Neurokinin-1 receptors (NK1R:s), alcohol consumption, and alcohol reward in mice
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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.
The objective of this study is to obtain an expanded preclinical validation of NK1R antagonism as a candidate therapeutic mechanism in alcohol use disorders.
The NK1R antagonist L-703,606 and NK1R KO mice were used in models that assess alcohol-related behaviors.
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.
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.
KeywordsNeurokinin-1 receptor Substance P Alcohol escalation Conditioned place preference
- Commons KG (2009) Neuronal pathways linking substance P to drug addiction and stress. Brain Res. doi:10.1016/j.brainres.2009.11.014
- Crawley J (2007) What's wrong with my mouse? Behavioral phenotyping of transgenic and knockout mice, 2nd edn. Wiley, HobokenGoogle Scholar
- D'Amour FE, Smith DL (1941) A method for determining loss of pain sensation. J Pharmacol Exp Ther 72:74–79Google Scholar
- Furmark T, Appel L, Michelgard A, Wahlstedt K, Ahs F, Zancan S, Jacobsson E, Flyckt K, Grohp M, Bergstrom M, Pich EM, Nilsson LG, Bani M, Langstrom B, Fredrikson M (2005) Cerebral blood flow changes after treatment of social phobia with the neurokinin-1 antagonist GR205171, citalopram, or placebo. Biol Psychiatry 58:132–142CrossRefPubMedGoogle Scholar
- Karlsson RM, Choe JS, Cameron HA, Thorsell A, Crawley JN, Holmes A, Heilig M (2008) The neuropeptide Y Y1 receptor subtype is necessary for the anxiolytic-like effects of neuropeptide Y, but not the antidepressant-like effects of fluoxetine, in mice. Psychopharmacology (Berl) 195:547–557CrossRefGoogle Scholar
- Kramer MS, Cutler N, Feighner J, Shrivastava R, Carman J, Sramek JJ, Reines SA, Liu G, Snavely D, Wyatt-Knowles E, Hale JJ, Mills SG, MacCoss M, Swain CJ, Harrison T, Hill RG, Hefti F, Scolnick EM, Cascieri MA, Chicchi GG, Sadowski S, Williams AR, Hewson L, Smith D, Rupniak NM et al (1998) Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science 281:1640–1645CrossRefPubMedGoogle Scholar
- Kramer MS, Winokur A, Kelsey J, Preskorn SH, Rothschild AJ, Snavely D, Ghosh K, Ball WA, Reines SA, Munjack D, Apter JT, Cunningham L, Kling M, Bari M, Getson A, Lee Y (2004) Demonstration of the efficacy and safety of a novel substance P (NK1) receptor antagonist in major depression. Neuropsychopharmacology 29:385–392CrossRefPubMedGoogle Scholar
- Rossi NA, Reid LD (1976) Affective states associated with morphine injections. Physiol Psychol 4:269–274Google Scholar
- Rupniak NMJ, Carlson EJ, Webb JK, Harrison T, Porsolt RD, Roux S, De Felipe C, Hunt SP, Oates B, Wheeldon A (2001) Comparison of the phenotype of NK1R-/- mice with pharmacological blockade of the substance P (NK1) receptor in assays for antidepressant and anxiolytic drugs. Behav Pharmacol 12:497–508PubMedGoogle Scholar
- Woolfe G, MacDonald AD (1944) The evaluation of the analgesic action of pethidine hydrochloride (Demerol). J Pharmacol Exp Ther 80:300Google Scholar