Suppression of ethanol self-administration by the neuropeptide Y (NPY) Y2 receptor antagonist BIIE0246: evidence for sensitization in rats with a history of dependence.
Evidence from genetically modified mice suggests a role for NPY in regulation of ethanol intake, but results of pharmacological studies have been more variable. We have previously shown that potentiation of NPY signaling through antagonism at NPY-Y2 receptors decreases operant responding for ethanol in Wistar rats without a history of dependence. Here, we examined the effects of Y2-antagonism in animals with a history of dependence induced by long-term intermittent exposure to ethanol vapor. The Y2-receptor antagonist BIIE0246 suppressed operant responding for ethanol (approximately 50%, p=0.01), at a dose (0.5 nmol i.c.v.) which was ineffective in subjects without a history of dependence. Responding for the ethanol-free control solution was unaffected. These data confirm that antagonism at central NPY-Y2 receptors selectively suppresses motivation to self-administer ethanol, and indicate that the NPY system is sensitized in animals with a history of dependence. This may render the NPY system, and Y2 receptors in particular, an attractive target for treatment of alcohol dependence.
Rimondini
Roberto
R
NEUROTEC, Karolinska Institutet, M57, Huddinge University Hospital, SE-14186 Huddinge, Sweden. roberto.rimondini@neurotec.ki.se
Thorsell
Annika
A
Heilig
Markus
M
D000437:Alcoholism / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D001552:Benzazepines / Q000494:pharmacology* / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D001923:Brain Chemistry / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D000431:Ethanol / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D009478:Neuropeptide Y / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012646:Self Administration
D001552:Benzazepines; D009478:Neuropeptide Y; D017476:Receptors, Neuropeptide Y; C095889:neuropeptide Y2 receptor; D000431:Ethanol; D001120:Arginine; C403256:BIIE 0246