Journal
BIOLOGICAL PSYCHIATRY
Volume 73, Issue 8, Pages 774-781Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.biopsych.2012.12.027
Keywords
Alcohol; amygdala; neurokinin; P-rat; self-administration; Substance P
Categories
Funding
- National Institute on Alcohol Abuse and Alcoholism [R24 AA015512]
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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 Tacr7 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.
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