Deficits in amygdaloid cAMP-responsive element-binding protein signaling play a role in genetic predisposition to anxiety and alcoholism.
We investigated the role of cAMP-responsive element-binding protein (CREB) in genetic predisposition to anxiety and alcohol-drinking behaviors using alcohol-preferring (P) and -nonpreferring (NP) rats. The levels of CREB, phosphorylated CREB, and neuropeptide Y (NPY) were innately lower in the central amygdala (CeA) and medial amygdala (MeA), but not in the basolateral amygdala (BLA), of P rats compared with NP rats. P rats displayed higher baseline anxiety-like behaviors and consumed higher amounts of alcohol compared with NP rats. Ethanol injection or voluntary intake reduced the higher anxiety levels in P rats. Ethanol also increased CREB function in the CeA and MeA, but not in the BLA, of P rats. Infusion of the PKA activator Sp-cAMP or NPY into the CeA decreased the alcohol intake and anxiety-like behaviors of P rats. PKA activator infusion also increased CREB function in the CeA of P rats. On the other hand, ethanol injection or voluntary intake did not produce any changes either in anxiety levels or on CREB function in the amygdaloid structures of NP rats. Interestingly, infusion of the PKA inhibitor Rp-cAMP into the CeA provoked anxiety-like behaviors and increased alcohol intake in NP rats. PKA inhibitor decreased CREB function in the CeA of NP rats. These novel results provide the first evidence to our knowledge that decreased CREB function in the CeA may be operative in maintaining the high anxiety and excessive alcohol-drinking behaviors of P rats.
Pandey
Subhash C
SC
Department of Psychiatry, Psychiatric Institute, University of Illinois at Chicago, and Jesse Brown VA Medical Center, Chicago, Illinois 60612, USA. spandey@psych.uic.edu
Zhang
Huaibo
H
Roy
Adip
A
Xu
Tiejun
T
D000437:Alcoholism / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D000679:Amygdala / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000378:metabolism*; D001522:Behavior, Animal / Q000187:drug effects; D000242:Cyclic AMP / Q000008:administration & dosage / Q000031:analogs & derivatives; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D009478:Neuropeptide Y / Q000096:biosynthesis; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D051381:Rats; D011919:Rats, Inbred Strains; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013873:Thionucleotides / Q000008:administration & dosage
D017362:Cyclic AMP Response Element-Binding Protein; D009478:Neuropeptide Y; D047428:Protein Kinase Inhibitors; D013873:Thionucleotides; C016957:adenosine-3',5'-cyclic phosphorothioate; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases