A team of Scripps Research Institute scientists has found a key biological mechanism underpinning the transition to alcohol dependence. This finding opens the door to the development of drugs to manage excessive alcohol consumption.
ÒOur focus in this study, like much of our labÕs research, was to examine the role of the brainÕs stress system in compulsive alcohol drinking driven by the aversive aspects of alcohol withdrawal,Ó said Scripps Research Associate Professor Marisa Roberto, Ph.D., senior author of the study.
ÒA major goal for this study,Ó added Research Associate Nicholas Gilpin, Ph.D., the paperÕs first author, Òwas to determine the neural circuitry that mediates the transition to alcohol dependence.Ó
In the new research, published in the June 1, 2011 issue of the journalÊBiological Psychiatry, the Scripps Research scientists demonstrated the key role of a receptor Ð a structure that binds substances, triggering certain biological effects Ð for neuropeptide Y in a part of the brain known as the central amygdala. The amygdala, a group of nuclei deep within the medial temporal lobes, performs an important role in the processing and memory of emotional reactions.
ÒWeÕve known for quite some time that neuropeptide Y is an endogenous [naturally occurring] anti-stress agent,Ó says Markus Heilig, clinical director of the National Institute of Alcohol Abuse and Alcoholism (NIAAA). ÒWeÕve also known that development of alcohol dependence gives rise to increased sensitivity to stress. This paper elegantly and logically brings these two lines of research together. It supports the idea that strengthening neuropeptide Y transmission in the amygdala would be an attractive treatment for alcoholism. The challenge remains to develop clinically useful medications based on this principle.Ó
Discovering the Circuitry
Building on GilpinÕs previous work on neuropeptide Y, in the new project, Gilpin, Roberto, and colleagues observed the effects of the administration neuropeptide Y in the central amygdala on alcohol drinking in rats. Alcohol-dependent rats were allowed to press levers for ethanol and water during daily withdrawal from chronic alcohol exposure.
ÒNormally, the transition to alcohol dependence is accompanied by gradually escalating levels of alcohol consumption during daily withdrawals,Ó Gilpin explained. ÒThe aim of this protocol was to examine whether neuropeptide Y infusions during daily withdrawals would block this escalation of alcohol drinking.Ó
The scientists report a suppression of alcohol consumption with chronic neuropeptide Y infusions and detailed some of the neurocircuitry involved. Ethanol normally produces robust increases in inhibitory GABAergic transmission Ð GABA is another neurotransmitter Ð in the central amygdala, but this effect is blocked and reversed by neuropeptide Y.
Gilpin notes the scientists were surprised at one aspect of the findings Ð the role of a subset of neuropeptide Y receptors known as Y2 receptors. ÒPrevious behavioral evidence suggested that antagonism of Y2 receptors in whole brain suppresses alcohol drinking, similar to the effects of neuropeptide Y,Ó he said. ÒHowever, our data suggest that Y2 receptor blockade in central amygdala might actually increase alcohol drinking, presumably by affecting pre-synaptic release of GABA. These data also suggest that antagonism of post-synaptic Y1 receptors in central amygdala provides a viable pharmacotherapeutic strategy, a hypothesis supported by previous work from other labs.Ó
Two additional aspects of the findings are worth noting, Roberto says. First, repeated neuropeptide Y administration not only blocked the development of excessive alcohol consumption in dependent rats, but also tempered the moderate increase in alcohol consumption following periods of abstinence in non-dependent rats. Second, neuropeptide Y exhibited long-term efficacy in suppressing alcohol self-administration, highlighting the potential of neuropeptide Y treatments for a clinical setting.
In addition to Roberto and Gilpin, authors of this paper, titled ÒNeuropeptide Y Opposes Alcohol Effects on GABA Release in Amygdala and Blocks the Transition to Alcohol DependenceÓ and scheduled to appear in the June 1, 2011 print edition ofÊBiological Psychiatry, include Kaushik Misra, Melissa Herman, Maureen Cruz, and George Koob, all of Scripps Research. .
This project was supported by the National Institutes of HealthÕs National Institute on Alcohol Abuse and Alcoholism, and the Pearson Center for Alcoholism and Addiction Research at Scripps Research.
Scripps Research Institute
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