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

  • Author Footnotes
    1 YC, CCYH, and TM contributed equally to this work.
    Yifeng Cheng
    1 YC, CCYH, and TM contributed equally to this work.
    Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M Health Science Center, Bryan, Texas
    Search for articles by this author
  • Author Footnotes
    1 YC, CCYH, and TM contributed equally to this work.
    Cathy C.Y. Huang
    1 YC, CCYH, and TM contributed equally to this work.
    Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M Health Science Center, Bryan, Texas
    Search for articles by this author
  • Author Footnotes
    1 YC, CCYH, and TM contributed equally to this work.
    Tengfei Ma
    1 YC, CCYH, and TM contributed equally to this work.
    Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M Health Science Center, Bryan, Texas
    Search for articles by this author
  • Xiaoyan Wei
    Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M Health Science Center, Bryan, Texas
    Search for articles by this author
  • Xuehua Wang
    Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M Health Science Center, Bryan, Texas
    Search for articles by this author
  • Jiayi Lu
    Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M Health Science Center, Bryan, Texas
    Search for articles by this author
  • Jun Wang
    Address correspondence to: Jun Wang, M.D., Ph.D., Texas A&M Health Science Center, Neuroscience and Experimental Therapeutics, 8447 State Highway 47, Suite 2106, Bryan, Texas 77807.
    Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M Health Science Center, Bryan, Texas
    Search for articles by this author
  • Author Footnotes
    1 YC, CCYH, and TM contributed equally to this work.



      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.


      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.


      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.


      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.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Luscher C.
        • Malenka R.C.
        Drug-evoked synaptic plasticity in addiction: From molecular changes to circuit remodeling.
        Neuron. 2011; 69: 650-663
        • Koob G.F.
        • Volkow N.D.
        Neurocircuitry of addiction.
        Neuropsychopharmacology. 2010; 35: 217-238
        • Hyman S.E.
        • Malenka R.C.
        • Nestler E.J.
        Neural mechanisms of addiction: The role of reward-related learning and memory.
        Annu Rev Neurosci. 2006; 29: 565-598
        • Filbey F.M.
        • Claus E.
        • Audette A.R.
        • Niculescu M.
        • Banich M.T.
        • Tanabe J.
        • et al.
        Exposure to the taste of alcohol elicits activation of the mesocorticolimbic neurocircuitry.
        Neuropsychopharmacology. 2008; 33: 1391-1401
        • Volkow N.D.
        • Morales M.
        The brain on drugs: From reward to addiction.
        Cell. 2015; 162: 712-725
        • Wang J.
        • Lanfranco M.F.
        • Gibb S.L.
        • Yowell Q.V.
        • Carnicella S.
        • Ron D.
        Long-lasting adaptations of the NR2B-containing NMDA receptors in the dorsomedial striatum play a crucial role in alcohol consumption and relapse.
        J Neurosci. 2010; 30: 10187-10198
        • Brown T.E.
        • Lee B.R.
        • Mu P.
        • Ferguson D.
        • Dietz D.
        • Ohnishi Y.N.
        • et al.
        A silent synapse-based mechanism for cocaine-induced locomotor sensitization.
        J Neurosci. 2011; 31: 8163-8174
        • Hyytia P.
        • Koob G.F.
        GABAA receptor antagonism in the extended amygdala decreases ethanol self-administration in rats.
        Eur J Pharmacol. 1995; 283: 151-159
        • Nie H.
        • Rewal M.
        • Gill T.M.
        • Ron D.
        • Janak P.H.
        Extrasynaptic delta-containing GABAA receptors in the nucleus accumbens dorsomedial shell contribute to alcohol intake.
        Proc Natl Acad Sci U S A. 2011; 108: 4459-4464
        • Everitt B.J.
        • Robbins T.W.
        From the ventral to the dorsal striatum: Devolving views of their roles in drug addiction.
