NPY signaling inhibits extended amygdala CRF neurons to suppress binge alcohol drinking.
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.
1] Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA. [2] Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
Kristen E
KE
Pleil
1] Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA. [2] Department of Psychology, University of North Carolina, Chapel Hill, North Carolina, USA.
Jennifer A
JA
Rinker
1] Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA. [2] Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
Emily G
EG
Lowery-Gionta
1] Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA. [2] Curriculum in Neurobiology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
Christopher M
CM
Mazzone
1] Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA. [2] Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
Nora M
NM
McCall
1] Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA. [2] Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
Alexis M
AM
Kendra
Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
David P
DP
Olson
Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
Bradford B
BB
Lowell
Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, USA.
Kathleen A
KA
Grant
1] Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA. [2] Department of Psychology, University of North Carolina, Chapel Hill, North Carolina, USA.
Todd E
TE
Thiele
1] Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA. [2] Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA. [3] Department of Psychology, University of North Carolina, Chapel Hill, North Carolina, USA.
Thomas L
0000000247474495
TL
Kash
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D063425:Binge Drinking / Q000188:drug therapy / Q000378:metabolism*; D002940:Circadian Rhythm / Q000187:drug effects; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism*; D004195:Disease Models, Animal; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D009478:Neuropeptide Y / Q000378:metabolism*; D017476:Receptors, Neuropeptide Y / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012686:Septal Nuclei / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D009478:Neuropeptide Y; D017476:Receptors, Neuropeptide Y; C097212:neuropeptide Y-Y1 receptor; C095889:neuropeptide Y2 receptor; D003346:Corticotropin-Releasing Hormone