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

Abstract

Adenosine signaling is associated with ethanol-related behaviors. We previously found that adenosine A 2A receptor (A 2A R) activation dampens ethanol drinking behaviors in equilibrative nucleoside transporter 1 (ENT1) knockout mice, and A 2A R 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 2A R 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 highconsumption 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 2A R 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 2A R activation and ENT1 inhibition by a novel adenosine analog isolated from Gastrodia elata, N6-(4hydroxybenzyl)-adenosine, decreases ethanol drinking and seeking behaviors. We suggest that NHBA is a potential therapeutic agent to treat alcohol use disorder.

Chronic Alcohol Exposure Induces Aberrant Mitochondrial Morphology and Inhibits Respiratory Capacity in the Medial Prefrontal Cortex of Mice

“…Alcohol vapor or air was delivered in Plexiglas inhalation chambers, as previously described (Griffin et al, 2009). We have used the vapor chamber system previously to successfully maintain stable blood alcohol concentration (BAC) in mice (Hong et al, 2019;Starski et al, 2019a). Mice were exposed to alcohol vapor or room air using vapor administration chambers for 16 h from 1600 to 0900, followed by 8 h of room air in their home cages.…”

Astrocytic equilibrative nucleoside transporter type 1 upregulations in the dorsomedial and dorsolateral striatum distinctly coordinate goal‐directed and habitual ethanol‐seeking behaviours in mice

“…Transition from the 10E10S to 10E rewards without a sucrose fading method successfully establishes the value of ethanol as the reward (Hong, Peyton, et al, 2019). Thus, we F I G U R E 5 Effects of DMS and DLS astrocytic ENT1 upregulation on 10E10S-seeking behaviours.…”

“…Transition from the 10E10S to 10E rewards without a sucrose fading method successfully establishes the value of ethanol as the reward (Hong, Peyton, et al., 2019). Thus, we conditioned mice with the 10E reward to investigate the role of DMS and DLS astrocytic ENT1 in ethanol‐seeking behaviours after the establishment of ethanol‐containing reward‐seeking behaviours.…”

“…Meanwhile, optogenetic DLS A 2A R activation and genetic DMS A 2A R blockade induce goal‐directed sucrose‐seeking behaviours (Li et al., 2016). In addition, DMS A 2A R activation suppresses goal‐directed sucrose‐seeking (Li et al., 2016) and the value of ethanol (Hong, Kang, et al., 2019; Hong, Peyton, et al., 2019). Thus, DMS astrocytic ENT1‐mediated behavioural changes in our study may be induced through DMS A 2A R signalling.…”

“…As illustrated in Figure 1, we employed the same operant chambers and modified operant schedules from our previous studies (Hong, Kang, Chen, & Choi, 2019; Hong, Peyton, Chern, & Choi, 2019; Nam, Hinton, et al., 2013). Briefly, mice were placed in two‐hole operant chambers (Med‐Associates, St Albans, VT, USA) where they poke a single active hole for a reward (10 µl per a reinforcer).…”