The contribution of medium spiny neuron subtypes in the nucleus accumbens core to compulsive-like ethanol drinking

Neuropharmacology. 2021 Apr 1;187:108497. doi: 10.1016/j.neuropharm.2021.108497. Epub 2021 Feb 11.


Compulsive alcohol use, or drinking that persists despite negative or aversive consequences, is a defining characteristic of alcohol use disorder. Here, chemogenetic technology (i.e. Designer Receptors Exclusively Activated by Designer Drugs; DREADDs) was used to inhibit or excite the NAc core or selectively inhibit D1-or D2 receptor-expressing neurons in the NAc core to understand the role of the NAc core and how these subpopulations of neurons may influence compulsive-like ethanol (EtOH) drinking using C57BL/6J, Drd1-cre, and Drd2-cre male and female mice. Compulsive-like EtOH drinking was modeled with a two-bottle choice, drinking in the dark paradigm. The major finding of this study was that mice decreased compulsive-like EtOH intake when the NAc core was inhibited and there was no change of EtOH + quinine intake when the NAc core was excited. Interestingly, inhibition of D1-or D2 receptor-expressing neurons did not alter compulsive-like EtOH intake. Control experiments showed that NAc core excitation and selective inhibition of D1-or D2-receptor-expressing neurons had no effect on baseline EtOH drinking, intake of water, or intake of quinine-adulterated water. CNO reduced amphetamine-induced locomotion in the D1-CRE+ (but not the D2CRE+) group in a control experiment. Finally, pharmacological antagonism of D1 and D2 receptors together, but not separately, reduced quinine-resistant EtOH drinking. These results suggest that the NAc core is a critical region involved in compulsive-like EtOH consumption, and that both D1-and D2 receptor-expressing medium spiny neurons participate in controlling this behavior.

Keywords: Alcohol; Aversion; Dopamine; Drinking in the dark; Nucleus accumbens; Reward.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alcohol Drinking*
  • Alcoholism
  • Animals
  • Behavior, Animal
  • Central Nervous System Depressants / administration & dosage*
  • Compulsive Behavior*
  • Disease Models, Animal
  • Dopaminergic Neurons / classification
  • Dopaminergic Neurons / metabolism*
  • Ethanol / administration & dosage*
  • Mice
  • Neurons / classification
  • Neurons / metabolism*
  • Nucleus Accumbens / cytology
  • Nucleus Accumbens / metabolism*
  • Quinine / pharmacology
  • Receptors, Dopamine D1 / genetics*
  • Receptors, Dopamine D1 / metabolism
  • Receptors, Dopamine D2 / genetics*
  • Receptors, Dopamine D2 / metabolism
  • Self Administration


  • Central Nervous System Depressants
  • DRD2 protein, mouse
  • Drd1 protein, mouse
  • Receptors, Dopamine D1
  • Receptors, Dopamine D2
  • Ethanol
  • Quinine