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Brain Circuitry ‘Out of Sync’

Looking for a solution to the withdrawal conundrum, Van Bockstaele and her colleagues trained their focus on a discrete group of nerve cells in the brain stem called the locus coeruleus (LC), the brain’s primary production facility for norepinephrine. One way the brain keeps norepinephrine levels in check is with opioids, the naturally occurring molecular cousins of synthetic opiate drugs: in the normal brain, natural opioids inhibit the “firing” of cells in the locus coeruleus. Opiate addiction floods the brain with molecular imposters of natural opioids, causing the brain to adapt by down-regulating its own production.

When the external drug supply stops, the brain can’t rebound fast enough, and locus coeruleus cells are left without the “brakes” that normally keep the system in check. The cells fire uncontrollably and pump excess norepinephrine out into the brain, triggering, it is believed, the physical and psychological symptoms of withdrawal.

“The whole circuit gets out of sync,” says Van Bockstaele. “If we can figure out what’s creating that hyperactivity in the locus coeruleus, we might have a way to deal with drug addiction.” Over several years, she and her colleagues have painstakingly traced the cellular processes involved and mapped the molecular and genetic signaling that unfolds, the first critical steps toward rational new treatments.

As a result of this work, it is now possible to identify different points at which drugs or chemical compounds might be applied to interrupt the molecular processes and – theoretically – prevent or reverse the behavioral symptoms of withdrawal. Van Bockstaele’s team is currently testing a special dosing regimen of an existing drug to see if it can dampen the overactivity of locus coeruleus cells and lessen the severity of withdrawal. (See next page.)

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