Don’t stress out

LA JOLLA, CA—As part of the ongoing efforts to fullyunderstand and fight the mechanisms of alcoholism, scientists at The Scripps ResearchInstitute have discovered an endogenous anti-stress peptide in the brain thatis capable of preventing and even reversing some of the cellular effects ofalcohol dependence. The study, led by Scripps Research Associate ProfessorMarisa Roberto, was published online by BiologicalPsychiatry. In the study, the researchers detailed their work with a pairof related peptides, a stress peptide that promotes excessive alcohol intakeand an anti-stress peptide that opposes it.

"Alcoholism is a complex disorder with many contributingfactors, one of which is stress," Maureen Cruz, a research associate inRoberto's lab and first author of the study, said in a press release. "Bytargeting a particular system that's associated with stress, we can better understandthe interaction of alcohol and stress in the brain."

The stress peptide the researchers studied,corticotropin-releasing factor (CRF), is largely responsible for the transitionfrom moderated alcohol use to alcohol dependence. Nociceptin, the anti-stresspeptide, is structurally similar to endogenous opioids and can prevent and evenreverse some of the effects of alcohol. The two peptides both demonstrate theireffects within the amygdala, the part of the brain associated with theheightened anxiety and excessive drinking seen in alcohol dependence. CRFstimulates the release of the inhibitory neurotransmitter gamma-amino butyricacid (GABA) by neurons in the central amygdala, and nociceptin inhibits therelease.

"We have previously demonstrated that the transition toalcohol dependence is defined by recruitment and/or functional upregulation ofCRF in the central amygdala, a brain region important in regulating emotion,"says Roberto. "CRF promotes anxiety-related behaviors in alcoholics, which leadsto subsequent relapse and compulsive alcohol-seeking and -drinking behaviors.Nociceptin is a ubiquitous peptide in the mammalian brain, and it has severalbehavioral effects that include reduction of anxiety. The anxiety-reducingeffects of nociceptin involve the central amygdala. Thus, by counteracting CRFeffects, nociceptin is able to reduce anxiety and reduce alcohol consumption.In our studies, we show that the nociceptin effect is likely attributable topre-synaptic modulation of GABA release by CRF."

To see if the peptides' contrasting mechanisms extended tonociceptin actually blocking the effects of CRF on a cellular level, theresearchers studied amygdala neurons from alcohol-dependent and control rats.When CRF and nociceptin were added and the neurons were electricallystimulated, nociceptin completely blocked CRF's effects on GABA release. Theyalso found that it made no difference whether nociceptin was introduced beforeor after CRF, as it counteracted the stress peptide and reduced GABA levelseither way. Both peptides were shown to have a stronger effect on the neuronsof alcohol-dependent rats compared to those of non-dependent rats, whichRoberto attributes to cellular changes in the brain caused by alcoholdependence. Roberto and her colleagues also discovered that the peptides bothrely on the same enzyme, protein kinase A, to modulate GABA release.

Though Roberto noted in a press release that "there won't bea single pill that will cure the multiple and complex aspects of this disease,"she says that seeking to block CRF or to increase nociceptin production bothrepresent viable options as treatments. There are already "CRF receptorantagonists in advanced stages of development as therapeutic targets," Robertoadds, something she says she would like to see tested in alcoholics.

"Both CRF receptor antagonists and nociceptin agonistsrepresent suitable strategies. CRF antagonists are at a more advanced stage ofdevelopment, but there are also nociceptin modulators at a clinical developmentstage," says Roberto. "Only the results of the clinical trials will tell uswhich drug will be more effective. It's well known that alcoholics represent aheterogeneous patient population, so it may happen that some of them willrespond better to one drug than the other drug and vice-versa. The moretherapeutic options we have, the better it is."

Additional authors for the paper, "Nociceptin/Orphanin FQBlockade of CRF-induced GABA Release in Central Amygdala is Enhanced afterChronic Ethanol Exposure," include Melissa A. Herman and Marsida Kallupi ofScripps Research. The study was supported by the Pearson Center for Alcoholismand Addiction Research as well as the National Institute on Alcohol Abuse andAlcoholism.