A growing body of research suggests that a brain system observed by scientists for only the past two decades could end up serving as a crucial target for long-awaited medication therapies to treat cocaine dependence.
The latest study, currently in press in Biological Psychiatry, finds that the orexin system in the hypothalamic region of the brain plays a critical role in expression of a persistent addiction-like state in rats. Discoveries about the role of orexin cells in reward associated with drug-seeking could ultimately lead to development of an antagonist medication that could break new ground in the treatment of cocaine addiction, researchers say.
“Our work is pointing more to the possibility that we can manipulate and use the orexin system to help cure some of the aspects of addiction,” study co-author Gary Aston-Jones, PhD, director of the Brain Health Institute at Rutgers University, tells Addiction Professional. Aston-Jones adds, “We see the orexin system as primarily a motivation system.”
In an interview with Addiction Professional, Aston-Jones and study lead author Morgan H. James, whose research at Rutgers focuses on the brain pathways involved in psychiatric disorders, discussed the progress of research into an orexin system first discovered in the late 1990s.
Also known as hypocretin, orexin is a neuropeptide that was initially studied for its role in arousal, with the discovery that a loss of orexin cells could lead to narcolepsy. Around a decade ago, it was found that orexin cells were activated in periods when laboratory animals were seeking reward in the form of food or addictive drugs. Further research concluded that orexin cells specifically in the lateral hypothalamus are involved in the reward system for addiction.
“Orexin seems to play a role in stimulus-induced drug seeking,” Aston-Jones says.
Studying a new use pattern
To examine this further, the new study examined orexin system function in rats under a number of cocaine-using conditions. They compared continuous access to cocaine — the access model most often used in animal research—to short access and to a pattern more common to cocaine-using humans: intermittent access, involving relatively short bursts of access followed by longer periods of no access. For this study, intermittent access sessions involved 12 periods of five minutes each followed by 25-minute periods of no access, and this continued over 14 days.
The research team found that even though the animals with continuous access to cocaine ended up consuming more of the drug, the animals that had intermittent access exhibited a stronger drug-seeking profile. The rats with intermittent access accepted a higher maximum electrical charge in a test of punished responding to cocaine stimuli, “revealing the development of a strong compulsive drug-seeking phenotype in [intermittent access] animals,” the researchers wrote in their paper.
The researchers found that almost immediately after intermittent access to cocaine began, these rats had observable increases in the number of orexin cells in the lateral hypothalamus. This increase persisted for six months post-abstinence, the researchers observed. “It’s as though the brain changed in that it was more dependent on the orexin system,” Aston-Jones says.
If the orexin system is indeed implicated in cocaine addiction, this extended presence and activity of orexin cells could help explain why cocaine-dependent individuals are so vulnerable to relapse in early recovery.
Also, selective knockdown of orexin neurons in the lateral hypothalamus reduced the rodents’ motivation for cocaine, the researchers found. Administration of an orexin receptor antagonist was most effective in reducing cocaine-seeking among the animals who had experienced intermittent access to cocaine, they reported.
The study authors wrote that “our results strongly implicate the orexin system in the addicted state and highlight this system as a promising target for addiction therapies.”
Now that this is increasingly suggested in research, “One thing we’d love to do is take to the clinic with an [orexin-1 receptor] antagonist,” says Aston-Jones, referring to a medication that could address addiction without producing sedation. An existing orexin receptor antagonist, suvorexant (brand name: Belsomra), is a mixed orexin-1 and -2 receptor antagonist and therefore is likely to be sedating, says James.
Aston-Jones says that while the search for medications for opioid dependence has been more successful than that for cocaine dependence treatments, “I don’t think for any of these we have a real cure.” The absence of a cocaine receptor also complicates the quest for a medication to assist in the treatment of cocaine dependence, James says.
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