Advances in Psychology and Neuroscience
Volume 2, Issue 2-1, March 2017, Pages: 38-41

Glia and Addiction: A Review

Alhassan Abdulwahab1, Sale Ibrahim Alhaji1, Lawan Ibrahim2, Uthman Garba Sadiq3

1Department of Human Physiology, Faculty of Medicine, Ahmadu Bello University, Zaria, Nigeria

2Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Ahmadu Bello University, Zaria, Nigeria

3Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Maiduguri, Maiduguri, Nigeria

Email address:

(A. Abdulwahab)
(S. I. Alhaji)
(L. Ibrahim)
(U. G. Sadiq)

To cite this article:

Alhassan Abdulwahab, Sale Ibrahim Alhaji, Lawan Ibrahim, Uthman Garba Sadiq. Glia and Addiction: A Review. Advances in Psychology and Neuroscience. Special Issue: Substance Abuse: Perspectives, Trends, Issues and the Way Forward. Vol. 2, No. 2-1, 2017, pp. 38-41.

Received: November 14, 2016; Accepted: November 19, 2016; Published: February 14, 2017

Abstract: Glia (including astrocytes, microglia and oligodendrocytes), which constitute the majority of cells in the brain were thought to function as passive supportive cells, bringing nutrients to and removing wastes from the neurons. Glia cells have almost the same receptors as neurons, secrete neurotransmitters, neurotrophic and neuroinflammatory factors and are intimately involved in synaptic plasticity. Glia has been found to have multiple functions in eventually all systems of the body (CNS, CVS, GIT etc) Considering the multiple functions of glia, and because glia are the most numerous cells in the brain, it is not surprising that psychostimulants affect their activity. Thus, this review is focused on works done to reveal the important roles played by glia in addiction and the possibility of manipulating the activity of glia as a target in the development of pharmacotherapeutic agents for treating disorders related to psychostimulants.

Keywords: Glia, Astroglia, Microglia, Oligodendrocytes, Addiction

1. Introduction

Drug addiction is manifested by compulsive drive to take licit or illicit substances despite repeated severe adverse consequences [1]. Drug addiction is one of the major medical, social and economic burdens of human behavior. Glial cells constitute the majority of cells in the brain [2]. Glia includes; astrocytes which support neurons and their environment, oligodendrodytes that myelinate neurons and speed up the transmission of signals between them and microglia which act as the immune cell of the brain, clean up debris and provide local surveillance in the nervous system [3]. Although these cell types have generally been viewed as supportive cells, secondary to the neurons of the brain, research in the past few decades has started to shine some new light on these underrated elements, indicating that these cells participate in a variety of complex processes important for proper brain function. These three major glial cell types in the brain, communicate with each other and with neurons by using neurotransmitters, other small molecules, and gap junctions [4]. Glia contain receptors, secrete neurotransmitters, neurotrophic and neuroinflammatory factors [5,6], control clearance of neurotransmitters from synaptic clefts [7] and are involved with synaptic plasticity [8]. Neurotransmitter transporters such as glutamate, dopamine and receptors for drugs of abuse are also localized on astrocytes and microglial cells, so it is expected that substance abuse may disrupt glial function in ways that subsequently alter neuronal function and communication. Given their prevalence, and their multiple modes of controlling neurological functionality, it is not surprising that glia and their secreted products have been reported to modulate, and be modulated by, the drugs of abuse including psychostimulants [9-11]. Glial transmission has been found to be necessary for reinstatement of drug-seeking behaviors triggered by cocaine [12].

Figure 1. Cells known as glia (Greek for "glue") were long believed to provide nothing more than support to nerve cells. [13].

These diverse features of glial cells suggest that alterations in the morphology and physiology of glial cells in brain areas critical for the manifestation of addictive behaviors, such as the prefrontal cortex, nucleus accumbens (NAcc), ventral tegmental area (VTA), amygdala or hippocampus may contribute to the vulnerability to initiate and persist in drug addiction. Gliosis and inflammatory responses are significant pathological features of substance use disorders [14].

2. Microglia

Reactive microgliosis has been detected in several regions of the brains of methamphetamine addicts who had been abstinent for several years [15]. Microglia prune synapses in part by monitoring synaptic transmission [16]. Microglial cells also display receptors to neuropeptides, neurotransmitters and transmitters released by astrocytes [17,18]. Cannabinoid receptors are expressed by microglia [19,20]. Methamphetamine administration to rats at doses that induce dependence causes activation of microglial cells in the striatum. Since the activation of microglia follows a course similar to the neurotoxicity caused by METH, it has been suggested that METH neurotoxicity might be at least in part mediated by the METH-activated microglia [21,22]. Evidence suggests that methamphetamine-induced damage to dopamine neuron terminals is associated with microglial activation [23]. Chronic ethanol intake in rats results in the appearance of microglial cells with aberrant morphologies in the hippocampus that clears out after withdrawal from alcohol [24]. Methamphetamine and cocaine directly affect microglia through actions at sigma1-receptors which are associated with the membrane of the endoplasmic reticulum [25]. Sigma1-receptors are one of several putative molecular targets of methamphetamine [26]. and cocaine [27,28]. In the brain, microglial cells are the main cause of neuroinflammatory responses due to drugs [29].

