Novel Adenosine Analog, N6-(4-Hydroxybenzyl)-Adenosine, Dampens Alcohol Drinking and Seeking Behaviors

Adenosine signaling is associated with ethanol-related behaviors. We previously found that adenosine A_2A receptor (A_2AR) activation dampens ethanol drinking behaviors in equilibrative nucleoside transporter 1 (ENT1) knockout mice, and A_2AR 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 A_2AR 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-hour drinking session in high-consumption 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 A_2AR 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 A_2AR activation and ENT1 inhibition by a novel adenosine analog isolated from Gastrodia elata, N6-(4-hydroxybenzyl)-adenosine, decreases ethanol drinking and seeking behaviors. We suggest that NHBA is a potential therapeutic agent to treat alcohol use disorder.