Stress- and Glucocorticoid-Induced Priming of Neuroinflammatory Responses: Potential Mechanisms of Stress-Induced Vulnerability to Drugs of Abuse

“Interestingly, TLR signaling, in particular TLR2 and TLR4, has been co-opted by endogenous signaling molecules which are thought to alert microglia to a variety of internal conditions such as cellular stress, damage or death (Kawai and Akira, 2010).”

“…of the innate immune system recognize microbial products via a relatively small number (roughly 30) of germ line-encoded receptors that recognize general molecular patterns that characterize different classes of pathogens (Pathogen Associated Molecular Patterns, PAMPs; Janeway and Medzhitov, 2002).”

“This relationship between major depression and alcohol abuse is of particular relevance in the context of the present review given that stress (Anisman, 2009), GCs (Pariante and Miller, 2001), and inflammatory processes (Dantzer et al., 2008) have been implicated in the etiology of major depression.”

“In the normal healthy CNS, microglia send out processes that sample the local environment at a rate of several times per second (Nimmerjahn et al., 2005) and have been termed ‘‘surveillant’’ microglia (Ransohoff and Cardona, 2010).”

“during an acute stressor is so obviously non-intuitive, several explanations have been offered to support why this might be rational (Munck et al., 1984).”

“Putative alarmins include high mobility group box 1 (HMGB1), S100 proteins, heat shock proteins (HSPs), and hyaluronan (Bianchi, 2007), with HMGB1 having received the most attention to date.”

“TLR4 recognizes the lipopolysaccharide (LPS) motif that is present in the cell membrane of all Gramnegative bacteria, while TLR2 recognizes lipoteichoic acid that characterizes Gram-positive bacteria (Kawai and Akira, 2007).”

“This facilitation of drug reward processes by stress has been the subject of numerous reviews (Briand and Blendy, 2010; Koob, 2009; Sinha, 2008) and need not be reviewed here.”

“The CNS parenchyma shows very low levels of basal MHCII (Ransohoff and Perry, 2009) as well as high-level expression of CD200 (Barclay et al.”

“There has been tremendous interest in the effects of stress and GCs on inflammation since the pioneering reports by Selye (1950) that ‘‘stress’’ produces thymic involution and subsequent findings that ‘‘stress’’ seemed to suppress various aspects of immune function (Selye, 1955).”

“text of the present review given that stress (Anisman, 2009), GCs (Pariante and Miller, 2001), and inflammatory processes (Dantzer”

“They are sometimes reported to be present on astrocytes and sometimes to be absent, and are typically reported to be absent on neurons (Lehnardt et al., 2003).”

“…phagocytes, constitute the predominant innate immune cell in the brain parenchyma and serve many functions including immunosurveillance of the brain microenvironment for pathogen invasion, cellular debris, apoptotic cells, and alterations in neuronal phenotype (Ransohoff and Cardona, 2010).”

“The subsequent discoveries of the GC hormones, and their role in mediating many of the effects of stressors, led naturally to the view that GCs are immunosuppressive in general and anti-inflammatory in particular (Boumpas et al., 1993).”

“Of these PRRs, TLRs have been the most extensively characterized (Barton and Kagan, 2009).”

“These effects of GCs on TLR2 and TLR4 are consistent with a small literature showing that GCs up-regulate TLRs on various peripheral cell types (Galon et al., 2002; Hermoso et al., 2004; Rozkova et al., 2006; Sakai et al., 2004; Shibata et al., 2009).”

“A considerable literature has demonstrated that Meth is neurotoxic, depending on dose and time course of administration (Krasnova and Cadet, 2009).”

“Importantly, TLR4 knockout (Fernandez-Lizarbe et al., 2009) and knockdown with siRNAs (Alfonso-Loeches et al., 2010) also blocked alcohol-induced neuroinflammatory responses in vivo.”

“Similar to our findings (Frank et al., 2007), chronic stress did not by itself tonically increase pro-inflammatory cytokine levels, although the activation state of microglia had been shifted toward a preferential pro-inflammatory immunophenotype.”

“Of particular relevance to the present focus, these cells can enter a state that can be called ‘‘sensitized’’ or ‘‘primed’’ (Perry, 2004).”

“Indeed, microglial activation, astrogliosis, and increased expression of PICs have been observed in postmortem examination of alcoholic brains (He and Crews, 2008).”

