Neurotransmitter Orexin and Reward Seeking in the Brain

Orexin, also known as hypocretin, is a neurotransmitter discovered in 1998 which is produced in the hypothalamus region of the brain that is involved in wakefulness and arousal.

Because of its role related to sleep, orexin has been targeted as a treatment for sleep disorders. Medications known as "orexin receptor antagonists" have been developed to block the signaling of the chemical in the brain to promote sleep.

Because orexin plays a role in keeping us awake and alert, blocking its effects could potentially improve sleep. The U.S. Food and Drug Administration has approved suborexant (Belsomra), an orexin receptor antagonist, as a sleeping aid.

Researchers found that orexin neurons extend into the regions of the brain linked to reward pathways suggesting that these transmitters may play a role in motivation and reward-seeking behavior.

Penn State researcher Glenda Harris, Ph.D., working with Gary Aston-Jones, Ph.D., in the Department of Psychiatry, investigated the relationship between orexin and reward-seeking by studying orexin function in rats using a behavioral test aimed at mimicking food- and drug-reward seeking and drug relapse.

"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."

The researchers found a strong link between the activation of orexin neurons in the lateral hypothalamus and reward-seeking of morphine, cocaine, and food. They found that the highest levels of activity in the orexin neurons appeared in rats demonstrating the greatest level of reward-seeking.

Turning Drug Seeking on and Off

The study revealed an association between orexins and the reward pathways of the lab rats in three ways:

• Activation of orexin neurons is related to preferences by the rats for cues associated with drug and food rewards
• Chemical activation of orexin neurons reinstated an extinguished drug-seeking behavior
• Direct injection of orexin reinstated drug-seeking behavior.

In addition, when the researchers gave the rats a specific orexin antagonist, the animals' initial learning of a drug preference and the reinstatement of extinguished drug-seeking behavior were blocked.

Reward-Seeking Can Be Extinguished

"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," the researchers wrote. "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," they said.

New Target for Developing Treatment

Using a neuropeptide that activates orexin neurons in the lateral hypothalamus, Harris, and colleagues were able to reinstate drug-seeking in the rats whose drug-seeking behavior was previously extinguished.

"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."