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Donít stress out
LA JOLLA, CAóAs part of the ongoing efforts to fully understand and fight the mechanisms of alcoholism, scientists at The Scripps Research Institute have discovered an endogenous anti-stress peptide in the brain that is capable of preventing and even reversing some of the cellular effects of alcohol dependence. The study, led by Scripps Research Associate Professor Marisa Roberto, was published online by Biological Psychiatry. In the study, the researchers detailed their work with a pair of related peptides, a stress peptide that promotes excessive alcohol intake and an anti-stress peptide that opposes it.
"Alcoholism is a complex disorder with many contributing factors, one of which is stress," Maureen Cruz, a research associate in Roberto's lab and first author of the study, said in a press release. "By targeting a particular system that's associated with stress, we can better understand the interaction of alcohol and stress in the brain."
The stress peptide the researchers studied, corticotropin-releasing factor (CRF), is largely responsible for the transition from moderated alcohol use to alcohol dependence. Nociceptin, the anti- stress peptide, is structurally similar to endogenous opioids and can prevent and even reverse some of the effects of alcohol. The two peptides both demonstrate their effects within the amygdala, the part of the brain associated with the heightened anxiety and excessive drinking seen in alcohol dependence. CRF stimulates the release of the inhibitory neurotransmitter gamma-amino butyric acid (GABA) by neurons in the central amygdala, and nociceptin inhibits the release.
"We have previously demonstrated that the transition to alcohol dependence is defined by recruitment and/or functional upregulation of CRF in the central amygdala, a brain region important in regulating emotion," says Roberto. "CRF promotes anxiety-related behaviors in alcoholics, which leads to subsequent relapse and compulsive alcohol-seeking and -drinking behaviors. Nociceptin is a ubiquitous peptide in the mammalian brain, and it has several behavioral effects that include reduction of anxiety. The anxiety-reducing effects of nociceptin involve the central amygdala. Thus, by counteracting CRF effects, nociceptin is able to reduce anxiety and reduce alcohol consumption. In our studies, we show that the nociceptin effect is likely attributable to pre-synaptic modulation of GABA release by CRF."
To see if the peptides' contrasting mechanisms extended to nociceptin actually blocking the effects of CRF on a cellular level, the researchers studied amygdala neurons from alcohol-dependent and control rats. When CRF and nociceptin were added and the neurons were electrically stimulated, nociceptin completely blocked CRF's effects on GABA release. They also found that it made no difference whether nociceptin was introduced before or after CRF, as it counteracted the stress peptide and reduced GABA levels either way. Both peptides were shown to have a stronger effect on the neurons of alcohol-dependent rats compared to those of non-dependent rats, which Roberto attributes to cellular changes in the brain caused by alcohol dependence. Roberto and her colleagues also discovered that the peptides both rely on the same enzyme, protein kinase A, to modulate GABA release.
Though Roberto noted in a press release that "there won't be a 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 both represent viable options as treatments. There are already "CRF receptor antagonists in advanced stages of development as therapeutic targets," Roberto adds, something she says she would like to see tested in alcoholics.
"Both CRF receptor antagonists and nociceptin agonists represent suitable strategies. CRF antagonists are at a more advanced stage of development, but there are also nociceptin modulators at a clinical development stage," says Roberto. "Only the results of the clinical trials will tell us which drug will be more effective. It's well known that alcoholics represent a heterogeneous patient population, so it may happen that some of them will respond better to one drug than the other drug and vice-versa. The more therapeutic options we have, the better it is."
Additional authors for the paper, "Nociceptin/Orphanin FQ Blockade of CRF-induced GABA Release in Central Amygdala is Enhanced after Chronic Ethanol Exposure," include Melissa A. Herman and Marsida Kallupi of Scripps Research. The study was supported by the Pearson Center for Alcoholism and Addiction Research as well as the National Institute on Alcohol Abuse and Alcoholism.