Astrocytic Dysfunction and Addiction: Consequences of Impaired Glutamate Homeostasis

Overview

Journal Neuroscientist

Publisher Sage Publications

Specialty Neurology

Date 2014 Feb 6

PMID 24496610

Citations 108

Authors

Michael D Scofield

Peter W Kalivas

Affiliations

Soon will be listed here.

Abstract

Addiction is characterized as a chronic relapsing disorder whereby addicted individuals persistently engage in drug seeking and use despite profound negative consequences. The results of studies using animal models of addiction and relapse indicate that drug seeking is mediated by alterations in cortico-accumbal plasticity induced by chronic drug exposure. Among the maladaptive responses to drug exposure are long-lasting alterations in the expression of proteins localized to accumbal astrocytes, which are responsible for maintaining glutamate homeostasis. These alterations engender an aberrant potentiation of glutamate transmission in the cortico-accumbens circuit that is linked to the reinstatement of drug seeking. Accordingly, pharmacological restoration of glutamate homeostasis functions as an efficient method of reversing drug-induced plasticity and inhibiting drug seeking in both rodents and humans.

Citing Articles

Dissociating the incubation of appetitive and consummatory behavior in a model of oral cocaine self-administration.

Namba M, Goldberg S, Side C, Yadlapalli A, Curran-Alfaro C, Kress D bioRxiv. 2025; .

PMID: 39990380 PMC: 11844540. DOI: 10.1101/2025.02.12.637922.

Role of Glial Cells in Neuronal Function, Mood Disorders, and Drug Addiction.

Tizabi Y, Getachew B, Hauser S, Tsytsarev V, Manhaes A, da Silva V Brain Sci. 2024; 14(6).

PMID: 38928557 PMC: 11201416. DOI: 10.3390/brainsci14060558.

Molecular Rhythmicity in Glia: Importance for Brain Health and Relevance to Psychiatric Disease.

Jenkins A, Ketchesin K, Becker-Krail D, McClung C Biol Psychiatry. 2024; 96(12):909-918.

PMID: 38735357 PMC: 11550267. DOI: 10.1016/j.biopsych.2024.05.007.

Synthesis and Structure-Activity Relationships for Glutamate Transporter Allosteric Modulators.

Fontana A, Poli A, Gour J, Srikanth Y, Anastasi N, Ashok D J Med Chem. 2024; 67(8):6119-6143.

PMID: 38626917 PMC: 11056993. DOI: 10.1021/acs.jmedchem.3c01909.

Astrocytic transcriptional and epigenetic mechanisms of drug addiction.

Holt L, Nestler E J Neural Transm (Vienna). 2023; 131(5):409-424.

PMID: 37940687 PMC: 11066772. DOI: 10.1007/s00702-023-02716-4.

References

Parpura V, Verkhratsky A . Astrocytes revisited: concise historic outlook on glutamate homeostasis and signaling. Croat Med J. 2013; 53(6):518-28. PMC: 3541578. DOI: 10.3325/cmj.2012.53.518. View

Schotanus S, Chergui K . Dopamine D1 receptors and group I metabotropic glutamate receptors contribute to the induction of long-term potentiation in the nucleus accumbens. Neuropharmacology. 2008; 54(5):837-44. DOI: 10.1016/j.neuropharm.2007.12.012. View

Xi Z, Ramamoorthy S, Baker D, Shen H, Samuvel D, Kalivas P . Modulation of group II metabotropic glutamate receptor signaling by chronic cocaine. J Pharmacol Exp Ther. 2002; 303(2):608-15. DOI: 10.1124/jpet.102.039735. View

Bossert J, Gray S, Lu L, Shaham Y . Activation of group II metabotropic glutamate receptors in the nucleus accumbens shell attenuates context-induced relapse to heroin seeking. Neuropsychopharmacology. 2005; 31(10):2197-209. PMC: 1570155. DOI: 10.1038/sj.npp.1300977. View

Baker D, McFarland K, Lake R, Shen H, Toda S, Kalivas P . N-acetyl cysteine-induced blockade of cocaine-induced reinstatement. Ann N Y Acad Sci. 2003; 1003:349-51. DOI: 10.1196/annals.1300.023. View

Albrecht J, Sidoryk-Wegrzynowicz M, Zielinska M, Aschner M . Roles of glutamine in neurotransmission. Neuron Glia Biol. 2011; 6(4):263-76. DOI: 10.1017/S1740925X11000093. View

