Elsevier

Brain Research Reviews

Volume 52, Issue 2, September 2006, Pages 368-380
Brain Research Reviews

Review
The urocortin 1 neurocircuit: Ethanol-sensitivity and potential involvement in alcohol consumption

https://doi.org/10.1016/j.brainresrev.2006.04.007Get rights and content

Abstract

One of the hallmarks of alcoholism is continued excessive consumption of alcohol-containing beverages despite the negative consequences of such behavior. The neurocircuitry regulating alcohol consumption is not well understood. Recent studies have shown that the neuropeptide urocortin 1 (Ucn1), a member of the corticotropin-releasing factor (CRF) family of peptides, could be an important player in the regulation of alcohol consumption. This evidence is accumulated along three directions of research: (1) Ucn 1-containing neurons are extremely sensitive to alcohol; (2) the Ucn1 neurocircuit may contribute to the genetic predisposition to high alcohol intake in mice and rats; (3) manipulation of the Ucn1 system alters alcohol consumption and sensitivity. This paper reviews the current knowledge of the Ucn1 neurocircuit and the evidence for its involvement in alcohol-related behaviors, and proposes a mechanism for its involvement in the regulation of alcohol consumption.

Section snippets

The neurocircuitry of Ucn1 peptide

Two highly homologous receptors, corticotropin-releasing factor receptors type 1 and 2 (CRF1 and CRF2), in the mammalian central nervous system display high affinity for the CRF-family of peptides (see extensive reviews by Bale and Vale, 2004, Gysling et al., 2004). CRF is the prototypical and best known ligand of these receptors (Vale et al., 1981). CRF is well known for its actions on CRF1 receptors in the pituitary leading to release of adrenocorticotrophic hormone (ACTH), which in turn

The Ucn1 neurocircuit is highly sensitive to self-administered alcohol

One of the most common methods to identify brain regions sensitive to administration of a drug involves mapping the expression of activity-dependent inducible transcription factors (ITFs) Fos, FosB and Egr1 in brain. One advantage of this method over other techniques to map neural activity (such as the 2-deoxyglucose method) is its cellular resolution. The disadvantages are that cellular activation does not always result in induction of ITFs and that it is difficult to detect decreases in

The Ucn1 system is not only sensitive, but also is involved in the genetic predisposition tohigh alcohol intake in rodents

The idea that the Ucn1 system could not only be sensitive, but may also regulate ethanol consumption was initially suggested after comparative analysis between C57 and DBA inbred strains of mice. This analysis showed that C57 mice, well known for their high alcohol preference, have substantially higher levels of Ucn1 in the npEW than DBA mice, known for their alcohol avoidance. This difference was due to both a difference in cell numbers containing Ucn1 and different levels of Ucn1 expression

Manipulations of the Ucn1 neurocircuit modulate alcohol consumption and sensitivity

In addition to the genetic studies described above, lesion and site-specific pharmacological approaches were used to further investigate whether alcohol consumption was regulated by neurons of the npEW and their projections. Neurons of the npEW were electrolytically lesioned in C57 mice (Bachtell et al., 2004, Weitemier and Ryabinin, 2005a). Mice with successful npEW lesions were compared to sham-operated controls. Most behaviors (including locomotor activity, oculomotor function and

A novel neurocircuit regulating alcohol consumption

The agreement between evidence along three directions of research described above, showing (1) that the Ucn1 neurocircuit is extremely sensitive to ethanol, (2) that Ucn1 levels are positively correlated predisposition to alcohol preference in rodent genetic models, and (3) that manipulation of the Ucn1 neurocircuit modulates alcohol consumption and/or sensitivity in a predictable manner, provides a strong case for the importance of this neurocircuit in the regulation of alcohol intake.

Where do we go from here?

When a novel neurocircuit for a behavior is identified, major efforts should be directed towards verification of its functional significance. However, Ucn1 studies raise other important questions. Some of the critical ones seem to be the following three questions:

  • (1)

    What is the endogenous function of the Ucn1 neurocircuitry? Most recent reviews discuss the function of CRF-like peptides in terms of anxiogenic and anxiolytic functions (Bale and Vale, 2004, Gysling et al., 2004). However,

Acknowledgments

This work was supported by NIH grants AA013738 and AA013484 (to A.E.R.). The authors would like to thank Dr. Deborah Finn for critical reading of the manuscript.

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