        Neurosci Biobehav Rev. 2013; 37: 1946-1954
        • Wang J.
        • Carnicella S.
        • Phamluong K.
        • Jeanblanc J.
        • Ronesi J.A.
        • Chaudhri N.
        • et al.
        Ethanol induces long-term facilitation of NR2B-NMDA receptor activity in the dorsal striatum: Implications for alcohol drinking behavior.
        J Neurosci. 2007; 27: 3593-3602
        • Balleine B.W.
        • O’Doherty J.P.
        Human and rodent homologies in action control: Corticostriatal determinants of goal-directed and habitual action.
        Neuropsychopharmacology. 2010; 35: 48-69
        • Volkow N.D.
        • Wang G.J.
        • Telang F.
        • Fowler J.S.
        • Logan J.
        • Childress A.R.
        • et al.
        Cocaine cues and dopamine in dorsal striatum: Mechanism of craving in cocaine addiction.
        J Neurosci. 2006; 26: 6583-6588
        • Nam H.W.
        • Hinton D.J.
        • Kang N.Y.
        • Kim T.
        • Lee M.R.
        • Oliveros A.
        • et al.
        Adenosine transporter ENT1 regulates the acquisition of goal-directed behavior and ethanol drinking through A2A receptor in the dorsomedial striatum.
        J Neurosci. 2013; 33: 4329-4338
        • Wang J.
        • Cheng Y.
        • Wang X.
        • Roltsch Hellard E.
        • Ma T.
        • Gil H.
        • et al.
        Alcohol elicits functional and structural plasticity selectively in dopamine D1 receptor-expressing neurons of the dorsomedial striatum.
        J Neurosci. 2015; 35: 11634-11643
        • Wang J.
        • Ben Hamida S.
        • Darcq E.
        • Zhu W.
        • Gibb S.L.
        • Lanfranco M.F.
        • et al.
        Ethanol-mediated facilitation of AMPA receptor function in the dorsomedial striatum: Implications for alcohol drinking behavior.
        J Neurosci. 2012; 32: 15124-15132
        • Gerfen C.R.
        • Surmeier D.J.
        Modulation of striatal projection systems by dopamine.
        Annu Rev Neurosci. 2011; 34: 441-466
        • Maia T.V.
        • Frank M.J.
        From reinforcement learning models to psychiatric and neurological disorders.
        Nat Neurosci. 2011; 14: 154-162
        • Sippy T.
        • Lapray D.
        • Crochet S.
        • Petersen C.C.
        Cell-type-specific sensorimotor processing in striatal projection neurons during goal-directed behavior.
        Neuron. 2015; 88: 298-305
        • Kreitzer A.C.
        Physiology and pharmacology of striatal neurons.
        Annu Rev Neurosci. 2009; 32: 127-147
        • Lovinger D.M.
        • White G.
        • Weight F.F.
        NMDA receptor-mediated synaptic excitation selectively inhibited by ethanol in hippocampal slice from adult rat.
        J Neurosci. 1990; 10: 1372-1379
        • Roberto M.
        • Madamba S.G.
        • Stouffer D.G.
        • Parsons L.H.
        • Siggins G.R.
        Increased GABA release in the central amygdala of ethanol-dependent rats.
        J Neurosci. 2004; 24: 10159-10166
        • Urban D.J.
        • Roth B.L.
        DREADDs (Designer Receptors Exclusively Activated by Designer Drugs): Chemogenetic tools with therapeutic utility.
        Annu Rev Pharmacol Toxicol. 2015; 55: 399-417
        • Hwa L.S.
        • Chu A.
        • Levinson S.A.
        • Kayyali T.M.
        • DeBold J.F.
        • Miczek K.A.
        Persistent escalation of alcohol drinking in C57BL/6J mice with intermittent access to 20% ethanol.
        Alcohol Clin Exp Res. 2011; 35: 1938-1947
        • Warnault V.
        • Darcq E.
        • Levine A.
