Granulocyte-colony stimulating factor controls neural and behavioral plasticity in response to cocaine

Calipari, Erin S.; Godino, Arthur; Peck, Emily G.; Salery, Marine; Mervosh, Nicholas L.; Landry, Joseph A.; Russo, Scott J.; Hurd, Yasmin L.; Nestler, Eric J.; Kiraly, Drew D.

doi:10.1038/s41467-017-01881-x

Cited by 225 publications

(172 citation statements)

References 66 publications

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“…anti-inflammatory; pro-inflammatory IL-1b drives increased behavioral response to cocaine and opioids (Hutchinson et al, 2012;Northcutt et al, 2015) while pro-inflammatory TNF-⍺ inhibits response to cocaine (Lewitus et al, 2016). Additionally, anti-inflammatory IL-10 reduces behavioral response for opioids (Lacagnina et al, 2017a) while G-CSF, which is primarily anti-inflammatory, enhances behavioral responses to cocaine (Calipari et al, 2018).…”

Section: Resultsmentioning

confidence: 99%

“…These immune mediators are expressed by, and have receptors on, myriad cell types in the brain and can have diverse and complex effects on plasticity and behavior that are only beginning to be understood (Wohleb et al ., ; Peineau et al ., ). Recently, our group identified granulocyte colony‐stimulating factor (G‐CSF) as a cytokine upregulated in both serum and brain after prolonged cocaine administration (Calipari et al ., ). Interestingly, G‐CSF treatment lead to increased neuronal activation in the NAc and prefrontal cortex after an acute cocaine injection.…”

Section: Inflammation and Psychostimulantsmentioning

confidence: 97%

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Neuroimmune mechanisms of psychostimulant and opioid use disorders

Hofford

Russo

Kiraly

2018

Eur J of Neuroscience

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Substance use disorders are global health problems with few effective treatment options. Unfortunately, most potential pharmacological treatments are hindered by abuse potential of their own, limited efficacy, or adverse side effects. As a consequence, there is a pressing need for the development of addiction treatments with limited abuse potential and fewer off target effects. Given the difficulties in developing new pharmacotherapies for substance use disorders, there has been growing interest in medications that act on non-traditional targets. Recent evidence suggests a role for dysregulated immune signaling in the pathophysiology of multiple psychiatric diseases. While there is evidence that immune responses in the periphery and the central nervous system are altered by exposure to drugs of abuse, the contributions of neuroimmune interactions to addictive behaviors are just beginning to be appreciated. In this review, we discuss the data on immunological changes seen in clinical populations with substance use disorders, as well as in translational animal models of addiction. Importantly, we highlight those mechanistic findings showing causal roles for central or peripheral immune mediators in substance use disorder and appropriate animal models. Based on the literature reviewed here, it is clear that brain-immune system interactions in substance use disorders are much more complex and important than previously understood. While much work remains to be done, there are tremendous potential therapeutic implications for immunomodulatory treatments in substance use disorders.

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Section: Resultsmentioning

confidence: 99%

Section: Inflammation and Psychostimulantsmentioning

confidence: 97%

Neuroimmune mechanisms of psychostimulant and opioid use disorders

Hofford

Russo

Kiraly

2018

Eur J of Neuroscience

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“…Conditioned place preference. An unbiased conditioned place preference assay was carried out in male mice as described previously (Calipari et al, 2018) using three conditioning sessions with a dose of 10 mg/kg, i.p., cocaine.…”

Section: Methodsmentioning

confidence: 99%

“…Microinfusion experiments. Mice were surgically implanted with bilateral guide cannula (Plastics One) as described previously (Calipari et al, 2018). The following coordinates were used to target the NAc bilaterally: from bregma, anteroposterior ϩ1.5 mm, mediolateral ϩ1.0 mm, and dorsoventral Ϫ4.3 mm.…”

Section: Methodsmentioning

confidence: 99%

Synaptic Microtubule-Associated Protein EB3 and SRC Phosphorylation Mediate Structural and Behavioral Adaptations During Withdrawal From Cocaine Self-Administration

et al. 2019

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Addictive behaviors, including relapse, are thought to depend in part on long-lasting drug-induced adaptations in dendritic spine signaling and morphology in the nucleus accumbens (NAc). While the influence of activity-dependent actin remodeling in these phenomena has been studied extensively, the role of microtubules and associated proteins remains poorly understood. We report that pharmacological inhibition of microtubule polymerization in the NAc inhibited locomotor sensitization to cocaine and contextual reward learning. We then investigated the roles of microtubule end-binding protein 3 (EB3) and SRC kinase in the neuronal and behavioral responses to volitionally administered cocaine. In synaptoneurosomal fractions from the NAc of self-administering male rats, the phosphorylation of SRC at an activating site was induced after 1 d of withdrawal, while EB3 levels were increased only after 30 d of withdrawal. Blocking SRC phosphorylation during early withdrawal by virally overexpressing SRCIN1, a negative regulator of SRC activity known to interact with EB3, abolished the incubation of cocaine craving in both male and female rats. Conversely, mimicking the EB3 increase observed after prolonged withdrawal increased the motivation to consume cocaine in male rats. In mice, the overexpression of either EB3 or SRCIN1 increased dendritic spine density and altered the spine morphology of NAc medium spiny neurons. Finally, a cocaine challenge after prolonged withdrawal recapitulated most of the synaptic protein expression profiles observed at early withdrawal. These findings suggest that microtubule-associated signaling proteins such as EB3 cooperate with actin remodeling pathways, notably SRC kinase activity, to establish and maintain long-lasting cellular and behavioral alterations following cocaine self-administration. Significance StatementDrug-induced morphological restructuring of dendritic spines of nucleus accumbens neurons is thought to be one of the cellular substrates of long-lasting drug-associated memories. The molecular basis of these persistent changes has remained incompletely understood. Here we implicate for the first time microtubule function in this process, together with key players such as microtubule-bound protein EB3 and synaptic SRC phosphorylation. We propose that microtubule and actin remodeling cooperate during withdrawal to maintain the plastic structural changes initially established by cocaine self-administration. This work opens new translational avenues for further characterization of microtubule-associated regulatory molecules as putative drug targets to tackle relapse to drug taking.

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“…Male 10-week-old GPx-1 KO and WT mice received a single dose of cocaine (60 mg kg −1 body weight) (Miller, Witkin, Ungard, & Gasior, 2000) and GPx-1 TG and non-TG mice received a single dose of cocaine (90 mg kg −1 body weight) (Golden et al, 2001) by intraperitoneal (i.p.) administration as conducted previously (Calipari et al, 2018;Duysen et al, 2008;Frantz, O'Dell, & Parsons, 2007;Wei, Zhang, Egan-Hafley, Liang, & Moore, 2000).…”

Section: Experimental Designmentioning

confidence: 99%

Protective potential of glutathione peroxidase‐1 gene against cocaine‐induced acute hepatotoxic consequences in mice

Nhu

Jung

Kim

et al. 2018

J of Applied Toxicology

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Since the cocaine-induced oxidative stress has been established to lead to hepatotoxicity, we examined the role of the glutathione peroxidase (GPx)-1 gene in cocaine-induced hepatotoxicity. Cocaine treatment significantly increased superoxide dismutase activity in as little as 1 hour, with a maximum level at 6 hours in wild-type mice, while significantly decreasing GPx activity and subsequently inducing oxidative damage (i.e., reactive oxygen species, lipid peroxidation and protein carbonylation). These changes were more prominent in the mitochondrial fraction than in the cytosolic fraction. In contrast, genetic overexpression of GPx-1 significantly attenuated cocaine-induced oxidative damage in mice. Cocaine treatment significantly increased alanine aminotransferase and aspartate aminotransferase levels in the serum. Consistently, cocaine significantly enhanced cleaved caspase-3 expression and intramitochondrial Ca , while significantly reducing mitochondrial transmembrane potential. Cocaine treatment potentiated cleavage of protein kinase C δ (PKCδ), mitochondrial translocation of PKCδ, cytosolic release of cytochrome c and activation of caspase-3, followed by hepatopathologic changes. These results were more prominent in GPx-1 knockout than in wild-type mice, and they were less pronounced in overexpressing transgenic than in non-transgenic mice. Combined, our results suggest that the GPx-1 gene possesses protective potential against mitochondrial oxidative burden, mitochondrial dysfunction and hepatic degeneration induced by cocaine and that the protective mechanisms are associated with anti-apoptotic activity via inactivation of PKCδ.

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Granulocyte-colony stimulating factor controls neural and behavioral plasticity in response to cocaine

Cited by 225 publications

References 66 publications

Neuroimmune mechanisms of psychostimulant and opioid use disorders

Neuroimmune mechanisms of psychostimulant and opioid use disorders

Synaptic Microtubule-Associated Protein EB3 and SRC Phosphorylation Mediate Structural and Behavioral Adaptations During Withdrawal From Cocaine Self-Administration

Protective potential of glutathione peroxidase‐1 gene against cocaine‐induced acute hepatotoxic consequences in mice

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