3. Astrocytes

Astrocytes are the most abundant glial cell type in the central nervous system [30]. An essential function of astrocytes is in the reuptake and management of glutamate released by neurons during synaptic activity [31,32] and glutamate is involved in learning processes that lead to behaviors of addiction [33,34]. Astrocytes can regulate synaptic transmission between neurons by modifying the concentration of extracellular potassium, controlling local blood flow, by releasing and/or taking up neurotransmitters or neuromodulators, by delivering nutrients to neurons, and by altering the geometry and volume of the brain extracellular space [4]. Cell membranes of astrocytes bear receptors for most neurotransmitters and peptides: glutamate, dopamine, norepinephrine, serotonin, gamma aminobutyric acid, acetylcholine and opioid peptides [11]. It is not surprising then that many drugs can affect astrocytic physiology not only directly but also through alterations in the release of neurochemicals from surrounding neurons. These characteristics of astrocytes suggest that altering their functions in reward circuits may contribute to drug addiction. Research has shown that the control of glutamate uptake and the release of neurotrophic factors by astrocytes influences behaviors of addiction and may play modulatory roles in psychostimulant, opiate, and alcohol abuse. Administration of cocaine, amphetamines and most psychostimulants induces activation of astrocytes [35,36] This activation is defined by an increase in the expression of glial fibrillary acidic protein (GFAP), a main component of the cytoskeleton of astrocytes. In rats chronically exposed to alcohol, astrocytes increase the expression of GFAP in the first few weeks while longer exposure result in decrease in the expression of GFAP [37]. Chronic treatment with morphine also results in increased GFAP expression or enlarged astrocytes in ventral tegmental area(VTA), nucleus accumbens (NAcc), frontal cortex, locus coeruleus and nucleus of the solitary tract of the rat [38,39]. Tolerance to morphine has been also related to downregulation of glial glutamate transporters GLT-1 and GLAST in the spinal cord [40] suggesting a link between structural and functional features of astrocytes involved in tolerance to morphine. A participation of glutamate transport in alcohol addiction is also supported by the work of [41]. According to [42,43] glutamate is highly involved in learning behaviors associated with addiction. Because of their essential role in managing glutamate, understanding the neurobiological consequences of psychostimulants in astrocytes is likely to reveal significant mechanisms of action.

4. Oligodendrocytes

Oligodendrocytes increase the speed of electrical transmission through nerve axons by forming the axonal myelin sheath and clustering ion channels at nodes of Ranvier [44]. At present, there is very little information available on the potential effects of drugs of abuse on oligodendrocytes. They have been minimally explored in the context of psychostimulant abuse. Oligodendrocytes are very sensitive to the exposure to ethanol, even more than astrocytes and neurons, and that the effects of ethanol almost always result in increased likelihood of oligodendrocyte or myelin degeneration [37]. Oligodendrocyte numbers [45] and myelin [46] are reduced following cocaine exposure in rats.

5. Conclusion

This mini review on glia and addiction has shown that, these cells might play important roles in the long-term manifestations of substance use disorders, both in terms of addiction to these agents and their long term neuropsychiatric consequences. It has also shown that understanding the numerous functions of glia other than supporting cells is growing and the possibility of developing anti-addiction therapies based on the regulation of growth factor expression in glial cells much better.


