New understanding of cocaine addiction

Recent TSRI study findings suggest pharmacological remedies are possible

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LA JOLLA, Calif.—Two recent studies conducted by The Scripps Research Institute (TSRI) offer promising clues about the facilitation of cocaine consumption and addiction. One study found that increased levels of a brain molecule called hypocretin might contribute to cocaine addiction, while blocking the compound can curb compulsive use. The other study suggests that system-wide delivery of a TrkB-blocker inhibits cocaine self-administration in rats. Taken together, the studies point to two distinct brain regions as potential areas for further study to finally find an effective strategy against cocaine addiction, which affects more than two million Americans.
The first TSRI study found that blocking hypocretin may reduce compulsive drug seeking behavior in cocaine-addicted rats, indicating that a pharmaceutical intervention could be on the horizon. Hypocretin impacts the brain’s hypothalamic hypocretin/orexin (HCRT) system, which has been shown to influence the brain’s reactions to addictive agents including cocaine.
In the study, one group of rats was given the option to self-administer cocaine for one hour a day, approximating occasional, recreational use, while the other group was allowed to self-administer for six hours a day, more consistent with compulsive use leading to and accompanying addiction.
Researchers discovered that the compulsive cocaine use (six hours per day) lead to increased hypocretin, thus triggering overactivity in the central amygdala. As cocaine sensitized the HCRT system, it produced a state of anxiety followed by an escalation in daily intakes in the rats. Introduction of a hypocretin antagonist, however, seemed to block stress-induced relapse in the rats.
“Blocking HCRT activity at one of the two HCRT receptors in the central amygdala helps decreasing [rats] drug-seeking behavior, suggesting a potential role for these compounds in treatments for addiction and relapse,” says Dr. Candice Contet, an associate professor and lead researcher at TSRI.
The second TSRI study built on previous work targeting the TrkB receptor, but for the first time, tested systematic administration of a brain-penetrant TrkB inhibitor. Researchers have long understood that cocaine produces pleasurable reactions in the “mesocorticolimbic reward system,” with evidence that repeated use causes long-lasting changes in the nucleus accumbens and medial prefrontal cortex. Studies have found that changes in the reward system impact production of brain-derived neurtrophic factor (BDNF), which works by activating TrkB receptors. In previous studies, researchers injected BDNF directly into the nucleus accumbens, thus strongly driving further addictive behavior, while blocking BDNF in this region reduced signs of dependency. Conversely, when BDNF was applied to the medial prefrontal cortex, also part of the reward system, it reduced dependency behaviors while blocking the BDNF/TrkB signaling increased those behaviors.
In the recent study, Contet and her colleagues examined the overall effects of blocking TrkB signaling, using a recently developed TrkB-receptor blocker, or “antagonist,” that can successfully get into the brain after being injected into the bloodstream. The study indicated that the TrkB blocker powerfully reduced basic behavioral measures of cocaine use and dependency—and did so more strongly when the dose was higher. According to the study findings, treated rats used much less cocaine, were much less willing to press the lever many times to get more cocaine and were less inclined to “relapse” when re-exposed to cocaine after a period of withdrawal.
The study found that the TrkB blocking treatment did not affect the rats’ appetite for a sweet-tasting glucose-saccharin solution, indicating the antagonist does suppress overall appetite, but specifically targets the sense of reward and motivation for cocaine. The findings indicate a promising potential role for TrkB antagonists in treating humans with cocaine addiction.
The two studies, read together, offer promising territories for further study. One study indicates that HCRT antagonism can block stress-induced relapses, while TrkB inhibition can help prevent a relapse triggered by re-exposure. “A dual strategy targeting both pathways could yield some functional synergism or complementary therapeutic benefit,” says Contet. “Efficient relapse prevention would be expected to protect against both triggers and may therefore benefit from concomitant blockade from both signaling pathways.”

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