        • Barak S.
        • Ron D.
        Chromatin remodeling—a novel strategy to control excessive alcohol drinking.
        Transl Psychiatry. 2013; 3: e231
        • Darcq E.
        • Warnault V.
        • Phamluong K.
        • Besserer G.M.
        • Liu F.
        • Ron D.
        MicroRNA-30a-5p in the prefrontal cortex controls the transition from moderate to excessive alcohol consumption.
        Mol Psychiatry. 2015; 20: 1219-1231
        • Holmes A.
        • Spanagel R.
        • Krystal J.H.
        Glutamatergic targets for new alcohol medications.
        Psychopharmacology (Berl). 2013; 229: 539-554
        • Gong S.
        • Doughty M.
        • Harbaugh C.R.
        • Cummins A.
        • Hatten M.E.
        • Heintz N.
        • Gerfen C.R.
        Targeting Cre recombinase to specific neuron populations with bacterial artificial chromosome constructs.
        J Neurosci. 2007; 27: 9817-9823
        • Madisen L.
        • Zwingman T.A.
        • Sunkin S.M.
        • Oh S.W.
        • Zariwala H.A.
        • Gu H.
        • et al.
        A robust and high-throughput Cre reporting and characterization system for the whole mouse brain.
        Nat Neurosci. 2010; 13: 133-140
        • Bertran-Gonzalez J.
        • Bosch C.
        • Maroteaux M.
        • Matamales M.
        • Herve D.
        • Valjent E.
        • Girault J.A.
        Opposing patterns of signaling activation in dopamine D1 and D2 receptor-expressing striatal neurons in response to cocaine and haloperidol.
        J Neurosci. 2008; 28: 5671-5685
        • Valjent E.
        • Bertran-Gonzalez J.
        • Herve D.
        • Fisone G.
        • Girault J.A.
        Looking BAC at striatal signaling: Cell-specific analysis in new transgenic mice.
        Trends Neurosci. 2009; 32: 538-547
        • Becker H.C.
        • Ron D.
        Animal models of excessive alcohol consumption: Recent advances and future challenges.
        Alcohol. 2014; 48: 205-208
        • Anacker A.M.
        • Loftis J.M.
        • Kaur S.
        • Ryabinin A.E.
        Prairie voles as a novel model of socially facilitated excessive drinking.
        Addict Biol. 2011; 16: 92-107
        • Carpenter-Hyland E.P.
        • Woodward J.J.
        • Chandler L.J.
        Chronic ethanol induces synaptic but not extrasynaptic targeting of NMDA receptors.
        J Neurosci. 2004; 24: 7859-7868
        • Paoletti P.
        • Bellone C.
        • Zhou Q.
        NMDA receptor subunit diversity: Impact on receptor properties, synaptic plasticity and disease.
        Nat Rev Neurosci. 2013; 14: 383-400
        • Kash T.L.
        • Baucum 2nd, A.J.
        • Conrad K.L.
        • Colbran R.J.
        • Winder D.G.
        Alcohol exposure alters NMDAR function in the bed nucleus of the stria terminalis.
        Neuropsychopharmacology. 2009; 34: 2420-2429
        • Weiner J.L.
        • Valenzuela C.F.
        Ethanol modulation of GABAergic transmission: The view from the slice.
        Pharmacol Ther. 2006; 111: 533-554
        • Luo R.
        • Partridge J.G.
        • Vicini S.
        Distinct roles of synaptic and extrasynaptic GABAAreceptors in striatal inhibition dynamics.
        Front Neural Circuits. 2013; 7: 186
        • Li Y.C.
        • Kellendonk C.
        • Simpson E.H.
        • Kandel E.R.
        • Gao W.J.
        D2 receptor overexpression in the striatum leads to a deficit in inhibitory transmission and dopamine sensitivity in mouse prefrontal cortex.
        Proc Natl Acad Sci U S A. 2011; 108: 12107-12112
        • Li Y.C.
