Skip to main content

Advertisement

SpringerLink
Log in

Neurokinin-1 receptors (NK1R:s), alcohol consumption, and alcohol reward in mice

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Ballard TM, Sanger S, Higgins GA (2001) Inhibition of shock-induced foot tapping behaviour in the gerbil by a tachykinin NK1 receptor antagonist. Eur J Pharmacol 412:255–264

    Article  CAS  PubMed  Google Scholar 

  • Bester H, De Felipe C, Hunt SP (2001) The NK1 receptor is essential for the full expression of noxious inhibitory controls in the mouse. J Neurosci 21:1039–1046

    CAS  PubMed  Google Scholar 

  • Boyce-Rustay JM, Holmes A (2006) Genetic inactivation of the NMDA receptor NR2A subunit has anxiolytic- and antidepressant-like effects in mice. Neuropsychopharmacology 31:2405–2414

    Article  CAS  PubMed  Google Scholar 

  • Cao YQ, Mantyh PW, Carlson EJ, Gillespie AM, Epstein CJH, Basbaum AI (1998) Primary afferent tachykinins are required to experience moderate to intense pain. Nature 392:390–394

    Article  CAS  PubMed  Google Scholar 

  • Cascieri MA, Ber E, Fong TM, Sadowski S, Bansal A, Swain C, Seward E, Frances B, Burns D, Strader CD (1992) Characterization of the binding of a potent, selective, radioiodinated antagonist to the human neurokinin-1 receptor. Mol Pharmacol 42:458–463

    CAS  PubMed  Google Scholar 

  • 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, Hoboken

    Google Scholar 

  • D'Amour FE, Smith DL (1941) A method for determining loss of pain sensation. J Pharmacol Exp Ther 72:74–79

    Google Scholar 

  • De Felipe C, Herrero JF, O'Brien JA, Palmer JA, Doyle CA, Smith AJ, Laird JM, Belmonte C, Cervero F, Hunt SP (1998) Altered nociception, analgesia and aggression in mice lacking the receptor for substance P. Nature 392:394–397

    Article  PubMed  Google Scholar 

  • Ebner K, Singewald N (2007) Stress-induced release of substance P in the locus coeruleus modulates cortical noradrenaline release. Naunyn Schmiedebergs Arch Pharmacol 376:73–82

    Article  CAS  PubMed  Google Scholar 

  • Ebner K, Rupniak NM, Saria A, Singewald N (2004) Substance P in the medial amygdala: emotional stress-sensitive release and modulation of anxiety-related behavior in rats. Proc Natl Acad Sci U S A 101:4280–4285

    Article  CAS  PubMed  Google Scholar 

  • Ebner K, Muigg P, Singewald G, Singewald N (2008a) Substance P in stress and anxiety: NK-1 receptor antagonism interacts with key brain areas of the stress circuitry. Ann N Y Acad Sci 1144:61–73

    Article  CAS  PubMed  Google Scholar 

  • Ebner K, Singewald GM, Whittle N, Ferraguti F, Singewald N (2008b) Neurokinin 1 receptor antagonism promotes active stress coping via enhanced septal 5-HT transmission. Neuropsychopharmacology 33:1929–1941

    Article  CAS  PubMed  Google Scholar 

  • Eide K, Hole K (1992) Interactions between substance P and norepinephrine in the regulation of nociception in mouse spinal cord. Pharmacol Toxicol 70:397–401

    Article  CAS  PubMed  Google Scholar 

  • Elliott PJ (1988) Place aversion induced by the substance P analogue, dimethyl-C7, is not state dependent: implication of substance P in aversion. Exp Brain Res 73:354–356

    Article  CAS  PubMed  Google Scholar 

  • File SE (1997) Anxiolytic action of a neurokinin1 receptor antagonist in the social interaction test. Pharmacol Biochem Behav 58:747–752

    Article  CAS  PubMed  Google 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 58:132–142

    Article  CAS  PubMed  Google Scholar 

  • Gadd CA, Murtra P, De Felipe C, Hunt SP (2003) Neurokinin-1 receptor-expressing neurons in the amygdala modulate morphine reward and anxiety behaviors in the mouse. J Neurosci 23:8271–8280

    CAS  PubMed  Google Scholar 

  • George DT, Gilman J, Hersh J, Thorsell A, Herion D, Geyer C, Peng X, Kielbasa W, Rawlings R, Brandt JE, Gehlert DR, Tauscher JT, Hunt SP, Hommer D, Heilig M (2008) Neurokinin 1 receptor antagonism as a possible therapy for alcoholism. Science 319:1536–1539

    Article  CAS  PubMed  Google Scholar 

  • Gilman JM, Hommer DW (2008) Modulation of brain response to emotional images by alcohol cues in alcohol-dependent patients. Addict Biol 13:423–434