“Over the years, a number of papers have reported either no effect or even pro-inflammatory effects of GCs (Sapolsky, 1999), but these have largely been ignored.”

“Particularly noteworthy is the high degree of comorbidity between major depression and alcohol abuse (Davis et al., 2008).”

“However, this issue has recently been re-examined in a review by Sorrells and Sapolsky (2007), with the authors concluding that GCs are indeed sometimes either without effect or strongly pro-inflammatory.”

“The first is a rapid, short duration (several hours) increase in inflammatory mediators (Nguyen et al., 1998).”

“Song and Zhao found that chronic morphine activated glia in both the spinal cord and brain (Song and Zhao, 2001).”

“In addition, blockade of morphine-induced IL-1b signaling potentiated morphine analgesia and prevented the development of hyperalgesia and morphine tolerance (Johnston et al., 2004).”

“Importantly, stress and GCs activate brain reward pathways, such as dopamine signaling in the nucleus accumbens, in a manner similar to drugs of abuse (Marinelli and Piazza, 2002).”

“both NF-jB and AP-1 mediated gene transcription (Smoak and Cidlowski, 2004).”

“For example, our laboratory has shown that the microglial activation marker MHCII is up-regulated, and the neuronal glycoprotein CD200 (which constitutively constrains microglial activation, see below) is down-regulated 24 h post-stress (Frank et al., 2007).”

“For example, Nair has shown that chronic restraint stress increases microglia proliferation as well as microglia activation (Nair and Bonneau, 2006).”

“This facilitation of drug reward processes by stress has been the subject of numerous reviews (Briand and Blendy, 2010; Koob, 2009; Sinha, 2008) and need not be reviewed here.”

“…et al., 1998; Fantegrossi et al., 2008; Goncalves et al., 2010; Guilarte et al., 2003; Ladenheim et al., 2000; LaVoie et al., 2004; Pubill et al., 2003; Sekine et al., 2008; Sharma and Kiyatkin, 2009; Sriram et al., 2006; Theodore et al., 2006; Thomas et al., 2004, 2008; Thomas and Kuhn, 2005).”

“…in which glial activation and the consequent release of inflammatory mediators could play a role in drug-related processes, it may be especially important that IL-1b can down-regulate the glutamate transporter GLT-1 (Tilleux and Hermans, 2007), thereby increasing glutamatergic neurotransmission.”

“Fernandez-Lizarbe et al. (2009) found all of these to be absent in microglia taken from TLR4 deficient mice.”

“An emerging body of evidence suggests that activated glia and glia-derived neuroinflammatory mediators play an important role in drug reward, dependence, tolerance and analgesic properties (Hutchinson et al., 2007).”

“Lastly, drugs of abuse signal through TLRs (see below for discussion).”

“similar profile of pro-inflammatory ‘‘cytokine signatures’’ in the CNS (Maier, 2003).”

“text of the present review given that stress (Anisman, 2009), GCs (Pariante and Miller, 2001), and inflammatory processes (Dantzer”

“these transcription factors, particularly NF-jB, are the key regulators of inflammatory genes (Solt and May, 2008).”

“Although a variety of mechanisms have been implicated, it is agreed that GCs inhibit both NF-jB and AP-1 mediated gene transcription (Smoak and Cidlowski, 2004).”

“In vivo GC treatment potentiated the PIC (IL-1b, TNFa) response to LPS ex vivo in a dose dependent manner.”

“In vitro, even a brief exposure to alcohol at physiological concentrations (50 nM) induces inflammatory processes in astrocytes (Blanco et al., 2005) and microglia (Fernandez-Lizarbe et al., 2009).”

“Indeed, a considerable literature shows that several different kinds of stressors induce pro-inflammatory cytokines in the CNS (Anisman, 2009; Hennessy et al., 2009; Minami et al., 1991; Shintani et al., 1995).”

“Brain levels of pro-inflammatory cytokines are already elevated immediately after a moderate duration ( 2 h) of stress (O’Connor et al., 2003) and persist for 4–6 h.”

“Indeed, a considerable literature shows that several different kinds of stressors induce pro-inflammatory cytokines in the CNS (Anisman, 2009; Hennessy et al., 2009; Minami et al., 1991; Shintani et al., 1995).”