  1. Volkow, N. D., Wang, G.-J., Fowler, J. S., and Tomasi, D. (2012). Addiction circuitry in the human brain. Annu. Rev. Pharmacol. Toxicol. 52, 321–336.
  2. Sherwood CC, Stimpson CD, Raghanti MA, Wildman DE, Uddin M, Grossman LI, Goodman M, Redmond JC, Bonar CJ, Erwin JM, Hof PR (2006). Evolution of increased glia-neuron ratios in the human frontal cortex. Proc Natl Acad Sci U S A. 103(37):13606–13611.
  3. Kettenmann H, Kirchhoff F, and Verkhratsky A. (2013). Microglia: new roles for the synaptic strippe. Neuron, 77(1):10-8.
  4. Araque, A., Carmignoto, G., Haydon, P. G., Oliet, S. H., Robitaille, R., and Volterra, A. (2014). Gliotransmitters travel in time and space. Neuron 81, 728–739.
  5. Benz B, Grima G, Do KQ.(2004). Glutamate-induced homocysteic acid release from astrocytes: possible implication in glia-neuron signaling. Neuroscience. 124(2):377–386.
  6. Watkins LR, Hutchinson MR, Ledeboer A, Wieseler-Frank J, Milligan ED, Maier SF. Norman.
  7. Camacho A, Massieu L. Role of glutamate transporters in the clearance and release of glutamate during ischemia and its relation to neuronal death. Arch Med Res. 2006; 37(1):11–18.
  8. Ullian EM, Christopherson KS, Barres BA. Role for glia in synaptogenesis(2004). Glia; 47 (3):209–216.
  9. Clark KH, Wiley CA, Bradberry CW(2013). Psychostimulant abuse and neuroinflammation: emerging evidence of their interconnection. Neurotox. Res. 23(2):174–188.
  10. Jones RS, Minogue AM, Connor TJ, Lynch MA. ((2013). Amyloid-beta-induced astrocytic phagocytosis is mediated by CD36, CD47 and RAGE. J Neuroimmune. Pharmacol. 8(1):301–311
  11. Haydon PG, Carmignoto G.(2006). Astrocyte control of synaptic transmission and neurovascular coupling. Physiol Rev 86(3): 1009-31.
  12. Turner, J. R., Ecke, L. E., Briand, L. A., Haydon, P. G., and Blendy, J. A. (2013). Cocaine-related behaviors in mice with deficient gliotransmission. Psychopharmacology (Berl) 226, 167–176.
  13. Tsunneko Mishima and Hajime Hirase (2010). In Vivo Intracellular Recording Suggests That Gray Matter Astrocytes in Mature Cerebral Cortex and Hippocampus Are Electrophysiologically Homogeneous. The Journal of Neuroscience 30 (8): 3093-3100.
  14. Cadet, J. L., Bisagno, V., and Milroy, C. M. (2014). Neuropathology of substance use disorders. Acta Neuropathol. 127, 91–107.
  15. Sekine Y, Ouchi Y, Sugihara G, Takei N, Yoshikawa E, Nakamura K (2008). Methamphetamine causes microglial activation in the brains of human abusers. J Neurosci. 28(22):5756-5761.
  16. Schafer, D. P., Lehrman, E. K., and Stevens, B. (2013). The "quad-partite" synapse: microgliasynapse interactions in the developing and mature CNS. Glia 61, 24–36.
  17. Noda M, Nakanishi H, Nabekura J, Akaike N (2000) AMPA-kainate subtypes of glutamate receptor in rat cerebral microglia. J Neurosci 20(1): 251-8.
  18. Burnstock G. Historical review: (2006). ATP as a neurotransmitter. Trends Pharmacol Sci 2006; 27(3): 166-76.
  19. Eljaschewitsch, E., Witting, A., Mawrin, C., Lee, T., Schmidt, P.M., Wolf, S., Hoertnagl, H., Raine, C.S., SchneiderStock, R., Nitsch, R., and Ullrich, O. (2006). The endocannabinoid anandamide protects neurons during CNS inflammation by induction of MKP-1 in microglial cells. Neuron 49, 67–79.
  20. Witting, A., Chen, L., Cudaback, E., Straiker, A., Walter, L., Rickman, B., Moller, T., Brosnan, C., and Stella, N. (2006) Experimental autoimmune encephalomyelitis disrupts endocannabinoid-mediated neuroprotection. Proc. Natl. Acad. Sci. U. S. A. 103, 6362–6367.
  21. Thomas DM, Dowgiert J, Geddes TJ, Francescutti-Verbeem D, Liu X, Kuhn DM (2004). Microglial activation is a pharmacologically specific marker for the neurotoxic amphetamines. Neurosci Lett; 367(3): 349-54.
  22. Thomas DM, Walker PD, Benjamins JA, Geddes TJ, Kuhn DM (2004). Methamphetamine neurotoxicity in dopamine nerve endings of the striatum is associated with microglial activation. J Pharmacol Exp Ther 311(1): 1-7.
  23. Kuhn, D.M., Francescutti-Verbeem, D.M., and Thomas, D.M. (2006) Dopamine quinones activate microglia and induce a neurotoxic gene expression profile: relationship to methamphetamine-induced nerve ending damage. Ann. N. Y. Acad. Sci. 1074, 31–41.
