Neurokinin-1 receptors (NK1R:s), alcohol consumption, and alcohol reward in mice.
BACKGROUND
Reduced voluntary alcohol consumption was recently found in neurokinin-1 receptor (NK1R)-deficient (KO) mice. It remains unknown whether this reflects developmental effects or direct regulation of alcohol consumption by NK1R:s, and whether the reduced consumption reflects motivational effects.


OBJECTIVE
The objective of this study is to obtain an expanded preclinical validation of NK1R antagonism as a candidate therapeutic mechanism in alcohol use disorders.


METHODS
The NK1R antagonist L-703,606 and NK1R KO mice were used in models that assess alcohol-related behaviors.


RESULTS
L-703,606 (3-10 mg/kg i.p.) dose-dependently suppressed alcohol intake in WT C57BL/6 mice under two-bottle free choice conditions but was ineffective in NK1R KO:s, demonstrating the receptor specificity of the effect. Alcohol reward, measured as conditioned place preference for alcohol, was reduced by NK1R receptor deletion in a gene dose-dependent manner. In a model where escalation of intake is induced by repeated cycles of deprivation and access, escalation was seen in WT mice, but not in KO mice. Among behavioral phenotypes previously reported for NK1R mice on a mixed background, an analgesic-like phenotype was maintained on the C57BL/6 background used here, while KO:s and WT:s did not differ in anxiety- and depression-related behaviors.


CONCLUSIONS
Acute blockade of NK1R:s mimics the effects of NKR1 gene deletion on alcohol consumption, supporting a direct rather than developmental role of the receptor in regulation of alcohol intake. Inactivation of NK1R:s critically modulates alcohol reward and escalation, two key characteristics of addiction. These data provide critical support for NK1R antagonism as a candidate mechanism for treatment of alcoholism.
Thorsell
Annika
A
The Laboratory of Clinical and Translational Studies, National Institute On Alcohol Abuse and Alcoholism, 10 Center Drive, 10-CRC/1-5330, Bethesda, MD 20892-1108, USA.
Schank
Jesse R
JR
Singley
Erick
E
Hunt
Stephen P
SP
Heilig
Markus
M
D000428:Alcohol Drinking / Q000235:genetics / Q000517:prevention & control*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003213:Conditioning, Psychological / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009042:Motivation; D064729:Neurokinin-1 Receptor Antagonists; D011812:Quinuclidines / Q000008:administration & dosage / Q000494:pharmacology*; D018040:Receptors, Neurokinin-1 / Q000235:genetics; D012201:Reward
D064729:Neurokinin-1 Receptor Antagonists; D011812:Quinuclidines; D018040:Receptors, Neurokinin-1; C076851:L 703606