Article

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

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.
Psychopharmacology (Impact Factor: 3.99). 03/2010; 209(1):103-11. DOI: 10.1007/s00213-010-1775-1
Source: PubMed

ABSTRACT 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.

0 Followers
 · 
124 Views
  • Source
    • "The NK1R is an attractive molecular target for the treatment of depression and anxiety [Ebner et al., 2009]. Previous in vivo studies show that Nk1r À/À mice display increased alcohol drinking behavior [Thorsell et al., 2010] and NK1R antagonist treatment significantly inhibits operant self-administration of 10% ethanol compared with vehicle in rats [Steensland et al., 2010; Schank et al., 2013]. Interestingly, a SNP upstream of TACR1 present in alcohol-preferring rats increased transcription factor binding, gene transcription, alcohol self-administration and sensitivity to the NK1R antagonist L822429 [Schank et al., 2013]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Single nucleotide polymorphisms (SNPs) in the tachykinin receptor 1 gene (TACR1) are nominally associated with bipolar affective disorder (BPAD) in a genome-wide association study and in several case-control samples of BPAD, alcohol dependence syndrome (ADS) and attention-deficit hyperactivity disorder (ADHD). Eighteen TACR1 SNPs were associated with BPAD in a sample (506 subjects) from University College London (UCL1), the most significant being rs3771829, previously associated with ADHD. To further elucidate the role of TACR1 in affective disorders, rs3771829 was genotyped in a second BPAD sample of 593 subjects (UCL2), in 997 subjects with ADS, and a subsample of 143 individuals diagnosed with BPAD and comorbid alcohol dependence (BPALC). rs3771829 was associated with BPAD (UCL1 and UCL2 combined: P = 2.0 × 10−3), ADS (P = 2.0 × 10−3) and BPALC (P = 6.0 × 10−4) compared with controls screened for the absence of mental illness and alcohol dependence. DNA sequencing in selected cases of BPAD and ADHD who had inherited TACR1-susceptibility haplotypes identified 19 SNPs in the promoter region, 5′ UTR, exons, intron/exon junctions and 3′ UTR of TACR1 that could increase vulnerability to BPAD, ADS, ADHD, and BPALC. Alternative splicing of TACR1 excludes intron 4 and exon 5, giving rise to two variants of the neurokinin 1 receptor (NK1R) that differ in binding affinity of substance P by 10-fold. A mutation in intron four, rs1106854, was associated with BPAD, although a regulatory role for rs1106854 is unclear. The association with TACR1 and BPAD, ADS, and ADHD suggests a shared molecular pathophysiology between these affective disorders. © 2014 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 06/2014; 165(4). DOI:10.1002/ajmg.b.32241 · 3.27 Impact Factor
  • Source
    • "wild-type and " anxious " rats (June et al., 2009). Importantly , the effect of TACR1 genotypes on alcohol consumption has been shown to be via a direct regulation of alcohol consumption, rather than a developmental effect on TACR1 function or structure (Thorsell et al., 2010). Gilman and Hommer (2008) demonstrated beneficial effects of a TACR1 antagonist in humans via a functional magnetic resonance imaging (fMRI) study of affective responses. "
    [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: The tachykinin receptor 1 (TACR1) gene is a promising candidate gene in the search for the genetic basis of alcohol dependence (AD); TACR1 antagonists improve symptomology not only in preclinical models of AD but also in a clinical sample of detoxified alcoholics (George et al., Science 319:1536, 2008). The purpose of the current study was to determine whether TACR1 single nucleotide polymorphisms (SNPs) were associated with (i) blood oxygen level dependent (BOLD) activation in response to gustatory alcohol cues in a sample of heavy drinkers and (ii) Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM-IV-TR) AD symptom count in a large, publicly available data set-the Study of Addictions: Genetics and Environment Genome Wide Association study (SAGE GWAS) (Bierut et al., 2010). METHODS: First, we examined relationships between TACR1 genotypes and neural responses during a craving task in 326 individuals with alcohol use disorders. Next, correlational analyses between 69 TACR1 SNPs and DSM-IV-TR AD symptoms were performed on the SAGE data set. RESULTS: rs3771863, rs3755459, and rs1106855 predicted BOLD activation in response to alcohol cues in those same reward and reinforcement brain areas, especially in the medial prefrontal cortex, striatum, and insula. rs3771863 also predicted AD symptom count in the SAGE data set and BOLD activation in the mesocorticolimbic pathway response to alcohol cues. CONCLUSIONS: Each of the 5 SNPs in the TACR1 gene that was significantly related to AD severity in the SAGE data set and/or the BOLD response to the craving task is near the 3' or 5' areas of the gene and may therefore be near mutations with potential functional significance. In particular, the potential functional significance of rs1106855 should be explored because of its location within a stop codon.
    Alcoholism Clinical and Experimental Research 10/2012; 37. DOI:10.1111/j.1530-0277.2012.01923.x · 3.31 Impact Factor
  • Source
    • "L-703,606 also binds with higher affinity to the human NK1 receptor (K d =0.3 nM) than to the rat receptor (K d =300 nM) (Cascieri et al. 1992). It has been used to block the rewarding effects of alcohol in C57BL/ 6J mice in a manner similar to genetic deletion (Thorsell et al. 2010). Although nonspecific effects of other NK1R antagonists have been reported (Rupniak et al. 2001; Rupniak and Jackson 1994), L-733,060 and L-703,606 had similar reward-devaluing effects when given before morphine, making it unlikely that off-target effects were responsible for behavioral observations reported here. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The abuse potential of opioids may be due to their reinforcing and rewarding effects, which may be attenuated by neurokinin-1 receptor (NK1R) antagonists. This study was conducted to measure the effects of opioid and NK1R blockade on the potentiation of brain stimulation reward (BSR) by morphine using the intracranial self-stimulation method. Adult male C57BL/6J mice (n = 15) were implanted with unipolar stimulating electrodes in the lateral hypothalamus and trained to respond for varying frequencies of rewarding electrical stimulation. The BSR threshold (θ(0)) and maximum response rate (MAX) were determined before and after intraperitoneal administration of saline, morphine (1.0-17.0 mg/kg), or the NK1R antagonists L-733,060 (1.0-17.0 mg/kg) and L-703,606 (1.0-17.0 mg/kg). In morphine antagonism experiments, naltrexone (0.1-1.0 mg/kg) or 10.0 mg/kg L-733,060 or L-703,606 was administered 15 min before morphine (1.0-10.0 mg/kg) or saline. Morphine dose-dependently decreased θ(0) (maximum effect = 62% of baseline) and altered MAX when compared to saline. L-703,606 and L-733,060 altered θ(0); 10.0 mg/kg L-733,060 and L-703,606, which did not affect θ(0) or MAX, attenuated the effects of 3.0 and 10.0 mg/kg morphine, and 1.0 and 0.3 mg/kg naltrexone blocked the effects of 10.0 mg/kg morphine. Naltrexone given before saline did not affect θ(0) or MAX. The decrease in θ(0) by morphine reflects its rewarding effects, which were attenuated by NK1R and opioid receptor blockade. These results demonstrate the importance of substance P signaling during limbic reward system activation by opioids.
    Psychopharmacology 09/2011; 220(1):215-24. DOI:10.1007/s00213-011-2469-z · 3.99 Impact Factor
Show more