Neuropeptide Promotes Drug-Seeking and Craving in Rats

Orexin emerges as a link in the chain of brain mechanisms regulating appetite for rewards.

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Orexin, a neuropeptide that stimulates eating and regulates wakefulness, also fosters animals' drug seeking and craving responses to drugs, according to two NIDA-funded studies. The research teams, led by Drs. Glenda Harris and Gary Aston-Jones at the University of Pennsylvania and Drs. Stephanie Borgland and Antonello Bonci at the University of California, San Francisco (UCSF), used different experimental procedures and studied different drugs. Their findings, however, point to the same conclusion: Augmenting orexin increases drug seeking, while blocking it has the opposite effect.

diagram of how reward cues activate orexin neurons which then stimulate the mesolimbic reward pathway  Orexin Stimulation Drives Drug-Seeking: Exposure to cues associated with drugs activate the orexin neurons (red), which stimulates neruons in the brain's mesolimbic reward pathway (blue).

Orexin, also called hypocretin, is produced by neurons in the hypothalamus—a brain structure that regulates hunger, thirst, sleep, and other processes essential to survival. Scientists recently discovered that people with narcolepsy lack orexin-producing neurons. The finding suggested an explanation for a striking observation made in the mid-1970s: People with narcolepsy rarely became addicted to the potent stimulants used to treat the disorder at the time. Perhaps, some scientists speculated, orexin contributes to the development of drug abuse.

Orexin and Drug Seeking

An observation in animals by Drs. Harris and Aston-Jones also seemed to suggest a possible connection. They noted that lateral hypothalamus (LH) cells in the same area as orexin neurons were activated during drug seeking using a behavioral assay called conditioned place preference (CPP; for more on CPP, see "Animal Experiments in Addiction Science (Archives)"). After repeated morphine injections in one chamber of a test cage and saline in the other, rats gravitate to the drugpaired area in an effort to re-experience the opiate effects. The time they spend in the area—their morphine place preference—indicates how intensely the drug motivates drug seeking. When Drs. Harris and Aston-Jones determined that the LH neurons activated during drug seeking produce orexin, they conducted further experiments.

The Pennsylvania researchers first demonstrated that activation of orexin neurons in the LH was tightly coupled with rats' place preferences for morphine, cocaine, and sweet food. Next, they gave a different group of rats morphine for 3 days to establish place preference, then stopped the drug and injected some rats with a compound (SB334867) that prevents orexin from interacting with brain cells. Following treatment with SB334867, rats spent 58 percent less time in the morphine-associated cage area—indicating a halving of their drug seeking. Rats given inert vehicle showed no significant change in drug seeking.

The investigators also tested orexin's impact on the tendency of a new group of rats to revert to drug seeking after CPP waned following extended testing without drug administration (extinction). In contrast to the first experiment, this time the investigators injected a compound (rat pancreatic polypeptide, rPP) that stimulates orexin neurons into the LH of some animals. These rats quickly resumed CPP—indicated by the difference in time spent in the morphine versus saline chambers—as marked as that of another group that received a morphine priming injection (353 seconds and 424 seconds for rPP and morphine, respectively). Rats that received a vehicle injection did not renew morphine CPP.

To establish that stimulation of orexin neurons by rPP, and not some other unidentified factor, was responsible for the effects in their second experiment, the investigators repeated the procedure. This time they blocked the extinction of orexin by giving the rats SB334867 prior to rPP. These rats did not resume CPP. Finally, the researchers infused orexin directly into rats' ventral tegmental area (VTA), the origin of the dopamine-rich reward pathway, and observed a resumption of drug-seeking behavior.

Drugs May Usurp Feeding System

The results, although in animals, suggest that orexin promotes drug abusers' desire for drugs and their risk for relapse. "It makes sense, anatomically and physiologically, that orexin might play a role in reward-seeking and craving," says Dr. Harris, now at the Centre de Regulacio Genomica in Spain. "Neurons in this part of the brain stimulate eating; intense cravings for food and water originate here. Our findings suggest that orexin from the lateral hypothalamus affects the reward pathway. Perhaps drugs take over the brain system for feeding and craving just as they usurp neural systems for reward."

"These behavioral findings extend the team's important anatomical work differentiating two populations of orexin-producing neurons in the hypothalamus. One population, located in the lateral hypothalamus, is involved in feeding, reward, and drug seeking, while the other regulates sleep and arousal," says Dr. Susan Volman of NIDA's Division of Basic Neuroscience and Behavioral Research. "The findings identify new neural pathways involved in drug abuse, craving, and relapse, and may ultimately help scientists find more effective therapies.

A Role in Cocaine Craving?

Drs. Borgland and Bonci and colleagues at the UCSF Ernest Gallo Clinic and Research Center demonstrated orexin effects on cocaine-related behaviors remarkably consistent with those the Pennsylvania team showed with respect to drug-related behaviors. They also provided evidence that orexin produces these effects at least in part by altering neurons in the VTA. The UCSF team used behavioral sensitization to evaluate orexin's impact on rats' responses to cocaine. Scientists generally think animals' behavioral sensitization—increased locomotor activity following repeated exposure to a drug—reflects drug-induced neural changes and corresponds to human craving for the drug. In the UCSF experiment, rats pretreated with an orexin blocker displayed only half as much increase in locomotor activity (138 percent) following five daily cocaine infusions (15 mg/kg) as rats pretreated with an inert vehicle (257 percent).

To explore the cellular bases for their behavioral observations, the UCSF group measured orexin's effects on the electrophysiological properties of dopamine-producing cells in brain slices removed from the VTA of rats. The results showed that orexin increased the number of receptors for neural excitation on the surfaces of these cells. Such strengthening of intercellular connections occurs during learning. Scientists believe it may foster the development of drug craving. When the researchers pretreated the rats with an orexin blocker, cocaine lost its ability to alter dopamine-producing cells in the VTA, suggesting that orexin may be necessary for cocaine-induced neuroplasticity and its behavioral consequences.

"Our findings point to a key role for orexin in the neural changes in the reward pathway that underlie craving and relapse," says Dr. Borgland. "The physiological alterations we observed likely influence those cells' dopamine release, perhaps affecting the activity of the reward pathway in a way that increases the likelihood of relapse. One implication of our findings is that addiction medication development efforts might do well to target orexin receptors," she says. The work of the Pennsylvania and UCSF teams points to orexin involvement in reward-seeking in general. Researchers studying the effects of orexin-blocking compounds in animal models of alcoholism and obesity have reported preliminary but promising findings. Both teams are currently determining whether giving such compounds to animals reduces self-administration of cocaine, say Dr. Bonci and Dr. Aston-Jones, the latter now at the Medical University of South Carolina.


Harris, G.C., Wimmer, M., and Aston-Jones, G. A role for lateral hypothalamic orexin neurons in reward seeking. Nature 437(7058):556-559, 2005. [Abstract]

Borgland, S.L., et al. Orexin A in the VTA is critical for the induction of synaptic plasticity and behavioral sensitization to cocaine. Neuron 49(4):589-601, 2006. [Abstract]