Neurotransmitter Orexin Associated With Pleasure And Reward Pathways In The Brain

Previous studies have linked orexin activity to sleep and arousal(wakefulness), as well as feeding and appetite. Anatomical studies haveshown that orexin neurons extend into the brain regions associated withreward pathways, including the ventral tagmental area and nucleusaccumbens. Communication between the lateral hypothalamus and thesebrain regions suggests that orexin neurons may have a role inmotivation and reward-seeking behavior. In order to examine therelationship between orexin and reward seeking, Glenda Harris, PhD,working with Gary Aston-Jones, PhD, in the Department of Psychiatry atPenn, examined orexin function in rats using a behavioral test aimed atmimicking food- and drug-reward seeking and drug relapse. This researchappeared online in Nature on August 14.

"The lateral hypothalamus has been tied to reward and pleasurefor decades, but the specific circuits and chemicals involved have beenelusive," says Aston-Jones. "This is the first indication that theneuropeptide orexin is a critical element in reward-seeking and drugaddiction. These results provide a novel and specific target fordeveloping new approaches to treat addiction, obesity, and otherdisorders associated with dysfunctional reward processing."

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

The researchers demonstrated the connection between orexinsand the reward pathway in three ways. First, the activation of orexinneurons is related to preferences by the rats for cues associated withdrug and food rewards. Second, chemical activation of orexin neuronsreinstated an extinguished drug-seeking behavior in rats. And finally,direct injection of orexin reinstated drug-seeking behavior. Inaddition, when the researchers administered a specific orexinantagonist, the initial learning of a drug preference and thereinstatement of extinguished drug-seeking behavior were blocked.

Because of the relationship between orexin activation andreinstatement of reward-seeking behavior, these findings may haveimplications for understanding drug-taking relapse in humans. Ananimal's reward seeking can be extinguished over time by repeatedlyexposing the animal to the environment possessing drug-related cueswithout the previous drug rewards. After extinguishing reward seeking,presenting a stimulus that was previously associated with the drug willlead animals to quickly resume reward seeking, similar to what happenswhen humans have a drug relapse. Using rPP, a neuropeptide thatactivates orexin neurons in the lateral hypothalamus, the researcherswere able to reinstate drug seeking in the rats formerly possessingextinguished drug-seeking behavior.

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

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