Marcos Mesa Sam Wordley via Shutterstock. The mechanism by which stress induces cocaine cravings may have been identified

The molecules that make cocaine addicts more likely to relapse when experiencing stress have been identified. The researchers involved in the study believe they may have found a target for future medical interventions.

"Relapse among cocaine addicts is a major problem," says Dr. Peter McCormick of the University of East Anglia. "We wanted to find out what causes it.”

We are so used to the idea that sober, recovering addicts are much more likely to relapse when faced with a stressful period in their lives that we seldom question why this might be. Therefore, McCormick decided to investigate the neuropeptides, which he calls “the brain's communication system,” that he thinks are responsible.

“We had speculated that there might be a direct communication between neuroreceptors controlling stress and reward,” McCormick says. “When we tested this, we found this to indeed be the case.”

The family of neuropeptides known as corticotropin-releasing factor (CRF), released under conditions of stress, was known to trigger the brain's reward response after exposure to cocaine, but the mechanism behind it was a mystery.

In the Journal of Neuroscience, McCormick and co-authors report, “Release of the neuropeptiedes CRF and orexin-A in the ventral tegmental area (VTA) play an important role in stress-induced cocaine-seeking behavior.”

Orexin-A excites neurons in ways that control sleep cycles. Its shortage makes us sleepy at undesirable times, and it has been hailed as a potential wakefullness drug. When CRF and Orexin-A bond together, McCormick found, they trigger dopamine release in a way neither does on its own.

The VTA is an important part of the brain's reward system, where drugs stimulate the release of chemicals that make us feel good. Cells in the VTA have σ1 receptors that become sensitized to the CRF/Orexin-A combination in rats fed cocaine. Future production of the CRF/Orexin-A combination, such as will occur in stressful situations, triggers a cocaine craving, whereas the same CRF/Orexin-A has no equivalent effect on rats that have never had cocaine.

The effect could be observed after a single exposure to cocaine. Consequently, the authors note, "One single administration could explain some effects of cocaine attributed previously to its repeated administration." However, further exposure does increase the number of σ1 receptors, entrenching the effect.

“Cocaine has a relatively unique effect on the brain. However, the reward center is crucial for addictive behaviours.” McCormick notes. “Similar studies have been published recently for binge drinking for alcohol and for methamphetamine use.”

The receptors for σ1, CRF and Orexin-A form a molecular complex known as an oligomer, and McCormick thinks this could be targeted to reduce the cravings that stress induces in recovering addicts. Although the study was done on rodents, McCormick is confident the architecture of human brains is sufficiently similar that the results are applicable to us as well.

McCormick adds that receptors in the same region of the brain have been found to be influenced by post-traumatic stress disorder, saying, “Although speculative, it would not surprise me to see similar results in other situations, whether drug or stress related.”

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