Regional elevations in microglial activation and cerebral glucose utilization in frontal white matter tracts of rhesus monkeys following prolonged cocaine self-administration
It has been shown that exposure to cocaine can result in neuroinflammatory responses. Microglia, the resident CNS immune cells, undergo a transition to an activated state when challenged. In rodents, and possibly humans, cocaine exposure activates microglia. The goal of this study was to assess the extent and magnitude of microglial activation in rhesus monkeys with an extensive history of cocaine self-administration. Male rhesus monkeys (N = 4/group) were trained to respond on a fixed-interval 3-min schedule of food or 0.3 mg/kg/injection cocaine presentation (30 reinforcers/session) for 300 sessions. At the end of the final session, monkeys were administered 2-[14C]deoxyglucose intravenously and 45 min later euthanized. Brain sections were used for autoradiographic assessments of glucose utilization and for microglia activation with [3H]PK11195, a marker for the microglial 18-kDa translocator protein. There were no group differences in gray matter [3H]PK11195 binding, while binding was significantly greater in cocaine self-administration animals as compared to food controls in 8 of the 11 white matter tracts measured at the striatal level. Binding did not differ from control at other levels. There were also significant increases in white matter local cerebral glucose utilization at the striatal level, which were positively correlated with [3H]PK11195 binding. The present findings demonstrate an elevation in [3H]PK11195 binding in forebrain white matter tracts of nonhuman primates with a prolonged history of cocaine self-administration. These elevations were also associated with greater cerebral metabolic rates. These data suggest that white matter deficits may contribute to behavioral, motivational, and cognitive impairments observed in cocaine abusers.
KeywordsCocaine Self-administration Microglia Neuroinflammation Rhesus monkey Local cerebral glucose utilization
Funding for this study was provided by the National Institute of Drug Abuse Grant nos. DA09085 and DA06634. The authors wish to thank Tonya Calhoun for her excellent technical assistance.
Compliance with ethical standards
Conflict of interest
The authors declare they have no conflicts of interest.
All applicable international, national, and institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution at which the studies were conducted.
- Colonna M, Butovsky O (2017) Microglia function in the central nervous system during health and neurodegeneration. Annu Rev Immunol 35:441–468. https://doi.org/10.1146/annurev-immunol-051116-052358 CrossRefGoogle Scholar
- Glushakova OY, Johnson D, Hayes RL (2014) Delayed increases in microvascular pathology after experimental traumatic brain injury are associated with prolonged inflammation, blood-brain barrier disruption, and progressive white matter damage. J Neurotrauma 31:1180–1193. https://doi.org/10.1089/neu.2013.3080 CrossRefGoogle Scholar
- Kovalevich J, Corley G, Yen W, Rawls SM, Langford D (2012) Cocaine-induced loss of white matter proteins in the adult mouse nucleus accumbens is attenuated by administration of a beta-lactam antibiotic during cocaine withdrawal. Am J Pathol 181:1921–1927. https://doi.org/10.1016/j.ajpath.2012.08.013 CrossRefGoogle Scholar
- Levandowski ML, Viola TW, Prado CH, Wieck A, Bauer ME, Brietzke E, Grassi-Oliveira R (2016b) Distinct behavioral and immunoendocrine parameters during crack cocaine abstinence in women reporting childhood abuse and neglect. Drug Alcohol Depend 167:140–148. https://doi.org/10.1016/j.drugalcdep.2016.08.010 CrossRefGoogle Scholar
- Moeller FG, Hasan KM, Steinberg JL et al (2005) Reduced anterior corpus callosum white matter integrity is related to increased impulsivity and reduced discriminability in cocaine-dependent subjects: diffusion tensor imaging. Neuropsychopharmacology 30:610–617. https://doi.org/10.1038/sj.npp.1300617 CrossRefGoogle Scholar
- Myers R, Manjil LG, Cullen BM, Price GW, Frackowiak RS, Cremer JE (1991) Macrophage and astrocyte populations in relation to [3H]PK 11195 binding in rat cerebral cortex following a local ischaemic lesion. J Cereb Blood Flow Metab 11:314–322. https://doi.org/10.1038/jcbfm.1991.64 CrossRefGoogle Scholar
- Narayana PA, Herrera JJ, Bockhorst KH, Esparza-Coss E, Xia Y, Steinberg JL, Moeller FG (2014) Chronic cocaine administration causes extensive white matter damage in brain: diffusion tensor imaging and immunohistochemistry studies. Psychiatry Res 221:220–230. https://doi.org/10.1016/j.pscychresns.2014.01.005 CrossRefGoogle Scholar
- Narendran R, Ahobila-Vajjula P, Ramu J et al (2014) Cocaine abuse in humans is not associated with increased microglial activation: an 18-kDa translocator protein positron emission tomography imaging study with [11C]PBR28. J Neurosci 34:9945–9950. https://doi.org/10.1523/JNEUROSCI.0928-14.2014 CrossRefGoogle Scholar
- Paxinos G, Huang XF, Toga AW (2000) The rhesus monkey brain in stereotaxic coordinates. Academic Press, San DiegoGoogle Scholar
- Raghavendra Rao VL, Dogan A, Bowen KK, Dempsey RJ (2000) Traumatic brain injury leads to increased expression of peripheral-type benzodiazepine receptors, neuronal death, and activation of astrocytes and microglia in rat thalamus. Exp Neurol 161:102–114. https://doi.org/10.1006/exnr.1999.7269 CrossRefGoogle Scholar
- Schroeter M, Dennin MA, Walberer M, Backes H, Neumaier B, Fink GR, Graf R (2009) Neuroinflammation extends brain tissue at risk to vital peri-infarct tissue: a double tracer [11C]PK11195- and [18F]FDG-PET study. J Cereb Blood Flow Metab 29:1216–1225. https://doi.org/10.1038/jcbfm.2009.36 CrossRefGoogle Scholar
- Suda S, Shinohara M, Miyaoka M, Lucignani G, Kennedy C, Sokoloff L (1990) The lumped constant of the deoxyglucose method in hypoglycemia: effects of moderate hypoglycemia on local cerebral glucose utilization in the rat. J Cereb Blood Flow Metab 10:499–509. https://doi.org/10.1038/jcbfm.1990.92 CrossRefGoogle Scholar
- Vallender EJ, Goswami DB, Shinday NM, Westmoreland SV, Yao WD, Rowlett JK (2017) Transcriptomic profiling of the ventral tegmental area and nucleus accumbens in rhesus macaques following long-term cocaine self-administration. Drug Alcohol Depend 175:9–23. https://doi.org/10.1016/j.drugalcdep.2017.01.030 CrossRefGoogle Scholar