“…et al., 1998; Fantegrossi et al., 2008; Goncalves et al., 2010; Guilarte et al., 2003; Ladenheim et al., 2000; LaVoie et al., 2004; Pubill et al., 2003; Sekine et al., 2008; Sharma and Kiyatkin, 2009; Sriram et al., 2006; Theodore et al., 2006; Thomas et al., 2004, 2008; Thomas and Kuhn, 2005).”

“In fact, we have found that serum GC levels rise rapidly during the initial stress and return to baseline within 2–6 h after the stressor used in the above studies (Fleshner et al., 1995).”

“flammatory effects including PIC, chemokines, and oxidative stress (Cadet and Krasnova, 2009; Krasnova and Cadet, 2009).”

“Of note, pro-inflammatory cytokines administered to humans induce depression-like symptoms (Pollak and Yirmiya, 2002).”

“The stressor regimen facilitated LPS-induced microglial activation (MHCII expression) and cytokine expression; such effects were blocked by daily RU486 (de Pablos et al., 2006).”

“…2006; Buchanan et al., 2010; Escubedo et al., 1998; Fantegrossi et al., 2008; Goncalves et al., 2010; Guilarte et al., 2003; Ladenheim et al., 2000; LaVoie et al., 2004; Pubill et al., 2003; Sekine et al., 2008; Sharma and Kiyatkin, 2009; Sriram et al., 2006; Theodore et al., 2006; Thomas et al.,…”

“This dissociation of metabolite characteristics was very interesting as the metabolite that had no attraction to TLR4–MD2 was morphine-6-glucuronide (M6G), which binds opioid receptors avidly and produces potent analgesia (Abbott and Palmour, 1988).”

“…et al., 1998; Fantegrossi et al., 2008; Goncalves et al., 2010; Guilarte et al., 2003; Ladenheim et al., 2000; LaVoie et al., 2004; Pubill et al., 2003; Sekine et al., 2008; Sharma and Kiyatkin, 2009; Sriram et al., 2006; Theodore et al., 2006; Thomas et al., 2004, 2008; Thomas and Kuhn, 2005).”

“CD200 functions to inhibit microglia and other CNS macrophages through the CD200 receptor expressed predominately on brain macrophages/microglia (Barclay et al., 2002; Koning et al., 2009), thereby constraining the onset of proinflammatory processes.”

“…withdrawal behaviors while potentiating morphine’s analgesic properties (Hutchinson et al., 2009) Importantly, in line with such observations, we demonstrated that TLR4 knock out mice exhibit enhanced morphine analgesia and attenuated development of morphine tolerance (Hutchinson et al., 2010b).”

“First, microglia express many of the TLRs characterized in rodents (Carpentier et al., 2008) (13 in all).”

“These effects of GCs on TLR2 and TLR4 are consistent with a small literature showing that GCs up-regulate TLRs on various peripheral cell types (Galon et al., 2002; Hermoso et al., 2004; Rozkova et al., 2006; Sakai et al., 2004; Shibata et al., 2009).”

“Consistent with several studies cited above, repeated Meth treatment in- creased TNFa throughout the brain (Nakajima et al., 2004).”

“TLR2 and TLR4 have been the most intensively studied PRRs within the CNS, and are densely expressed on microglial cells (Aravalli et al., 2007).”

“For example, activated glucocorticoid receptors (GRs) induce IkBalpha expression, preventing NF-jB translocation to the nucleus (Aljada et al., 1999) and also block NF-jB binding activity via interactions with the NF-jB p65 subunit (McKay and Cidlowski, 2000).”

“These effects of GCs on TLR2 and TLR4 are consistent with a small literature showing that GCs up-regulate TLRs on various peripheral cell types (Galon et al., 2002; Hermoso et al., 2004; Rozkova et al., 2006; Sakai et al., 2004; Shibata et al., 2009).”

“Consistent with these findings, glial inhibition potentiated morphine analgesia and attenuated morphine tolerance (Mika et al., 2009).”

“…2010; Escubedo et al., 1998; Fantegrossi et al., 2008; Goncalves et al., 2010; Guilarte et al., 2003; Ladenheim et al., 2000; LaVoie et al., 2004; Pubill et al., 2003; Sekine et al., 2008; Sharma and Kiyatkin, 2009; Sriram et al., 2006; Theodore et al., 2006; Thomas et al., 2004, 2008; Thomas…”

“dopamine efflux in the nucleus accumbens (Bland et al., 2009; Northcutt et al., 2010).”

