TY - JOUR
T1 - Indirect medium spiny neurons in the dorsomedial striatum regulate ethanol-containing conditioned reward seeking
AU - Hong, Sa Ik
AU - Kang, Seungwoo
AU - Chen, Jiang Fan
AU - Choi, Doo Sup
N1 - Funding Information:
This work was supported by the Samuel C. Johnson for Genomics of Addiction Program at Mayo Clinic, the Ulm Foundation, the Godby Foundation, David Lehr Research Award from American Society for Pharmacology and Experimental Therapeutics, and National Institute on Alcohol Abuse and Alcoholism (AA018779). We thank DeAnn Frederixon and Amanda Grebinoski for proofreading the paper and helpful comments, and Dr. Karl Deisseroth at Stanford University for providing viruses for optogenetics. *S.-I.H. and S.K. contributed equally to this work.
Publisher Copyright:
Copyright © 2019 the authors.
PY - 2019/9/4
Y1 - 2019/9/4
N2 - Adenosine 2A receptor (A2AR)-containing indirect medium spiny neurons (iMSNs) in the dorsomedial striatum (DMS) contribute to reward-seeking behaviors. However, those roles for ethanol-seeking behaviors remain unknown. To investigate ethanol-seeking behaviors, we used an ethanol-containing reward (10% ethanol and 10% sucrose solution; 10E10S). Upon conditioning with 10E10S, mice that initially only preferred 10% sucrose, not 10E10S, showed a stronger preference for 10E10S. Then, we investigated whether the manipulation of the DMS– external globus pallidus (GPe) iMSNs circuit alters the ethanol-containing reward (10E10S) seeking behaviors using the combination of pharmacologic and optogenetic approaches. DMS A2AR activation dampened operant conditioning-induced ethanol-containing reward, whereas A2AR antagonist abolished the effects of the A2AR agonist and restored ethanol-containing reward-seeking. Moreover, pre-ethanol exposure potentiated the A2AR-dependent reward-seeking. Interestingly, mice exhibiting ethanol-containing reward-seeking showed the reduction of the DMS iMSNs activity, suggesting that disinhibiting iMSNs decreases reward-seeking behaviors. In addition, we found that A2AR activation reversed iMSNs neural activity in the DMS. Similarly, optogenetic stimulation of the DMS-GPe iMSNs reduced ethanol-containing reward-seeking, whereas optogenetic inhibition of the DMS-GPe iMSNs reversed this change. Together, our study demonstrates that DMS A2AR and iMSNs regulate ethanol-containing reward-seeking behaviors.
AB - Adenosine 2A receptor (A2AR)-containing indirect medium spiny neurons (iMSNs) in the dorsomedial striatum (DMS) contribute to reward-seeking behaviors. However, those roles for ethanol-seeking behaviors remain unknown. To investigate ethanol-seeking behaviors, we used an ethanol-containing reward (10% ethanol and 10% sucrose solution; 10E10S). Upon conditioning with 10E10S, mice that initially only preferred 10% sucrose, not 10E10S, showed a stronger preference for 10E10S. Then, we investigated whether the manipulation of the DMS– external globus pallidus (GPe) iMSNs circuit alters the ethanol-containing reward (10E10S) seeking behaviors using the combination of pharmacologic and optogenetic approaches. DMS A2AR activation dampened operant conditioning-induced ethanol-containing reward, whereas A2AR antagonist abolished the effects of the A2AR agonist and restored ethanol-containing reward-seeking. Moreover, pre-ethanol exposure potentiated the A2AR-dependent reward-seeking. Interestingly, mice exhibiting ethanol-containing reward-seeking showed the reduction of the DMS iMSNs activity, suggesting that disinhibiting iMSNs decreases reward-seeking behaviors. In addition, we found that A2AR activation reversed iMSNs neural activity in the DMS. Similarly, optogenetic stimulation of the DMS-GPe iMSNs reduced ethanol-containing reward-seeking, whereas optogenetic inhibition of the DMS-GPe iMSNs reversed this change. Together, our study demonstrates that DMS A2AR and iMSNs regulate ethanol-containing reward-seeking behaviors.
KW - AR
KW - Dorsomedial striatum
KW - Ethanol
KW - Medium spiny neuron
KW - Reward
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U2 - 10.1523/JNEUROSCI.0876-19.2019
DO - 10.1523/JNEUROSCI.0876-19.2019
M3 - Article
C2 - 31315945
AN - SCOPUS:85071784165
SN - 0270-6474
VL - 39
SP - 7206
EP - 7217
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 36
ER -