Striatal D1 and D2 Dopamine Receptor Activity Exert Opposite Influences on Alcohol Drinking

Promising class of new cancer drugs might cause memory loss in mice
Promising class of new cancer drugs might cause memory loss in mice
Inhibition of D1 dopamine receptors in medium spiny neurons, or excitation of D1 dopamine receptors in medium spiny neurons, of the striatum, attenuated excessive alcohol consumption in mice.

The CDC rank alcohol-attributable mortality as the third leading cause of preventable death in the United States.1 The chronic, excessive consumption of alcohol affects various brain regions and modifies selective neural systems of the brain, and alters functional connectivity between subcortical and cortical brain areas due to compromised white matter fiber tract integrity.2

New findings, reported in Biological Psychiatry, indicate that repeated cycles of excessive alcohol intake and withdrawal in mice contribute to alcohol consumption by potentiating excitatory glutamatergic strength of D1 dopamine receptors in medium spiny neurons (MSNs) of the dorsomedial striatum (DMS), and by potentiating inhibitory GABAergic strength of D2 dopamine receptors in MSNs of the DMS.3 

“Since the DMS is part of the cortico-striato-thalamo-cortex circuit, which is known to control action-outcome learning and goal-directed behavior, these glutamatergic and GABAergic changes presumably enhance process of goal-directed information in this circuit,” the authors affiliated with Texas A&M Health Science Center explained in their publication.

To establish high levels of alcohol consumption in mice, researchers used the intermittent-access two-bottle-choice procedure. Following a period of alcohol deprivation, animals transiently increase their voluntary intake of alcohol above baseline drinking conditions upon re-instatement of alcohol. This phenomenon is called the alcohol deprivation effect and it has previously been reported in humans, monkeys, rats, and mice.

One day after the last alcohol-drinking session, NMDA receptor activity in D1 and D2 MSNs of the DMS was recorded. Whole-cell recordings data indicate that the amplitude of NMDA-induced currents in D1-MSNs was significantly greater in alcohol-drinking mice, compared with that of control animals. The opposite was found with respect to the NMDA current in D2-MSNs; alcohol-drinking mice exhibited significantly smaller amplitude of NMDA-induced currents. “These results suggest that repeated cycles of alcohol consumption and withdrawal selectively potentiated synaptic NMDA receptor activity in D1-MSNs, but not in D2-MSNs, within the DMS,” the authors wrote.

The investigators also measured GABAergic activity in D1 and D2 MSNs of the DMS, at 24 hours following the last alcohol-drinking session. The results indicate that “inhibitory GABAergic transmission is potentiated selectively in DMS D2-MSNs, but not in D1-MSNs, following repeated cycles of excessive alcohol consumption and withdrawal,” they wrote.

Pharmacogenetic techniques, such as the use of DREADDs (Designer Receptors Exclusively Activated by Designer Drugs), have become essential neurophysiologic methods to permit the study of cell- and region-specific control of neuronal activity.

To extend their findings, researchers used in vivo chemogenetics (DREADDs) to selectively excite D1-MSNs or inhibit D2-MSNs in the DMS. “Since D1-MSNs control “Go” and D2-MSNs control “NoGo” actions in rewarding behaviors,” they hypothesized that the “resulting increase in “Go” and reduction of “NoGo” [would] both promote alcohol consumption.”

The selective excitation or inhibition of D1-MSNs or D2-MSNs, respectively, was reported to be sufficient in increasing alcohol consumption. On the other hand, in vivo chemogenetic inhibition of D1-MSNs or excitation of D2-MSNs attenuated excessive alcohol consumption in mice.

They concluded that, “alterations of D1 dopamine receptor activity in medium spiny neurons (MSNs) of the dorsomedial striatum (DMS) and D2 dopamine receptor activity in medium spiny neurons (MSNs) of the dorsomedial striatum (DMS) … drive alcohol consumption, and … exert opposite influences on [alcohol drinking] behavior.”

In humans, low DRD2 (dopamine D2 receptor) availability may render an individual more vulnerable to alcohol abuse.4 For example, the brains of individuals with alcoholism show reduced DRD2 levels in the striatum, whereas non-alcoholic individuals with risk of alcoholism due to family history appear to be protected against alcoholism due to high levels of striatal DRD2.5,6 Also, predisposition to severe alcoholism is linked to polymorphisms that may result in reduced expression levels of DRD2.7 And, in rats, overexpression of DRD2 in nucleus accumbens (NAc) was shown to significantly attenuate alcohol drinking.8

In the present study, researchers also show that selective activation of DRD2 in the DMS reduces alcohol intake. More specifically, “DRD2 signaling suppresses GABAergic transmission in D2-MSNs of the DMS and inhibits excessive alcohol consumption,” they wrote.

The authors concluded that these findings may assist in “identifying both synaptic and neuronal therapeutic targets for the development of new approaches to the treatment of alcohol abuse.”


1. Mokdad AH, Marks JS, Stroup DF, Gerberding JL. Actual causes of death in the United States, 2000. J Am Med Assoc. 2004;291:1238-1245.

2. Sullivan EV, Pfefferbaum A. Neurocircuitry in alcoholism: a substrate of disruption and repair. Psychopharmacology. 2005;180:583-594.

3. Yifeng C, Huang CY, Ma T, et al. Distinct synaptic strengthening of the striatal direct and indirect pathways drives alcohol consumption. Biol Psychiatry. 2016. doi: 10.1016/j.biopsych.2016.05.016. [Epub ahead of print]

4. Volkow ND, Fowler JS, Wang GJ. Role of dopamine in drug reinforcement and addiction in humans: results from imaging studies. Behav Pharmacol. 2002;13:355-366.

5. Volkow ND, Wang GJ, Begleiter H, et al. High levels of dopamine D2 receptors in unaffected members of alcoholic families. Arch Gen Psychiatry. 2006;63:999-1008.

6. Volkow ND, Wang GJ, Fowler JS, et al. Decreases in dopamine receptors but not in dopamine transporters in alcoholics. Alcohol Clin Exp Res. 1996;20:1594-1598.

7. Noble EP, Blum K, Ritchie T, et al. Allelic association of the D2 dopamine receptor gene with receptor-binding characteristics in alcoholism. Arch Gen Psychiatry. 1991;48:648-654.

8. Thanos PK, Volkow ND, Freimuth P, et al. Overexpression of dopamine D2 receptors reduces alcohol self-administration. J Neurochem. 2001;78:1094-1103.