“…number of reports show that Meth activates microglia (Bowyer and Ali, 2006; Buchanan et al., 2010; Escubedo et al., 1998; Fantegrossi et al., 2008; Goncalves et al., 2010; Guilarte et al., 2003; Ladenheim et al., 2000; LaVoie et al., 2004; Pubill et al., 2003; Sekine et al., 2008; Sharma and…”

“…for 9 days resulted in microglia activation (as reflected by increased MHCII expression) and potentiated the neuroinflammatory response (IL-1b, tumor necrosis factor (TNF)a, nitric oxide synthase (NOS), inducible (i)NOS and p38 MAPK) to intra-hippocampal LPS (Espinosa-Oliva et al., 2011).”

“, 1998) and GC injection before the stressor inhibits it (Nguyen et al., 2000).”

“Further, drugs of abuse activate the hypothalamo-pituitary–adrenal (HPA) axis (Armario, 2010).”

“dative stress, and neurotoxicity in several brain regions including the striatum, frontal cortex, and hippocampus (Ladenheim et al., 2000).”

“These macrophage subtypes also serve a critical role in the brain’s innate immune response (Schiltz and Sawchenko, 2003) and may potentially contribute to the processes under discussion, but will not be further addressed here.”

“These same points can be made with regard to the immediate neuroinflammatory response to immune activators such as LPS (Goujon et al., 1996).”

“This facilitation of drug reward processes by stress has been the subject of numerous reviews (Briand and Blendy, 2010; Koob, 2009; Sinha, 2008) and need not be reviewed here.”

“…that Meth activates microglia (Bowyer and Ali, 2006; Buchanan et al., 2010; Escubedo et al., 1998; Fantegrossi et al., 2008; Goncalves et al., 2010; Guilarte et al., 2003; Ladenheim et al., 2000; LaVoie et al., 2004; Pubill et al., 2003; Sekine et al., 2008; Sharma and Kiyatkin, 2009; Sriram et…”

“Briefly, a considerable literature has documented the high degree of comorbidity between substance abuse and psychiatric disorders (Merikangas and Kalaydjian, 2007).”

“…et al., 1998; Fantegrossi et al., 2008; Goncalves et al., 2010; Guilarte et al., 2003; Ladenheim et al., 2000; LaVoie et al., 2004; Pubill et al., 2003; Sekine et al., 2008; Sharma and Kiyatkin, 2009; Sriram et al., 2006; Theodore et al., 2006; Thomas et al., 2004, 2008; Thomas and Kuhn, 2005).”

“These effects of GCs on TLR2 and TLR4 are consistent with a small literature showing that GCs up-regulate TLRs on various peripheral cell types (Galon et al., 2002; Hermoso et al., 2004; Rozkova et al., 2006; Sakai et al., 2004; Shibata et al., 2009).”

“This profile of long-lived presence plus potent pain enhancement has gained focus on M3G as an attenuator of the pain-relieving effects of its parent compound, morphine, and an important contributor to the development of morphine tolerance (Mazoit et al., 2007).”

“A considerable number of reports show that Meth activates microglia (Bowyer and Ali, 2006; Buchanan et al., 2010; Escubedo et al., 1998; Fantegrossi et al., 2008; Goncalves et al., 2010; Guilarte et al., 2003; Ladenheim et al., 2000; LaVoie et al., 2004; Pubill et al., 2003; Sekine et al., 2008;…”

“Likewise, acute Meth increased TNFa and IL-1b in striatum and potentiated cytokine response to HIV TAT (Flora et al., 2003), as well as the chemokine expression to the HIV Tat protein (Theodore et al., 2006).”

“Lastly, treatment with the glial inhibitor, Ibudilast (a drug used extensively in our laboratory to modulate the pro-inflammatory effects of morphine; see above), attenuated stress-induced reinstatement of extinguished Meth-maintained responding (Beardsley et al., 2010).”

“…et al., 1998; Fantegrossi et al., 2008; Goncalves et al., 2010; Guilarte et al., 2003; Ladenheim et al., 2000; LaVoie et al., 2004; Pubill et al., 2003; Sekine et al., 2008; Sharma and Kiyatkin, 2009; Sriram et al., 2006; Theodore et al., 2006; Thomas et al., 2004, 2008; Thomas and Kuhn, 2005).”

“For example, it has been suggested (Blanco et al., 2008) that alcohol interacts with lipid rafts in such a way that TLR4 is recruited, triggering its endocytosis and interaction with co-signaling molecules such as MD2, and the consequent induction of downstream signaling.”