    Article  PubMed  Google Scholar 

  • Haddjeri N, Blier P (2001) Sustained blockade of neurokinin-1 receptors enhances serotonin neurotransmission. Biol Psychiatry 50:191–199

    Article  CAS  PubMed  Google Scholar 

  • Haddjeri N, Blier P (2008) Neurokinin-1 receptor antagonists modulate brain noradrenaline and serotonin interactions. Eur J Pharmacol 600:64–70

    Article  CAS  PubMed  Google Scholar 

  • Halasz J, Toth M, Mikics E, Hrabovszky E, Barsy B, Barsvari B, Haller J (2008) The effect of neurokinin1 receptor blockade on territorial aggression and in a model of violent aggression. Biol Psychiatry 63:271–278

    Article  CAS  PubMed  Google Scholar 

  • Hall ME, Stewart JM (1983) Substance P and antinociception. Peptides 4:31–35

    Article  CAS  PubMed  Google Scholar 

  • Heilig M, Koob GF (2007) A key role for corticotropin-releasing factor in alcohol dependence. Trends Neurosci 30:399–406

    Article  CAS  PubMed  Google Scholar 

  • Jasmin L, Tien D, Weinshenker D, Palmiter RD, Green PG, Janni G, Ohara PT (2002) The NK1 receptor mediates both the hyperalgesia and the resistance to morphine in mice lacking noradrenaline. Proc Natl Acad Sci U S A 99:1029–1034

    Article  CAS  PubMed  Google Scholar 

  • Kamdar NK, Miller SA, Syed YM, Bhayana R, Gupta T, Rhodes JS (2007) Acute effects of naltrexone and GBR 12909 on ethanol drinking-in-the-dark in C57BL/6J mice. Psychopharmacology (Berl) 192:207–217

    Article  CAS  Google 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) 195:547–557

    Article  CAS  Google Scholar 

  • Koob GF, Le Moal M (2008) Addiction and the brain antireward system. Annu Rev Psychol 59:29–53

    Article  PubMed  Google 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 281:1640–1645

    Article  CAS  PubMed  Google 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 29:385–392

    Article  CAS  PubMed  Google Scholar 

  • Lecci A (2001) Antinociceptive and pro-inflammatory roles for NPY Y(1) receptors. Trends Pharmacol Sci 22:221

    Article  CAS  PubMed  Google Scholar 

  • Mantyh PW, Hunt SP, Maggio JE (1984) Substance-P receptors—localization by light microscopic autoradiography in rat-brain using [H-3]Sp as the radioligand. Brain Res 307:147–165

    Article  CAS  PubMed  Google Scholar 

  • McCutcheon JE, Fisher AS, Guzdar E, Wood SA, Lightman SL, Hunt SP (2008) Genetic background influences the behavioural and molecular consequences of neurokinin-1 receptor knockout. Eur J NeuroSci 27:683–690

    Article  CAS  PubMed  Google Scholar 

  • McLellan AT, Lewis DC, O'Brien CP, Kleber HD (2000) Drug dependence, a chronic medical illness: implications for treatment, insurance, and outcomes evaluation. JAMA 284:1689–1695

    Article  CAS  PubMed  Google Scholar 

  • Melendez RI, Middaugh LD, Kalivas PW (2006) Development of an alcohol deprivation and escalation effect in C57BL/6J mice. Alcohol Clin Exp Res 30:2017–2025

    Article  PubMed  Google Scholar 

  • Morcuende S, Gadd CA, Peters M, Moss A, Harris EA, Sheasby A, Fisher AS, De Felipe C, Mantyh PW, Rupniak NM, Giese KP, Hunt SP (2003) Increased neurogenesis and brain-derived neurotrophic factor in neurokinin-1 receptor gene knockout mice. Eur J NeuroSci 18:1828–1836

    Article  PubMed  Google Scholar 

  • Murtra P, Sheasby AM, Hunt SP, De Felipe C (2000) Rewarding effects of opiates are absent in mice lacking the receptor for substance P. Nature 405:180–183

    Article  CAS  PubMed  Google Scholar 

  • Nakaya Y, Kaneko T, Shigemoto R, Nakanishi S, Mizuno N (1994) Immunohistochemical localization of substance P receptor in the central nervous system of the adult rat. J Comp Neurol 347:249–274

    Article  CAS  PubMed  Google Scholar 

  • Papp M, Vassout A, Gentsch C (2000) The NK1-receptor antagonist NKP608 has an antidepressant-like effect in the chronic mild stress model of depression in rats. Behav Brain Res 115:19–23

    Article  CAS  PubMed  Google Scholar 

  • Pellow S, Chopin P, File SE, Briley M (1985) Validation of open: closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods 14:149–167

