Study: The Brain Learns to Become Addicted

Scientists have identified a molecule that appears to trigger the brain to learn a craving for cocaine to the extent that addiction is a result of a "rewiring" of the brain, more compelling than the simple memory of drug-induced pleasure.

Researchers hope the identification of the action of the molecule will result in a target for future drugs to treat addiction by short-circuiting the process.

Antonello Bonci and colleagues at the University of California, San Francisco's Ernest Gallo Clinic and Research Center found that a short protein, or peptide, called orexin A acts on the ventral tegmental area (VTA) of the brain which is central to the adaptation of addictive drugs.

The researchers found that orexin A is involved in the process in the brain that is necessary for the development of drug-craving.

"Inasmuch as arousal or stress can trigger drug-seeking in drug-free animals, the neuroadaptations discovered by the Bonci group are important not only for how rewarding the drug is after an animal starts taking it, but, perhaps more importantly, for how likely the animal is to initiate drug-seeking during periods of abstinence," National Institutes of Health neuroscientist Roy Wise said. "Because it is during periods of abstinence, not periods of intoxication, that addicts seek treatment, the peptide signaling pathways for orexin and CRF may prove to be fruitful targets in the search for addiction medications."

Blocking Cocaine's Behavioral Sensitization

In experiments with the brains of laboratory rats, Bonci and his colleagues made the following discoveries:

• Orexin A does increase activity of neurons in the VTA associated with neural adaptation, or plasticity, usually seen with addictive drugs are used.

• Orexin A was required for "behavioral sensitization" to cocaine, which shows itself as a long-lasting increase in activity by the animals when they receive the drug and is an indicator that the animals are experiencing an increased craving for the drug.

• When the researchers "microinjected" directly into the VTA region of animals a drug that blocks orexin receptors, they found they could block the development of behavioral sensitization.

"The findings presented here establish a potential mechanism for the role of orexin signaling in plasticity related to addiction," concluded the researchers. "this orexin-induced plasticity in the VTA is likely an important substrate of behaviors relevant to addiction, as we show that activation of [orexin] receptors in the VTA is necessary for the development of cocaine-mediated behavioral sensitization. Thus, orexin receptors may provide novel pharmacotherapeutic targets for motivational disorders such as addiction."

Source: "Orexin A in the VTA is critical for the induction of synaptic plasticity and behavioral sensitization to cocaine." Publishing in Neuron 49, 589–601, February 16, 2006. See also: How the brain learns to become addicted and UCSF research pinpoints brain molecule's role in developing addiction.