Neurokinin 1 receptor blockade in the medial amygdala attenuates alcohol drinking in rats with innate anxiety but not in Wistar rats.
OBJECTIVE
Substance P and its preferred neurokinin receptor NK1 have been implicated in stress and anxiety and have been proposed as possible therapeutic targets for the treatment of anxiety/depression. Attention is also being focused on the role this neuropeptide system may play in drug addiction, because stress-related mechanisms promote drug abuse.


METHODS
The effects of the rat-specific NK1 receptor antagonist, L822429, on alcohol intake and seeking behaviour was investigated in genetically selected Marchigian Sardinian alcohol preferring rats. These rats demonstrate an anxious phenotype and are highly sensitive to stress and stress-induced drinking.


RESULTS
Systemic administration of L822429 significantly reduced operant alcohol self-administration in Marchigian Sardinian alcohol preferring rats, but did not reduce alcohol self-administration in stock Wistar rats. NK1 receptor antagonism also attenuated yohimbine-induced reinstatement of alcohol seeking at all doses tested but had no effect on cue-induced reinstatement of alcohol seeking. L822429 reduced operant alcohol self-administration when injected into the lateral cerebroventricles or the medial amygdala. L822429 injected into the medial amygdala also significantly reduced anxiety-like behaviour in the elevated plus maze test. No effects on alcohol intake were observed following injection of L822429 into the dorsal or the ventral hippocampus. Conclusions and Implications Our results suggest that NK1 receptor antagonists may be useful for the treatment of alcohol addiction associated with stress or comorbid anxiety disorders. The medial amygdala appears to be an important brain site of action of NK1 receptor antagonism.
School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino, 62032, Italy.
Lydia O
LO
Ayanwuyi
School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino, 62032, Italy.
Serena
S
Stopponi
School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino, 62032, Italy.
Massimo
M
Ubaldi
School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino, 62032, Italy.
Andrea
A
Cippitelli
School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino, 62032, Italy.
Cinzia
C
Nasuti
Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), Bethesda, MD, 20892-1108, USA.
Ruslan
R
Damadzic
Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), Bethesda, MD, 20892-1108, USA.
Markus
M
Heilig
Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, GA, 30602, USA.
Jesse
J
Schank
Drug Design and Synthesis Section, Chemical Biology Research Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
Kejun
K
Cheng
Drug Design and Synthesis Section, Chemical Biology Research Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
Kenner C
KC
Rice
School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino, 62032, Italy.
Roberto
R
Ciccocioppo
D000428:Alcohol Drinking; D000679:Amygdala / Q000187:drug effects* / Q000503:physiopathology; D000818:Animals; D001007:Anxiety / Q000523:psychology*; D007276:Injections, Intraventricular; D008297:Male; D018782:Maze Learning; D064729:Neurokinin-1 Receptor Antagonists / Q000494:pharmacology*; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D015016:Yohimbine / Q000494:pharmacology
C532739:N-((2-cyclopropoxy-5-(5-trifluomethyl)tetrazol-1-yl)benzyl)-2-phenylpiperidin-3-amine; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D015016:Yohimbine