    Article  CAS  PubMed  Google Scholar 

  • Porsolt RD, Bertin A, Jalfre M (1978) “Behavioural despair” in rats and mice: strain differences and the effects of imipramine. Eur J Pharmacol 51:291–294

    Article  CAS  PubMed  Google Scholar 

  • Ripley TL, Gadd CA, De Felipe C, Hunt SP, Stephens DN (2002) Lack of self-administration and behavioural sensitisation to morphine, but not cocaine, in mice lacking NK1 receptors. Neuropharmacology 43:1258–1268

    Article  CAS  PubMed  Google Scholar 

  • Rossi NA, Reid LD (1976) Affective states associated with morphine injections. Physiol Psychol 4:269–274

    Google Scholar 

  • Rupniak NM (2002) Elucidating the antidepressant actions of substance P (NK1 receptor) antagonists. Curr Opin Investig Drugs 3:257–261

    CAS  PubMed  Google Scholar 

  • Rupniak NM, Jackson A (1994) Non-specific inhibition of dopamine receptor agonist-induced behaviour by the tachykinin NK1 receptor antagonist CP-99, 994 in guinea-pigs. Eur J Pharmacol 262:171–175

    Article  CAS  PubMed  Google Scholar 

  • Rupniak NM, Boyce S, Williams AR, Cook G, Longmore J, Seabrook GR, Caeser M, Iversen SD, Hill RG (1993) Antinociceptive activity of NK1 receptor antagonists: non-specific effects of racemic RP67580. Br J Pharmacol 110:1607–1613

    CAS  PubMed  Google Scholar 

  • Rupniak NM, Carlson EC, Harrison T, Oates B, Seward E, Owen S, De Felipe C, Hunt S, Wheeldon A (2000) Pharmacological blockade or genetic deletion of substance P (NK(1)) receptors attenuates neonatal vocalisation in guinea-pigs and mice. Neuropharmacology 39:1413–1421

    Article  CAS  PubMed  Google 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 12:497–508

    CAS  PubMed  Google Scholar 

  • Sanchis-Segura C, Borchardt T, Vengeliene V, Zghoul T, Bachteler D, Gass P, Sprengel R, Spanagel R (2006) Involvement of the AMPA receptor GluR-C subunit in alcohol-seeking behavior and relapse. J Neurosci 26:1231–1238

    Article  CAS  PubMed  Google Scholar 

  • Santarelli L, Gobbi G, Debs PC, Sibille ET, Blier P, Hen R, Heath MJ (2001) Genetic and pharmacological disruption of neurokinin 1 receptor function decreases anxiety-related behaviors and increases serotonergic function. Proc Natl Acad Sci U S A 98:1912–1917

    Article  CAS  PubMed  Google Scholar 

  • Schmidt AW, McLean S, Heym J (1992) The substance P receptor antagonist CP-96, 345 interacts with Ca2+ channels. Eur J Pharmacol 219:491–492

    Article  CAS  PubMed  Google Scholar 

  • Spanagel R, Holter SM (2000) Pharmacological validation of a new animal model of alcoholism. J Neural Transm (Budapest) 107:669–680

    Article  CAS  Google Scholar 

  • Teixeira RM, Santos AR, Ribeiro SJ, Calixto JB, Rae GA, De Lima TC (1996) Effects of central administration of tachykinin receptor agonists and antagonists on plus-maze behavior in mice. Eur J Pharmacol 311:7–14

    Article  CAS  PubMed  Google Scholar 

  • Varty GB, Cohen-Williams ME, Morgan CA, Pylak U, Duffy RA, Lachowicz JE, Carey GJ, Coffin VL (2002) The gerbil elevated plus-maze II: anxiolytic-like effects of selective neurokinin NK1 receptor antagonists. Neuropsychopharmacology 27:371–379

    Article  CAS  PubMed  Google Scholar 

  • Woolfe G, MacDonald AD (1944) The evaluation of the analgesic action of pethidine hydrochloride (Demerol). J Pharmacol Exp Ther 80:300

    CAS  Google Scholar 

Download references

Acknowledgment

Funding for this study was provided by the NIAAA Intramural budget.

Disclosures

The authors have no conflict of interest to declare.

Author information

Authors and Affiliations

  1. 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

    Annika Thorsell, Jesse R. Schank, Erick Singley & Markus Heilig

  2. Department of Cell and Developmental Biology, University College London, London, UK

    Stephen P. Hunt

Authors
  1. Annika Thorsell
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jesse R. Schank
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Erick Singley
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Stephen P. Hunt
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Markus Heilig
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Markus Heilig.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Thorsell, A., Schank, J.R., Singley, E. et al. Neurokinin-1 receptors (NK1R:s), alcohol consumption, and alcohol reward in mice. Psychopharmacology 209, 103–111 (2010). https://doi.org/10.1007/s00213-010-1775-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-010-1775-1

Keywords

Search

Navigation