Nalmefene alleviates the neuroimmune response to repeated binge‐like ethanol exposure: A TSPO PET imaging study in adolescent rats

Abstract

A large body of preclinical research has shown that neuroimmunity plays a key role in the deleterious effects of alcohol (ethanol) to the brain. Translational imaging techniques are needed to monitor the efficacy of strategies to prevent or mitigate neuroinflammation and alleviate ethanol‐induced neurotoxicity. Opioid receptor antagonists such as nalmefene are antagonists of the toll‐like receptor 4, which may block the proinflammatory signaling cascade induced by ethanol at this specific target. Male adolescent rats received a validated protocol of ethanol injection (i.p, 3 g/kg daily for two consecutive days followed by two resting days) during 14 days. Positron emission tomography (PET) imaging with the translocator protein 18 kDa (TSPO) radioligand [18F]DPA‐714 was performed at day‐15. Toxicity induced by repeated binge‐like ethanol exposure (71% mortality) was drastically reduced by nalmefene pretreatment (0.4 mg/kg, 14% mortality). No mortality was observed in animals that received vehicle (control) or nalmefene alone. Compared with control animals (n = 10), a significant 2.8‐fold to 4.6‐fold increase in the volume of distribution (VT) of [18F]DPA‐714 was observed among brain regions in animals exposed to ethanol only (n = 9). Pretreatment with nalmefene significantly alleviated the neuroimmune response to ethanol exposure in all brain regions (1.2‐fold to 2.5‐fold increase in VT; n = 5). Nalmefene alone (n = 6) did not impact [18F]DPA‐714 VT compared with the control group. Nalmefene may protect against the neuroinflammatory response and overall toxicity associated with binge drinking. [18F]DPA‐714 PET imaging can be used to noninvasively address the neuroimmune impact of ethanol exposure and its modulation by pharmacological strategies in vivo, with translational perspectives.

Acute and Chronic Ethanol Effects during Adolescence on Neuroimmune Responses: Consequences and Potential Pharmacologic Interventions

“…Furthermore, using in vitro primary cultured astrocytes from female C57BL/6 mice and TLR4 knockout mice, their findings indicated that nalmefene can perturb TLR4 activation succeeding ethanol induction [76]. Additionally, nalmefene pre-treatment in a chronic alcohol exposure rat model system reduced TSPO in a PET imaging study, showing a significant decrease in alcohol-induced neuroimmune responses in all brain regions [77]. Similar findings have been observed with naltrexone.…”

Primed for addiction: A critical review of the role of microglia in the neurodevelopmental consequences of adolescent alcohol drinking

“…In adolescent models of alcohol misuse, morphological changes and increased cell surface marker expression signifying microglial activation are consistent, but the activation phenotype is not clear. As detailed in Table 1, increased binding of translocator protein 18 kD ligands using PET imaging was observed after EtOH exposure in adolescent nonhuman primates and rats, indicating microglial activation but not phenotype specificity (Marshall et al, 2013; Saba et al, 2018; Tournier et al, 2020). Increased immunoreactivity or immunopositive (+) cell numbers using Iba1, the calcium binding protein specific to microglia, are observed in regions such as the cortex, hippocampus, amygdala, and substantia nigra in multiple adolescent rat alcohol models (Table 1).…”

“…While there is evidence for differential sensitivity to alcohol‐induced neuroadaptations in the mesolimbic system in adolescents versus adults (Alaux‐Cantin et al, 2013; Jacobsen et al, 2018; Liu & Crews, 2015; Nees et al, 2015), how microglia influence these changes is difficult to disentangle from the few neuroimmune effects reported. For example, nalmefene, an opioid receptor and TLR4 antagonist approved for reduction in alcohol consumption in patients with AUD, reduced microglial activation and other neuroimmune effects in the striatum and NAc, but astrocytes may be the site of action (Montesinos et al, 2017; Tournier et al, 2020). A role for BDNF has been described in reward processing in adolescents, with specific gene polymorphisms differentially impacting reward processing and striatal function and associated with adolescent drinking onset (Nees et al, 2015).…”