brain. By identifying the relationship between orexin neurons and behaviors associated with reward seeking, drug relapse, and addiction, researchers hope to find new treatments for drug addiction.

Previous studies have linked orexin activity to sleep and arousal (wakefulness), as well as feeding and appetite. Anatomical studies have shown that orexin neurons extend into the brain regions associated with reward pathways, including the ventral tagmental area and nucleus accumbens. Communication between the lateral hypothalamus and these brain regions suggests that orexin neurons may have a role in motivation and reward-seeking behavior. In order to examine the relationship between orexin and reward seeking, Glenda Harris, PhD, working with Gary Aston-Jones, PhD, in the Department of Psychiatry at Penn, examined orexin function in rats using a behavioral test aimed at mimicking food- and drug-reward seeking and drug relapse. This research appeared online in Nature on August 14.

"The lateral hypothalamus has been tied to reward and pleasure for decades, but the specific circuits and chemicals involved have been elusive," says Aston-Jones. "This is the first indication that the neuropeptide orexin is a critical element in reward-seeking and drug addiction. These results provide a novel and specific target for developing new approaches to treat addiction, obesity, and other disorders associated with dysfunctional reward processing."

Harris and Aston-Jones found a strong association between the activation of orexin neurons in the lateral hypothalamus and reward seeking of morphine, cocaine, and food. Using Fos, a chemical marker of neuronal stimulation, the researchers found that the highest levels of activity in the orexin neurons appeared in rats demonstrating the greatest level of reward seeking.

The researchers demonstrated the connection between orexins and the reward pathway in three ways. First, the activation of orexin neurons is related to preferences by the rats for cues associated with drug and food rewards. Second, chemical activation of orexin neurons reinstated an extinguished drug-seeking behavior in rats. And finally, direct injection of orexin reinstated drug-seeking behavior. In addition, when the researchers administered a specific orexin antagonist, the initial learning of a drug preference and the reinstatement of extinguished drug-seeking behavior were blocked.

Because of the relationship between orexin activation and reinstatement of reward-seeking behavior, these findings may have implications for understanding drug-taking relapse in humans. An animal's reward seeking can be extinguished over time by repeatedly exposing the animal to the environment possessing drug-related cues without the previous drug rewards. After extinguishing reward seeking, presenting a stimulus that was previously associated with the drug will lead animals to quickly resume reward seeking, similar to what happens when humans have a drug relapse. Using rPP, a neuropeptide that activates orexin neurons in the lateral hypothalamus, the researchers were able to reinstate drug seeking in the rats formerly possessing extinguished drug-seeking behavior.

"These findings indicate a new set of neurons and associated neuronal receptors that are critical in consummatory reward processing," says Aston-Jones. "This provides a new target for developing drugs to treat disorders of reward processing such as drug and alcohol addiction, smoking, and obesity."


Mathieu Wimmer, also in the Aston-Jones lab, was a co-author on the study. This research was funded by the National Institute on Drug Abuse.

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