Orexin's role in developing addiction

A molecule in the brain essential for wakefulness and appetite has been found to play a central role in strengthening the neuron connections that lead to addiction. The discovery of how the neuropeptide orexin works at the molecular level makes it a strong new target for potential drugs to treat addiction, the researchers say.

The discovery by neuroscientists at UCSF's Ernest Gallo Clinic and Research Center is being reported February 16 in the journal Neuron.

The research focused on orexin's role in strengthening communication between neurons that release dopamine, a brain chemical central to learning and memory. The strengthened communication is known to play a key role in the experience of a drug high and subsequent drug craving.

Orexin is produced in the brain's lateral hypothalmus (LH) region. The scientists demonstrated in studies of rats that orexin acutely enhances the ability of receptors at dopamine neuron synapses - known as NMDA receptors - to promote the release of dopamine.

They showed that orexin creates a long-lasting potential for strengthened transmission between neurons of the LH region and dopamine-releasing neurons in a brain region known as the ventral tegmental area (VTA). This fundamental change in the neurons, called synaptic plasticity, is known to be critical for new learning and memory formation essential to addiction.

The researchers also showed that blocking normal orexin action in the VTA weakened this critical neuron-to-neuron communication and reversed cocaine-craving behavior in rats.

"This is an exciting finding," said Antonello Bonci, MD, senior author of the paper and UCSF associate professor of neurology, Howard J. Weinberger Chair in Addiction Research and principal investigator at the Gallo Center. "Not only can we see that orexin directly enables the neural communication underlying the development of addiction, but the research points to a novel target in the circuitry of addiction for new medicines to counter the craving for drugs of abuse, or to prevent relapse."

Studies have shown that addicts seek treatment during periods of abstinence. The team's demonstration of orexin's ability to counter cocaine-craving in mice suggests its promise in preventing cured addicts from relapsing to their drug habit, he adds.

"We now know that orexin strengthens neural communication in the VTA and is important for the development of addictive behaviors," said Stephanie Borgland, PhD, lead author of the paper and associate research scientist at the Gallo Center. "Now we are trying to determine if blocking orexin signaling can reverse already well established addictions."

The scientists caution that any potential drug to target orexin must be designed to avoid triggering narcolepsy or dampening orexin's normal role in maintaining an appetite.

Borgland used electrophysiological techniques to assess the activity of NMDA receptors at dopamine neuron synapses in the VTA--a measure of the strength of neural connections. She observed that orexin greatly boosted NMDA receptors, an effect expected to increase the output of dopamine neurons to their targets.

"The research suggests that heightened motivation for drugs of abuse involve the same pathway that motivates one to eat when hungry," Bonci said. "In normal physiological situations, orexin is released during 'heightened metabolic states,' such as when an animal is hungry. But when the animal is addicted to drugs of abuse, this motivational neural pathway is enhanced, resulting in increased orexin release onto dopamine neurons of the VTA."

The discovery of orexin's molecular role explains why narcoleptic patients, whose LH neurons fail to produce normal amounts of the neuropeptide, rarely become addicted when medicated with amphetamines, in contrast to most people who receive the drugs. Lacking normal orexin production, narcoleptics are simply less prone to addiction.