Bell R, Lopez M, Cui C, Egli M, Johnson K, Franklin K . Ibudilast reduces alcohol drinking in multiple animal models of alcohol dependence. Addict Biol. 2013; 20(1):38-42. PMC: 4017009. DOI: 10.1111/adb.12106. View

Liu L, Wong T, Pozza M, Lingenhoehl K, Wang Y, Sheng M . Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity. Science. 2004; 304(5673):1021-4. DOI: 10.1126/science.1096615. View

McFarland K, Lapish C, Kalivas P . Prefrontal glutamate release into the core of the nucleus accumbens mediates cocaine-induced reinstatement of drug-seeking behavior. J Neurosci. 2003; 23(8):3531-7. PMC: 6742291. View

10.

Shen H, Moussawi K, Zhou W, Toda S, Kalivas P . Heroin relapse requires long-term potentiation-like plasticity mediated by NMDA2b-containing receptors. Proc Natl Acad Sci U S A. 2011; 108(48):19407-12. PMC: 3228456. DOI: 10.1073/pnas.1112052108. View

11.

Reissner K, Brown R, Spencer S, Tran P, Thomas C, Kalivas P . Chronic administration of the methylxanthine propentofylline impairs reinstatement to cocaine by a GLT-1-dependent mechanism. Neuropsychopharmacology. 2013; 39(2):499-506. PMC: 3870775. DOI: 10.1038/npp.2013.223. View

12.

Madayag A, Lobner D, Kau K, Mantsch J, Abdulhameed O, Hearing M . Repeated N-acetylcysteine administration alters plasticity-dependent effects of cocaine. J Neurosci. 2007; 27(51):13968-76. PMC: 2996827. DOI: 10.1523/JNEUROSCI.2808-07.2007. View

13.

Zorec R, Araque A, Carmignoto G, Haydon P, Verkhratsky A, Parpura V . Astroglial excitability and gliotransmission: an appraisal of Ca2+ as a signalling route. ASN Neuro. 2012; 4(2). PMC: 3310306. DOI: 10.1042/AN20110061. View

14.

Yao L, McFarland K, Fan P, Jiang Z, Inoue Y, Diamond I . Activator of G protein signaling 3 regulates opiate activation of protein kinase A signaling and relapse of heroin-seeking behavior. Proc Natl Acad Sci U S A. 2005; 102(24):8746-51. PMC: 1142483. DOI: 10.1073/pnas.0503419102. View

15.

Anderson A, Reid M, Li S, Holmes T, Shemanski L, Slee A . Modafinil for the treatment of cocaine dependence. Drug Alcohol Depend. 2009; 104(1-2):133-9. PMC: 2818032. DOI: 10.1016/j.drugalcdep.2009.04.015. View

16.

Tawfik V, LaCroix-Fralish M, Bercury K, Nutile-McMenemy N, Harris B, DeLeo J . Induction of astrocyte differentiation by propentofylline increases glutamate transporter expression in vitro: heterogeneity of the quiescent phenotype. Glia. 2006; 54(3):193-203. DOI: 10.1002/glia.20365. View

17.

Ramirez-Nino A, DSouza M, Markou A . N-acetylcysteine decreased nicotine self-administration and cue-induced reinstatement of nicotine seeking in rats: comparison with the effects of N-acetylcysteine on food responding and food seeking. Psychopharmacology (Berl). 2012; 225(2):473-82. PMC: 3697766. DOI: 10.1007/s00213-012-2837-3. View

18.

Gipson C, Reissner K, Kupchik Y, Smith A, Stankeviciute N, Hensley-Simon M . Reinstatement of nicotine seeking is mediated by glutamatergic plasticity. Proc Natl Acad Sci U S A. 2013; 110(22):9124-9. PMC: 3670307. DOI: 10.1073/pnas.1220591110. View

19.

Poskanzer K, Yuste R . Astrocytic regulation of cortical UP states. Proc Natl Acad Sci U S A. 2011; 108(45):18453-8. PMC: 3215035. DOI: 10.1073/pnas.1112378108. View

20.

Snider S, Hendrick E, Beardsley P . Glial cell modulators attenuate methamphetamine self-administration in the rat. Eur J Pharmacol. 2013; 701(1-3):124-30. PMC: 3593742. DOI: 10.1016/j.ejphar.2013.01.016. View