TY - JOUR T1 - Novel Adenosine Analog, N6-(4-hydroxybenzyl)-adenosine, Dampens Alcohol-Drinking and –Seeking Behaviors JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.119.261529 SP - jpet.119.261529 AU - Sa-Ik Hong AU - Lee Peyton AU - Yijuang Chern AU - Doo-Sup Choi Y1 - 2019/01/01 UR - http://jpet.aspetjournals.org/content/early/2019/08/13/jpet.119.261529.abstract N2 - Adenosine signaling is associated with ethanol-related behaviors. We previously found that adenosine A2A receptor (A2AR) activation dampens ethanol-drinking behaviors in equilibrative nucleoside transporter 1 (ENT1) knockout mice, and A2AR inhibition augments reward-seeking behavior in wild-type mice. The novel adenosine analog N6-(4-hydroxybenzyl)-adenosine (NHBA) which is isolated from the rhizomes of Gastrodia elata activates A2AR and inhibits ENT1. Here, we examined the effects of NHBA on ethanol-drinking in the two-bottle choice test and operant ethanol-seeking behaviors. We selected mice exhibiting high ethanol-drinking behavior in the two-bottle choice test. NHBA (0.1 mg/kg, i.p.) reduced ethanol-drinking behavior in a limited access 3 h drinking session in high ethanol-drinking mice, and NHBA (0.1 mg/kg, i.p.) did not alter locomotor activity in the open-field test. Operant conditioning with 10% ethanol and 10% sucrose (10E10S) reward increased zone entries and time spent in the ethanol zone, while NHBA (0.1 mg/kg, i.p.) dampened ethanol zone preference in the Y-maze. Furthermore, NHBA (0.1 mg/kg, i.p.) devalued 10E10S and 10% ethanol (10E) reward after operant conditioning with 10E10S and 10E. Taken together, NHBA through A2AR activation and ENT1 modulation may dampen ethanol-drinking and -seeking behaviors, suggesting that NHBA is a potential therapeutic agent for treating alcohol use disorder.SIGNIFICANCE STATEMENT Our work highlights that adenosine A2AR receptor (A2AR) activation and equilibrative nucleoside transporter 1 (ENT1) inhibition by a novel adenosine analog isolated from Gastrodia elata, N6-(4-hydroxybenzyl)-adenosine, decreases ethanol-drinking and -seeking behaviors. Therefore, we suggest that NHBA is a potential therapeutic agent to treat alcohol use disorder. ER -