The work could lead to the development of novel drugs to treat alcoholism.

The new study, led by Scripps Research Associate Professor Marisa Roberto, throws light on the cellular mechanisms that govern the transition from alcohol use to alcohol dependence.

Specifically, the study examined the interaction between two competing agents - one a stress peptide that promotes excessive alcohol drinking, the other an anti-stress peptide that opposes it. The results confirm that drugs derived from the anti-stress peptide nociceptin could play an important role in treating a complex and multi-faceted disease.

“Alcoholism is a complex disorder with many contributing factors, one of which is stress,” said Maureen Cruz, a research associate in Roberto’s lab and first author of the study. “By targeting a particular system that's associated with stress, we can better understand the interaction of alcohol and stress in the brain.”

In previous animal studies, Ms Roberto and her colleagues demonstrated that a particular stress peptide produced in the amygdala, corticotropin-releasing factor (CRF), plays a key role in the transition from alcohol use to alcohol dependence.

“This peptide,” said Ms Roberto, “drives craving for alcohol.” Ms Roberto and her colleagues also demonstrated that nociceptin, a peptide that structurally resembles endogenous opioids, can both prevent and reverse some effects of alcohol.

Intriguingly, CRF and nociceptin exert opposite effects on the inhibitory neurotransmitter, gamma-amino butyric acid (GABA), in central amygdala. CRF stimulates the release of GABA by neurons in the amygdala, while nociceptin inhibits it.

In the new study, Ms Roberto, Cruz, and their colleagues examined how these two competing agents interact. At the behavioral level, nociceptin regulates anxiety and alcohol drinking in rats. "We were interested in seeing if nociceptin blocked the effect of CRF on a cellular level," Roberto said.

To find out if that were indeed the case, the scientists examined amygdala neurons from both alcohol-dependent and control rats. They added CRF and nociceptin and electrically stimulated the neurons to see how they would behave under the influence of both peptides. The result: nociceptin completely blocked the effects of CRF on GABA release.

But that was not all. By varying the sequence in which the scientists introduced the two opposing peptides, the researchers established that it did not matter whether they introduced nociceptin before or after CRF had done its work: In either case, nociceptin counteracted CRF and drove GABA levels down. "No matter when CRF is added, nociceptin wins," said Ms Roberto. "That's a really consistent effect."

The researchers also found that both CRF and nociceptin had a more powerful effect on the amygdala neurons of alcohol-dependent rats compared to those from non-dependent animals. Roberto believes that this has to do with cellular changes that alcohol dependence causes in the brain - changes that heighten sensitivity to alcohol, compounding the effects of both drinking and withdrawal.

In addition, the team was able to determine that nociceptin and CRF both rely on the same enzyme, protein kinase A (PKA), to modulate GABA release in the amygdala.

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