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: 3.88). 03/2010; 209(1):103-11. DOI: 10.1007/s00213-010-1775-1
Source: PubMed


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.

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    • "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]. "
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    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 · 3.42 Impact Factor
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    • "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. "
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    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(s1). DOI:10.1111/j.1530-0277.2012.01923.x · 3.21 Impact Factor
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    • "In animal models, acute physical restraint, which promotes experimental anxiety, suppresses NPY expression within the amygdala and cortex, an effect that parallels the anxiety-inducing effects of stress. In contrast, repeated exposure to a siren stressor leads to complete behavioral and endocrine habituation, accompanied by an upregulation of amygdalar NPY expression (Thorsell et al. 1999, 2010). These findings suggest that NPY expression seems to be involved in the behavioral adaptation to stressors. "
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    ABSTRACT: Alcohol dependence is a chronic relapsing disorder characterized by neuroadaptations that may result in the emergence of negative affective states and stress responses upon discontinuation of alcohol use. Clinical studies have demonstrated that alcohol-dependent people are more sensitive to relapse provoking cues such as alcohol, negative affect, and stress. Moreover, stress relief during protracted abstinence is thought to be a major motivation for excessive alcohol consumption. The relationship between chronic alcohol use, stress, and relapse has implications for the treatment of alcohol dependence. Recent research suggests that neural systems mediating stress responses may offer useful targets for pharmacotherapy of alcoholism.
    Alcohol research : current reviews 03/2012; 34(4):516-21.
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