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

doi:10.1016/j.biopsych.2016.05.016

Biological Psychiatry

Volume 81, Issue 11, 1 June 2017, Pages 918-929

https://doi.org/10.1016/j.biopsych.2016.05.016 Get rights and content

Abstract

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.

Section snippets

Methods and Materials

A detailed description of all materials and methods can be found in Supplemental Methods and Materials. The intermittent-access two-bottle-choice drinking procedure was used to establish high levels of alcohol consumption in mice (15, 24, 25, 26). Twenty-four hours after the last alcohol-drinking session, animals were sacrificed and 200-µm coronal sections containing the DMS or 200-µm sagittal sections containing the external part of the globus pallidus (GPe) were prepared. The external

Selective Potentiation of Excitatory Transmission in DMS D₁-MSNs Following Repeated Cycles of Excessive Alcohol Consumption and Withdrawal

The NMDAR is one of the major targets of alcohol (21, 27). However, it was unclear whether NMDAR-mediated excitatory transmission in D₁- or D₂-MSNs was altered by alcohol consumption and withdrawal. To measure NMDAR activity in these two subpopulations of striatal neurons, we generated new lines of mice to visualize fluorescently labeled D₁- and D₂-MSNs. These new mice were crossed by dopamine receptor D₁ Drd1a-Cre (D₁-Cre) and dopamine receptor D₂ Drd2-Cre (D₂-Cre) mice with Cre reporter lines

Discussion

The present study found that repeated cycles of excessive alcohol intake and withdrawal selectively potentiated GluN2B-NMDAR activity in direct-pathway D₁-MSNs and GABAergic transmission in indirect-pathway D₂-MSNs of the DMS. These changes in synaptic strength serve to excite D₁-MSNs and inhibit D₂-MSNs, and we discovered that D₁-MSN excitation or D₂-MSN inhibition using an in vivo chemogenetic approach promotes alcohol consumption. Conversely, D₁-MSN inhibition or D₂-MSN excitation suppress

Acknowledgments and Disclosures

This research was supported by National Institute on Alcohol Abuse and Alcoholism Grant No. R01AA021505 (to JW) and by Texas Research Society on Alcoholism (to YC).

We thank Mr. Roger Wang for counting neurons; Ms. Lauren Benefield, Ms. Nihal Salem, Ms. Sasha Burrowes, and Dr. Rajesh Miranda for technical support; and Dr. Emily Roltsch Hellard for the critical reading of the manuscript.

The authors report no biomedical financial interests or potential conflicts of interest.

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¹: YC, CCYH, and TM contributed equally to this work.

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

Abstract

Background

Methods

Results

Conclusions

Section snippets

Methods and Materials

Selective Potentiation of Excitatory Transmission in DMS D1-MSNs Following Repeated Cycles of Excessive Alcohol Consumption and Withdrawal

Discussion

Acknowledgments and Disclosures

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

Selective Potentiation of Excitatory Transmission in DMS D₁-MSNs Following Repeated Cycles of Excessive Alcohol Consumption and Withdrawal