        • Wang M.J.
        • Gao W.J.
        Hyperdopaminergic modulation of inhibitory transmission is dependent on GSK-3β signaling-mediated trafficking of GABAA receptors.
        J Neurochem. 2012; 122: 308-320
        • Janssen M.J.
        • Ade K.K.
        • Fu Z.
        • Vicini S.
        Dopamine modulation of GABA tonic conductance in striatal output neurons.
        J Neurosci. 2009; 29: 5116-5126
        • Janssen M.J.
        • Yasuda R.P.
        • Vicini S.
        GABA(A) receptor β3 subunit expression regulates tonic current in developing striatopallidal medium spiny neurons.
        Front Cell Neurosci. 2011; 5: 15
        • Beaulieu J.M.
        • Gainetdinov R.R.
        • Caron M.G.
        Akt/GSK3 signaling in the action of psychotropic drugs.
        Annu Rev Pharmacol Toxicol. 2009; 49: 327-347
        • Beurel E.
        • Grieco S.F.
        • Jope R.S.
        Glycogen synthase kinase-3 (GSK3): Regulation, actions, and diseases.
        Pharmacol Ther. 2015; 148: 114-131
        • Lovinger D.M.
        • White G.
        • Weight F.F.
        Ethanol inhibits NMDA-activated ion current in hippocampal neurons.
        Science. 1989; 243: 1721-1724
        • Pascoli V.
        • Terrier J.
        • Espallergues J.
        • Valjent E.
        • O’Connor E.C.
        • Luscher C.
        Contrasting forms of cocaine-evoked plasticity control components of relapse.
        Nature. 2014; 509: 459-464
        • Beaulieu J.M.
        • Gainetdinov R.R.
        The physiology, signaling, and pharmacology of dopamine receptors.
        Pharmacol Rev. 2011; 63: 182-217
        • Sulzer D.
        How addictive drugs disrupt presynaptic dopamine neurotransmission.
        Neuron. 2011; 69: 628-649
        • Huang Y.H.
        • Lin Y.
        • Mu P.
        • Lee B.R.
        • Brown T.E.
        • Wayman G.
        • et al.
        In vivo cocaine experience generates silent synapses.
        Neuron. 2009; 63: 40-47
        • Li Y.C.
        • Xi D.
        • Roman J.
        • Huang Y.Q.
        • Gao W.J.
        Activation of glycogen synthase kinase-3 beta is required for hyperdopamine and D2 receptor-mediated inhibition of synaptic NMDA receptor function in the rat prefrontal cortex.
        J Neurosci. 2009; 29: 15551-15563
        • Neasta J.
        • Ben Hamida S.
        • Yowell Q.V.
        • Carnicella S.
        • Ron D.
        AKT signaling pathway in the nucleus accumbens mediates excessive alcohol drinking behaviors.
        Biol Psychiatry. 2011; 70: 575-582
        • Liu F.
        • Laguesse S.
        • Legastelois R.
        • Morisot N.
        • Ben Hamida S.
        • Ron D.
        mTORC1-dependent translation of collapsin response mediator protein-2 drives neuroadaptations underlying excessive alcohol-drinking behaviors.
        Mol Psychiatry. 2017; 22: 89-101
        • Xi D.
        • Li Y.C.
        • Snyder M.A.
        • Gao R.Y.
        • Adelman A.E.
        • Zhang W.
        • et al.
        Group II metabotropic glutamate receptor agonist ameliorates MK801-induced dysfunction of NMDA receptors via the Akt/GSK-3β pathway in adult rat prefrontal cortex.
        Neuropsychopharmacology. 2011; 36: 1260-1274
        • Barak S.
        • Carnicella S.
        • Yowell Q.V.
        • Ron D.
        Glial cell line-derived neurotrophic factor reverses alcohol-induced allostasis of the mesolimbic dopaminergic system: Implications for alcohol reward and seeking.