  24. Kalehua A, Streit WJ, Walker DW, Hunter BE(1992). Chronic ethanol treatment promotes aberrant microglial morphology in area CA1 of the rat hippocampus. Alcohol Clin Exp Res. 16(2): 401
  25. Hayashi T, Su TP. (2007). Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival. Cell. 131(3):596–610.
  26. Kaushal N, Matsumoto RR.(2011)Role of sigma receptors in methamphetamine-induced neurotoxicity. Curr. Neuropharmacol. 9(1):54–57.
  27. Katz JL, Su TP, Hiranita T, Hayashi T, Tanda G, Kopajtic T (2011). A Role for Sigma Receptors in Stimulant Self Administration and Addiction. Pharmaceuticals; 4(6):880–914.
  28. Kourrich S, Hayashi T, Chuang JY, Tsai SY, Su TP, Bonci A (2013). Dynamic interaction between sigma-1 receptor and Kv1.2 shapes neuronal and behavioral responses to cocaine. Cell. 152(1–2): 236–247.
  29. Jeong, H. K., Ji, K., Min, K., and Joe, E. H. (2013). Brain inflammation and microglia: facts and misconceptions. Exp. Neurobiol. 22, 59–67.
  30. Pope A. Neuroglia: Quantitative aspects. In: Schoffeniels E, Franck G, Hertz L, Tower DB (1978). Dynamic Properties of Glia Cells. London: Pergamon, p. 13-20.
  31. Hertz L, Zielke HR(2004). Astrocytic control of glutamatergic activity: astrocytes as stars of the show. Trends Neurosci: 27(12): 735-43.
  32. Boileau I, Rusjan P, Houle S, Wilkins D, Tong J, Selby P (2008). Increased vesicular monoamine transporter binding during early abstinence in human methamphetamine users: Is VMAT2 a stable dopamine neuron biomarker? J Neurosci. 2008; 28(39):9850–9856.
  33. Hyman SE.(2005). Addiction: a disease of learning and memory. Am J Psychiatry; 162(8): 1414-22.
  34. Kalivas PW.(2003). Glutamate systems in cocaine addiction. Curr Opin Pharmacol 4(1): 23-29.
  35. Itzhak Y, Achat-Mendes C. (2004). Methamphetamine and MDMA (ecstasy) neurotoxicity: 'of mice and men'. IUBMB Life 56(5): 249-55.
  36. Hebert MA, O'Callaghan JP. (2000). Protein phosphorylation cascades associated with methamphetamine-induced glial activation. Ann N Y Acad Sci: 914: 238-62.
  37. Snyder, A (1996) Responses of Glia to Alcohol. In: Aschner N, Kimelberg H, Eds. The Role of Glia in Neurotoxicity. Boca Raton: CRC Press; pp. 111-135.
  38. Marie-Claire C, Courtin C, Roques BP, Noble F (2004). Cytoskeletal genes regulation by chronic morphine treatment in rat striatum. Neuropsychopharmacology 29(12): 2208 -2215.
  39. Alonso E, Garrido E, Diez-Fernandez C (2007). Yohimbine prevents morphine-induced changes of glial fibrillary acidic protein in brainstem and alpha2-adrenoceptor gene expression in hippocampus. Neurosci Lett: 412(2): 163-7.
  40. Mao J, Sung B, Ji RR, Lim G (2002). Chronic morphine induces downregulation of spinal glutamate transporters: implications in morphine tolerance and abnormal pain sensitivity. J Neurosci 22(18): 8312-8323.
  41. Melendez RI, Hicks MP, Cagle SS, Kalivas PW (2005). Ethanol exposure decreases glutamate uptake in the nucleus accumbens. Alcohol Clin Exp Res: 29(3): 326-33.
  42. Kalivas PW, Volkow ND.(2011) New medications for drug addiction hiding in glutamatergic neuroplasticity. Mol. Psychiatry. 16(10):974–986.
  43. Stuber GD, Britt JP, Bonci A (2012). Optogenetic modulation of neural circuits that underlie reward seeking. Biol.Psychiatry: 71(12):1061–1067.
  44. Nave, K. A. (2010). Myelination and support of axonal integrity by glia. Nature 468, 244–252.
  45. George, O., Mandyam, C. D., Wee, S., and Koob, G. F. (2008). Extended access to cocaine selfadministration produces long-lasting prefrontal cortex-dependent working memory impairments. Neuropsychopharmacology 33, 2474–2482.
  46. Kovalevich, J., Corley, G., Yen, W., Rawls, S. M., and Langford, D. (2012). Cocaine-induced loss of white matter proteins in the adult mouse nucleus accumbens is attenuated by administration of a β-lactam antibiotic during cocaine withdrawal. Am. J. Pathol. 181, 1921–1927.

Article Tools
Follow on us
Science Publishing Group
NEW YORK, NY 10018
Tel: (001)347-688-8931