Distinct Synaptic Strengthening of the Striatal Direct and Indirect Pathways Drives Alcohol Consumption

Biol Psychiatry. 2017 Jun 1;81(11):918-929. doi: 10.1016/j.biopsych.2016.05.016. Epub 2016 May 27.


Background: Repeated exposure to addictive drugs or alcohol triggers glutamatergic and gamma-aminobutyric acidergic (GABAergic) plasticity in many neuronal populations. The dorsomedial striatum (DMS), a brain region critically involved in addiction, contains medium spiny neurons (MSNs) expressing dopamine D1 or D2 receptors, which form direct and indirect pathways, respectively. It is unclear how alcohol-evoked plasticity in the DMS contributes to alcohol consumption in a cell type-specific manner.

Methods: Mice were trained to consume alcohol using an intermittent-access two-bottle-choice drinking procedure. Slice electrophysiology was used to measure glutamatergic and GABAergic strength in DMS D1- and D2-MSNs of alcohol-drinking mice and control mice. In vivo chemogenetic and pharmacologic approaches were employed to manipulate MSN activity, and their consequences on alcohol consumption were measured.

Results: Repeated cycles of alcohol consumption and withdrawal in mice strengthened glutamatergic transmission in D1-MSNs and GABAergic transmission in D2-MSNs. In vivo chemogenetic excitation of D1-MSNs, mimicking glutamatergic strengthening, promoted alcohol consumption; the same effect was induced by D2-MSN inhibition, mimicking GABAergic strengthening. Importantly, suppression of GABAergic transmission via D2 receptor-glycogen synthase kinase-3β signaling dramatically reduced excessive alcohol consumption, as did selective inhibition of D1-MSNs or excitation of D2-MSNs.

Conclusions: Our results suggest that repeated cycles of excessive alcohol intake and withdrawal potentiate glutamatergic strength exclusively in D1-MSNs and GABAergic strength specifically in D2-MSNs of the DMS, which concurrently contribute to alcohol consumption. These results provide insight into the synaptic and cell type-specific mechanisms underlying alcohol addiction and identify targets for the development of new therapeutic approaches to alcohol abuse.

Keywords: Alcoholism; DREADDs; Dopamine D(2) receptor; Dorsomedial striatum; GABAergic plasticity; GSK3β.

Publication types

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

MeSH terms

  • Alcohol Drinking / physiopathology*
  • Animals
  • Corpus Striatum / drug effects
  • Corpus Striatum / physiology*
  • Designer Drugs / pharmacology
  • GABAergic Neurons / physiology*
  • Glycogen Synthase Kinase 3 beta / physiology
  • Male
  • Mice
  • Mice, Transgenic
  • Neural Pathways / physiology*
  • Neurons / drug effects
  • Neurons / physiology
  • Substance Withdrawal Syndrome
  • gamma-Aminobutyric Acid / physiology*


  • Designer Drugs
  • gamma-Aminobutyric Acid
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse