Adolescent Morphine Exposure Affects Long-Term Microglial Function and Later-Life Relapse Liability in a Model of Addiction

Abstract

Adolescence in humans represents a unique developmental time point associated with increased risk-taking behavior and experimentation with drugs of abuse. We hypothesized that exposure to drugs of abuse during adolescence may increase the risk of addiction in adulthood. To test this, rats were treated with a sub-chronic regimen of morphine or saline in adolescence, and their preference for morphine was examined using conditioned place preference (CPP) and drug-induced reinstatement in adulthood. The initial preference for morphine did not differ between groups; however, rats treated with morphine during adolescence showed robust reinstatement of morphine CPP following drug re-exposure in adulthood. This effect was not seen in rats pre-treated with a sub-chronic regimen of morphine as adults, suggesting that exposure to morphine specifically during adolescence increases the risk of relapse to drug-seeking behavior in adulthood. We have previously established a role for microglia, the immune cells of the brain, and immune molecules in the risk of drug-induced reinstatement of morphine CPP. Thus, we examined the role of microglia within the Nucleus Accumbens (NAcc) of these rats and determined that rats exposed to morphine during adolescence had a significant increase in Toll-like Receptor (TLR) 4 mRNA and protein expression specifically on microglia. Morphine binds to TLR4 directly and this increase in TLR4 was associated with exaggerated morphine-induced TLR4 signaling and microglial activation in rats previously exposed to morphine during adolescence. These data suggest that long-term changes in microglial function, caused by adolescent morphine exposure, alter the risk of drug-induced reinstatement in adulthood.

Evaluation of effect of minocycline on rewarding potential and alcohol relapse in place preference model in mice

“…reward due to alcohol. It is postulated that long-term changes in microglial function are important in relapse of drug seeking behavior [32]. Notably, glial cells are activated by drugs of abuse and morphine-induced pro-inflammatory glial activation alters neuronal excitability and synaptic connectivity, opposes morphine-induced withdrawal, and reward to morphine [21].…”

CC-Chemokine Ligand 2 Facilitates Conditioned Place Preference to Methamphetamine Through the Activation of Dopamine Systems

“…Morphine also upregulates chemokines and activates glial cells in the brain (24), and these activations might be based on CCL2. Psychic dependence on methamphetamine or morphine was attenuated by agents that suppress the activity of microglia and astrocytes, such as minocycline or ibudilast (30,31). We previously reported that behavioral sensitization to methamphetamine was improved by peroxisome proliferator-activated receptorg agonists, being suppressive agents for inflammatory macrophages and microglia (32).…”

The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis

“…Systemic administration of ibudilast inhibits ethanol (Bell et al, 2015) and methamphetamine intake (Snider et al, 2013), sensitization of the locomotor response to methamphetamine (Snider et al, 2012), as well as stress-and drug-primed reinstatement of methamphetamine seeking (Beardsley et al, 2010). Ibudilast also reduces morphine withdrawal and CPP, likely as a result of its ability to reduce morphine-induced dopamine release in the NAc (Rolan et al, 2009;Schwarz and Bilbo, 2013). Although ibudilast treatment has a variety of effects that could be beneficial in the pharmacological treatment of addiction, it has yet to be determined whether inhibition of PDE activity, inflammation, or neurotrophic factor release is responsible for its effects on the inhibition of drugseeking and drug-related behaviors.…”