        J Neurosci. 2011; 31: 9885-9894
        • Koob G.F.
        • Le Moal M.
        Addiction and the brain antireward system.
        Annu Rev Psychol. 2008; 59: 29-53
        • Gittis A.H.
        • Hang G.B.
        • LaDow E.S.
        • Shoenfeld L.R.
        • Atallah B.V.
        • Finkbeiner S.
        • Kreitzer A.C.
        Rapid target-specific remodeling of fast-spiking inhibitory circuits after loss of dopamine.
        Neuron. 2011; 71: 858-868
        • Tyagarajan S.K.
        • Fritschy J.M.
        Gephyrin: A master regulator of neuronal function?.
        Nat Rev Neurosci. 2014; 15: 141-156
        • Rui Y.
        • Myers K.R.
        • Yu K.
        • Wise A.
        • De Blas A.L.
        • Hartzell H.C.
        • Zheng J.Q.
        Activity-dependent regulation of dendritic growth and maintenance by glycogen synthase kinase 3β.
        Nat Commun. 2013; 4: 2628
        • Brickley S.G.
        • Mody I.
        Extrasynaptic GABA(A) receptors: Their function in the CNS and implications for disease.
        Neuron. 2012; 73: 23-34
        • D’Souza M.
        • Ikegami A.
        • Olsen C.M.
        • Duvauchelle C.L.
        Chronic D1 agonist and ethanol coadministration facilitate ethanol-mediated behaviors.
        Pharmacol Biochem Behav. 2003; 76: 335-342
        • El-Ghundi M.
        • George S.R.
        • Drago J.
        • Fletcher P.J.
        • Fan T.
        • Nguyen T.
        • et al.
        Disruption of dopamine D1 receptor gene expression attenuates alcohol-seeking behavior.
        Eur J Pharmacol. 1998; 353: 149-158
        • Hodge C.W.
        • Samson H.H.
        • Chappelle A.M.
        Alcohol self-administration: Further examination of the role of dopamine receptors in the nucleus accumbens.
        Alcohol Clin Exp Res. 1997; 21: 1083-1091
        • Thanos P.K.
        • Volkow N.D.
        • Freimuth P.
        • Umegaki H.
        • Ikari H.
        • Roth G.
        • et al.
        Overexpression of dopamine D2 receptors reduces alcohol self-administration.
        J Neurochem. 2001; 78: 1094-1103
        • Phillips T.J.
        • Brown K.J.
        • Burkhart-Kasch S.
        • Wenger C.D.
        • Kelly M.A.
        • Rubinstein M.
        • et al.
        Alcohol preference and sensitivity are markedly reduced in mice lacking dopamine D2 receptors.
        Nat Neurosci. 1998; 1: 610-615
        • Dyr W.
        • McBride W.J.
        • Lumeng L.
        • Li T.K.
        • Murphy J.M.
        Effects of D1 and D2 dopamine receptor agents on ethanol consumption in the high-alcohol-drinking (HAD) line of rats.
        Alcohol. 1993; 10: 207-212
        • Gunaydin L.A.
        • Kreitzer A.C.
        Cortico-basal ganglia circuit function in psychiatric disease.
        Annu Rev Physiol. 2016; 78: 327-350

      Linked Article

      • Tipping the Scales Toward Addiction
        Biological PsychiatryVol. 81Issue 11
        • Preview
          Despite diverse acute pharmacological actions, all drugs of abuse produce many similar behaviors, such as psychomotor sensitization, conditioned drug taking, drug seeking, and relapse (1). The development of these addiction-related behaviors is thought to arise from diverse molecular and cellular adaptations, which collectively result in convergent long-term functional alterations of the striatum. However, at the cellular level, on the one hand, exposure to different classes of drugs, such as stimulants versus opioids (2), induces distinct and often opposing forms of adaptations in striatal medium spiny neurons (MSNs).
        • Full-Text
        • PDF