Regional elevations in microglial activation and cerebral glucose utilization in frontal white matter tracts of rhesus monkeys following prolonged cocaine self-administration

Abstract

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-[ 14 C]deoxyglucose intravenously and 45 min later euthanized. Brain sections were used for autoradiographic assessments of glucose utilization and for microglia activation with [ 3 H]PK11195, a marker for the microglial18kda translocator protein. There were no group differences in gray matter [ 3 H]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 [ 3 H]PK11195 binding. The present findings demonstrate an elevation in [ 3 H]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.

Neurite orientation dispersion and density imaging in cocaine use disorder

“…These changes could be caused by genetic polymorphisms associated with different neurotransmitters that are implicated in drug consumption, previously described as a possible cause for WM changes (Azadeh et al, 2016). Cocaine consumption mediates microglial activation inducing inflammatory responses which may enhance the synaptic dopamine or glutamate concentrations, as reported in striatum of murine models (Burkovetskaya et al, 2020) and in white matter tracts in non-human primates brains, thus, contributing to the behavioral, cognitive and brain structural deficits (Smith et al, 2019).…”

Role of Microglia in Psychostimulant Addiction

“…In non-human primates, striatal sections from monkeys subjected to the cocaine self-administration paradigm for approximately 15 months presented a greater binding of [3H]PK11195 - a marker for the microglial 18-kDa translocator protein (TSPO) in the autoradiography [ 121 ]. A study that evaluated cocaine users during abstinence did not observe any alteration in TSPO, as assessed by the PET imaging with [11C]PBR28 [ 122 ].…”

Neurocognitive correlates of psychostimulant use.

“…There are alternative hypotheses as to the mechanisms underlying neurocognitive decrements in people who use cocaine. For instance, it has been proposed that lowered neurocognitive function may be related to oxidative stress associated with accumulation of extracellular dopamine (Hirsiger et al, 2019) or that chronic neuroinflammatory responses associated with repeated cocaine use may produce white matter degeneration, potentially contributing to cognitive declines (H. R. Smith et al, 2019). To date, evidence does not suggest that cocaine produces clear neurotoxic effects that could result in neuropsychological issues.…”