In an article in the February 16, 2006, issue of Neuron, Antonello Bonci and colleagues established that a short protein, or peptide, called orexin A acts on a brain region central to the adaptation to addictive drugs. Specifically, they found in their studies with rats that orexin A induces an adaptation that is necessary for the development of behaviors associated with drug-craving in human addicts. The latest findings follow an earlier discovery by the same group that another molecule, corticotropin releasing factor (CRF), acts similarly.
Such adaptations are believed to create a need that is far more compelling than the simple memory of drug-induced pleasure and represent a "rewiring" of the brain into an addictive state.
In a preview article on the paper in the same issue of Neuron, NIH neuroscientist Roy Wise commented that "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.
"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."
Bonci and his colleagues based their experiments on past studies by other researchers showing that orexins are important regulatory peptides released by a brain center called the lateral hypothalamus. It was also known that orexins tend to activate circuitry in a region called the ventral tegmental area (VTA), known to be a critical site of neural adaptation, or plasticity, induced by addictive drugs. However, it wasn't known whether orexin actually induced such plasticity.
In experiments with rat brain slices, the researchers demonstrated that orexin A does increase activity of neurons in the VTA associated with such plasticity.
And in experiments with whole animals, the researchers found that orexin A was required for "behavioral sensitization" to cocaine. This sensitization 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.
Importantly, 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. The researchers wrote that 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.
The researchers include Stephanie L. Borgland, Sharif A. Taha, Federica Sarti, Howard L. Fields, and Antonello Bonci1 of the University of California, San Francisco in San Francisco, CA. This work was supported by a NARSAD Essel Foundation young investigator grant to S.L.B., the State of California for medical research on alcohol and substance abuse through the University of California, San Francisco (A.B. and H.L.F.), The Wheeler Center for the Neurobiology of Addiction (A.B. and H.L.F.), the National Institute on Drug Abuse, and the National Institutes of Health 1RO1DA15096-01 (A.B.).
Borgland et al.: "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. DOI 10.1016/j.neuron.2006.01.016 www.neuron.org
Journal
Neuron