Glial modulators as potential treatments of psychostimulant abuse - PubMed (original) (raw)

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Glial modulators as potential treatments of psychostimulant abuse

Patrick M Beardsley et al. Adv Pharmacol. 2014.

Abstract

Glia (including astrocytes, microglia, and oligodendrocytes), which constitute the majority of cells in the brain, have many of the same receptors as neurons, secrete neurotransmitters and neurotrophic and neuroinflammatory factors, control clearance of neurotransmitters from synaptic clefts, and are intimately involved in synaptic plasticity. Despite their prevalence and spectrum of functions, appreciation of their potential general importance has been elusive since their identification in the mid-1800s, and only relatively recently have they been gaining their due respect. This development of appreciation has been nurtured by the growing awareness that drugs of abuse, including the psychostimulants, affect glial activity, and glial activity, in turn, has been found to modulate the effects of the psychostimulants. This developing awareness has begun to illuminate novel pharmacotherapeutic targets for treating psychostimulant abuse, for which targeting more conventional neuronal targets has not yet resulted in a single, approved medication. In this chapter, we discuss the molecular pharmacology, physiology, and functional relationships that the glia have especially in the light in which they present themselves as targets for pharmacotherapeutics intended to treat psychostimulant abuse disorders. We then review a cross section of preclinical studies that have manipulated glial processes whose behavioral effects have been supportive of considering the glia as drug targets for psychostimulant-abuse medications. We then close with comments regarding the current clinical evaluation of relevant compounds for treating psychostimulant abuse, as well as the likelihood of future prospects.

Keywords: Astroglia; Cocaine; Glia; Medication; Methamphetamine; Microglia.

© 2014 Elsevier Inc. All rights reserved.

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Conflict of interest statement

Conflict of Interest Statement: The authors have no conflicts of interest to declare.

Figures

Figure 1

Figure 1

Psychostimulants increase synaptic damage through direct actions on neurons and glia including both microglia and astroglia. Psychostimulants damage presynaptic terminals of neurons causing the production of reactive oxygen (ROS) and nitrogen (species), and the production of damage-associated molecular patterns (DAMPs) that trigger activation of pattern recognition receptors (PRRs), including Toll-like receptors (TLRs), NOD-like receptors (NLRs) and other PRRs associated with microglia, and to a lesser extent astroglia. Dopaminergic neurons are particularly vulnerable to methamphetamine, which disrupts dopamine transporter (DAT) and vesicular monoamine transporter 1 (VMAT2) function. Importantly, psychostimulants disrupt glial function directly by increasing intracellular Ca2+ concentration ([Ca2+]i), NF-κB transcriptional activity, and by activating sigma1-receptors (sigma1-R) and enzyme systems driving oxidative and nitrosative stress especially in microglia (and other cell types). Increases in NF-κB transcriptional activity result in the increased production of tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and interleukin-6 (IL-6) (among others) cytokines by microglia and to a lesser degree by astroglia. Psychostimulants also obstruct the buffering of extracellular glutamate by inhibiting excitatory amino acid transporters-1/2 (EAAT1/2) and the conversion of glutamate to glutamine by inhibiting glutamine synthetase, as well as limiting glucose metabolism in astrocytes. Collectively, neuronal damage combined with a heightened state of glial activation promotes positive microglial-astroglial, and neuronal-glial feedback that cause spiraling increases in neuroinflammation and neuronal injury. If unchecked, the cumulative insults result in lasting neurodegenerative changes. Modified and reprinted from reference (Hauser et al., 2012)—an “open access article distributed under the terms of the Creative Commons Attribution License (

http://creativecommons.org/licenses/by/2.5/

), which permits unrestrictive use, distribution, and reproduction in any medium, provided the original work is properly cited.”

Figure 2

Figure 2

Panel A: Results on distance travelled (cm) by mice treated b.i.d. for seven days with ibudilast (IBUD) or its vehicle (VEH1), beginning two days before five days of treatment with 3 mg/kg methamphetamine. Ibudilast was administered at 1.8, 7.5, or 13 mg/kg. Data points represent group means (±S.E.M.) obtained during 1-h experimental sessions. Filled data points represent sessions preceded by 3 mg/kg i.p. methamphetamine injections. Unfilled data points represent sessions preceded by i.p. saline injections. N=8 for each treatment group. *P<0.05 with respect to mice treated with ibudilast's vehicle. Modified and reprinted with permission from reference (Snider et al., 2012). Panel B: Effects of ibudilast or its vehicle on group mean infusions of methamphetamine (0.001, 0.03, and 0.1 mg/kg/inf) obtained during daily 2-h self-administration sessions. Ibudilast was administered at 1, 7.5, or 10 mg/kg i.p. b.i.d. for 3 consecutive days at each methamphetamine self-administered dose. Data points represent the group means of total infusions obtained during the third day of testing at each ibudilast dose. Bars through symbols indicate ±S.E.M. Data point above "S" on the abscissa indicates results when saline was self-administered when ibudilast's vehicle was given b.i.d. N = 4 rats. *p < 0.05 with respect to infusions obtained under ibudilast’s vehicle condition. Modified and reprinted with permission from reference (Snider et al., 2013). Panel C: Mean number of active lever presses during the methamphetamine-prime reinstatement test session as a function of ibudilast dose. Brackets through the bars indicate ±SEM. "VEH" = results of the vehicle-treatment group. Dashed horizontal lines indicate the range of the means of active lever presses across test groups occurring during the last session of extinction. Asterisk (*) indicates significantly different from vehicle (P<0.05). Modified and reprinted with permission from reference (Beardsley et al., 2010). Panel D: Mean number of active lever presses during the footshock-induced reinstatement test session as a function of ibudilast dose. Other details as in Panel C.

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