At The Scripps Research Institute (TSRI) in a new
study scientists suggests that increased levels of a
molecule in the brain, called hypocretin, may
contribute to cocaine addiction.
The research shows that blocking hypocretin may
reduce compulsive drug-seeking behavior in rat
models of cocaine addiction.
“Cocaine addiction is a disorder that affects
millions of people worldwide,” said Marisa Roberto,
professor in TSRI’s Committee on the Neurobiology of
Addictive Disorders (CNAD) and co-author of the
study with Brooke Schmeichel, a former TSRI
researcher now at NIDA, George Koob, the CNAD
chairman currently on a leave of absence to direct
the NIAAA, and Melissa Herman, a senior research
associate at TSRI. “Understanding the mechanisms
underlying cocaine addiction is important for
identifying potential new targets for therapeutic
“The results of this study would suggest that the
hypocretin system could be considered a
pharmacological target, with the hopes that such a
medication could be used in combination with
cognitive behavioral therapies,” added Schmeichel.
To design treatments for addiction and relapse,
scientists need to understand what motivates a
person to transition from occasional drug use to
compulsive drug use.
In the new study, the researchers, led by Schmeichel,
focused on changes in the central amygdala, a brain
region associated with stress and negative emotions
during drug withdrawal.
Hypocretin is a main player in the brain’s
hypothalamic hypocretin/orexin (HCRT) system, a
network that sends signals between brain regions and
has been shown to influence the brain’s reactions to
cocaine, nicotine, alcohol and opioids and the
desire to relapse.
Until now, however, scientists did not fully
understand the HCRT’s role in cocaine addiction.
For the study, one group of rats was given the
option to self-administer cocaine for one hour a
day, mimicking conditions of short-term, occasional
A second group had the option to self-administer
cocaine for six hours a day, which mimicked the
conditions that lead to compulsive drug use and
The researchers found that compulsive cocaine use
triggers a dangerous cycle in the brain, with
cocaine sensitizing the HCRT system, which motivates
Specifically, compulsive cocaine use leads to
increased hypocretin, which contributes to
overactivity in the central amygdala.
This overactivity corresponds with an anxiety-like
state in rat models that appears to help maintain
the motivation to continue to seek the drug.
“The rats escalate their daily intake as many human
users would,” said Roberto.
Interestingly, giving the rats an “antagonist” to
block HCRT activity at one of the two HCRT receptors
in the central amygdala helped reduce their
drug-seeking behavior, suggesting a potential role
for these compounds in treatments for addiction and
For more information
Hypocretin Neurotransmission within the Central
Amygdala Mediates Escalated Cocaine
Self-Administration and Stress-induced Reinstatement
The Scripps Research Institute (TSRI)
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