title: Tacr1 gene variation and neurokinin 1 receptor expression is associated with antagonist efficacy in genetically selected alcohol-preferring rats.
abstract: BACKGROUND
  Genetic deletion or antagonism of the neurokinin 1 receptor (NK1R) decreases alcohol intake, alcohol reward, and stress-induced alcohol relapse in rodents, while TACR1 variation is associated with alcoholism in humans.
  
  
  METHODS
  We used L822429, a specific antagonist with high affinity for the rat NK1R, and examined whether sensitivity to NK1R blockade is altered in alcohol-preferring (P) rats. Operant alcohol self-administration and progressive ratio responding were analyzed in P-rats and their founder Wistar line. We also analyzed Tacr1 expression and binding and sequenced the Tacr1 promoter from both lines.
  
  
  RESULTS
  Systemic L822429 decreased alcohol self-administration in P-rats but did not affect the lower rates of alcohol self-administration in Wistar rats. Tacr1 expression was elevated in the prefrontal cortex and the amygdala of P-rats. In central amygdala, elevated Tacr1 expression was accompanied by elevated NK1R binding. Central amygdala (but not prefrontal cortex) infusion of L822429 replicated the systemic antagonist effects on alcohol self-administration in P-rats. All P-rats, but only 18% of their founder Wistar population, were CC homozygous for a-1372G/C single nucleotide polymorphism. In silico analysis indicated that the Tacr1-1372 genotype could modulate binding of the transcription factors GATA-2 and E2F-1. Electromobility shift and luciferase reporter assays suggested that the-1372C allele confers increased transcription factor binding and transcription.
  
  
  CONCLUSIONS
  Genetic variation at the Tacr1 locus may contribute to elevated rates of alcohol self-administration, while at the same time increasing sensitivity to NK1R antagonist treatment.
authors: Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institute of Health, Bethesda, MD 20892-1108, USA.
authors: Jesse R
authors: JR
authors: Schank
authors: Jenica D
authors: JD
authors: Tapocik
authors: Estelle
authors: E
authors: Barbier
authors: Ruslan
authors: R
authors: Damadzic
authors: Robert L
authors: RL
authors: Eskay
authors: Hui
authors: H
authors: Sun
authors: Kelly E
authors: KE
authors: Rowe
authors: Courtney E
authors: CE
authors: King
authors: Mengdi
authors: M
authors: Yao
authors: Meghan E
authors: ME
authors: Flanigan
authors: Matthew G
authors: MG
authors: Solomon
authors: Camilla
authors: C
authors: Karlsson
authors: Kejun
authors: K
authors: Cheng
authors: Kenner C
authors: KC
authors: Rice
authors: Markus
authors: M
authors: Heilig
mesh_terms: D000428:Alcohol Drinking / Q000235:genetics*; D000679:Amygdala / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D050687:E2F1 Transcription Factor / Q000378:metabolism; D000431:Ethanol / Q000008:administration & dosage / Q000494:pharmacology*; D050980:GATA Transcription Factors / Q000378:metabolism; D008297:Male; D008845:Microinjections; D064729:Neurokinin-1 Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D018040:Receptors, Neurokinin-1 / Q000235:genetics / Q000378:metabolism*; D012646:Self Administration
chemical_list: D050687:E2F1 Transcription Factor; C493755:E2f1 protein, rat; D050980:GATA Transcription Factors; C532739:N-((2-cyclopropoxy-5-(5-trifluomethyl)tetrazol-1-yl)benzyl)-2-phenylpiperidin-3-amine; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D018040:Receptors, Neurokinin-1; D000431:Ethanol