NPY signaling inhibits extended amygdala CRF neurons to suppress binge alcohol drinking
Open accessAbstract
Binge alcohol drinking is a tremendous public health problem because it leads to the development of numerous pathologies, including alcohol abuse and anxiety. It is thought to do so by hijacking brain systems that regulate stress and reward, including neuropeptide Y (NPY) and corticotropin-releasing factor (CRF). The central actions of NPY and CRF have opposing functions in the regulation of emotional and reward-seeking behaviors; thus, dysfunctional interactions between these peptidergic systems could be involved in the development of these pathologies. We used converging physiological, pharmacological and chemogenetic approaches to identify a precise neural mechanism in the bed nucleus of the stria terminalis (BNST), a limbic brain region involved in pathological reward and anxiety behaviors, underlying the interactions between NPY and CRF in the regulation of binge alcohol drinking in both mice and monkeys. We found that NPY Y1 receptor (Y1R) activation in the BNST suppressed binge alcohol drinking by enhancing inhibitory synaptic transmission specifically in CRF neurons via a previously unknown Gi-mediated, PKA-dependent postsynaptic mechanism. Furthermore, chronic alcohol drinking led to persistent alterations in Y1R function in the BNST of both mice and monkeys, highlighting the enduring, conserved nature of this effect across mammalian species. Together, these data provide both a cellular locus and signaling framework for the development of new therapeutics for treatment of neuropsychiatric diseases, including alcohol use disorders.
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Similar effects on dependence-induced drinking in rats and binge-like drinking in mice are observed with injections of NPY in the amygdala, BNST, and NAc shell but not in the hypothalamus, suggesting a focus of NPY effects on alcohol drinking in the extended amygdala.
“Similar effects on dependenceinduced drinking in rats and binge-like drinking in mice were observed with injections of NPY in the amygdala, BNST, and NAc shell but not in the hypothalamus, suggesting a focus of the effects of NPY on alcohol drinking on the extended amygdala (Kelley et al., 2001;Gilpin et al., 2008;Pleil et al., 2015).”
From Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development (2021) · cites this paper as Pleil et al., 2015
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References 50 · Cited by 195
- Authors
- Pleil, K. E., Rinker, J. A., Lowery-Gionta, E. G., Mazzone, C. M., McCall, N. M., Kendra, A. M., Olson, D. P., Lowell, B. B., Grant, K. A., Thiele, T. E., & Kash, T. L.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Beth Israel Deaconess Medical Center (US)
- Oregon National Primate Research Center (US)
- Corresponding author
- Kash, Thomas L
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2015-03-09
- Volume
- 18
- Issue
- 4
- Pages
- 545-552
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC4376619
- OpenAlex
- W2017495352
- Cited by
- 195
- References
- 50
- Citations by year
- 2026: 10 · 2025: 12 · 2024: 12 · 2023: 14 · 2022: 11 · 2021: 21 · 2020: 18 · 2019: 19 · 2018: 25 · 2017: 21 · 2016: 21 · 2015: 11
- FWCI
- 12.07
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- Center for Alcohol Studies
- National Institute on Alcohol Abuse and Alcoholism (P50AA011605, AA019454, AA022048, AA011605, AA 109431, AA013573, AA013541, F32AA021043, R01AA013573, AA020911, AA021043, P60AA011605, R37AA013573, R01AA019454, U01AA020911, R01AA022048)
- National Institute on Drug Abuse (T32DA007244)
- National Institute of General Medical Sciences (T32GM008322)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK057521, R01DK075632, R01DK089044, DK071561, P30DK046200, K08DK071561, DK046200, DK096010, DK-057521, R01DK096010, P30DK020572, DK075632)
- National Institute of Neurological Disorders and Stroke (P30NS045892)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- neuropeptide Y, corticotropin-releasing factor, binge drinking, extended amygdala, bed nucleus of the stria terminalis, NPY Y1 receptor, protein kinase A, synaptic inhibition, chronic ethanol exposure, alcoholism, chemogenetics
- MeSH terms
- Animals, Behavior, Animal, Circadian Rhythm, Corticotropin-Releasing Hormone, Disease Models, Animal, Macaca mulatta, Male, Mice, Inbred C57BL, Neural Inhibition, Neuropeptide Y, Septal Nuclei, Signal Transduction, Receptors, Neuropeptide Y, Mice, Binge Drinking
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