“In vivo GC treatment potentiated the PIC (IL-1b, TNFa) response to LPS ex vivo in a dose dependent manner.”

“These effects of GCs on TLR2 and TLR4 are consistent with a small literature showing that GCs up-regulate TLRs on various peripheral cell types (Galon et al., 2002; Hermoso et al., 2004; Rozkova et al., 2006; Sakai et al., 2004; Shibata et al., 2009).”

“A considerable number of reports show that Meth activates microglia (Bowyer and Ali, 2006; Buchanan et al., 2010; Escubedo et al., 1998; Fantegrossi et al., 2008; Goncalves et al., 2010; Guilarte et al., 2003; Ladenheim et al., 2000; LaVoie et al., 2004; Pubill et al., 2003; Sekine et al., 2008;…”

“enhancement by as-yet-to-be-discovered mechanisms (Bartlett et al., 1994).”

“Prior chronic stress was also found to potentiate the hyperthermic response to Meth, which was blocked by treating animals with the glucocorticoid synthesis inhibitor, metyrapone, during chronic stress exposure (Tata and Yamamoto, 2008).”

“For example, activated glucocorticoid receptors (GRs) induce IkBalpha expression, preventing NF-jB translocation to the nucleus (Aljada et al., 1999) and also block NF-jB binding activity via interactions with the NF-jB p65 subunit (McKay and Cidlowski, 2000).”

“A regimen of chronic unpredictable stress potentiated the hyperthermic response to Meth (Matuszewich and Yamamoto, 2004).”

“Our laboratory has also found that stress as well as GCs sensitizes the rewarding properties of morphine, and that just as with stress-induced potentiation of later inflammatory responses to immune activation, adrenalectomy blocks stress-induced potentiation of drug reward (Der-Avakian et al., 2005).”

“…et al., 1998; Fantegrossi et al., 2008; Goncalves et al., 2010; Guilarte et al., 2003; Ladenheim et al., 2000; LaVoie et al., 2004; Pubill et al., 2003; Sekine et al., 2008; Sharma and Kiyatkin, 2009; Sriram et al., 2006; Theodore et al., 2006; Thomas et al., 2004, 2008; Thomas and Kuhn, 2005).”

“including striatum, hypothalamus, hippocampus, cortex, and cerebellum, and prior Meth also potentiated the microglial activation induced by LPS (Buchanan et al., 2010).”

“Indeed, a considerable literature shows that several different kinds of stressors induce pro-inflammatory cytokines in the CNS (Anisman, 2009; Hennessy et al., 2009; Minami et al., 1991; Shintani et al., 1995).”

“In rhesus monkeys, chronic Meth increased interferon a/b in frontal lobe (Coutinho et al., 2008) and striatal expression of TNF and NF-jB (Lai et al., 2009).”

“…et al., 1998; Fantegrossi et al., 2008; Goncalves et al., 2010; Guilarte et al., 2003; Ladenheim et al., 2000; LaVoie et al., 2004; Pubill et al., 2003; Sekine et al., 2008; Sharma and Kiyatkin, 2009; Sriram et al., 2006; Theodore et al., 2006; Thomas et al., 2004, 2008; Thomas and Kuhn, 2005).”

“In rhesus monkeys, chronic Meth increased interferon a/b in frontal lobe (Coutinho et al., 2008) and striatal expression of TNF and NF-jB (Lai et al.”

“What our group has discovered is that the strong attraction of M3G to the key TLR4–MD2 binding pocket is paralleled by: (a) activation of TLR4 receptor signaling, blocked by LPS-RS (LPS derived from Rhodobacter sphaeroides), a classic TLR4 antagonist, (b) stimulation by M3G of IL-1b production in microglial cells, and…”

“Their review has elicited a great deal of controversy (e.g. see comment, Miller, 2007) because the conclusion that GCs are anti-inflammatory is strongly entrenched, and the issue is of great importance both theoretically and clinically.”

“There has been tremendous interest in the effects of stress and GCs on inflammation since the pioneering reports by Selye (1950) that ‘‘stress’’ produces thymic involution and subsequent findings that ‘‘stress’’ seemed to suppress various aspects of immune function (Selye, 1955).”

“Recently, some studies have shown that glucocorticoid pretreatment sensitizes inflammatory response in the CNS (Frank et al., 2011, 2012), which is previously considered as the events of glucocorticoid resistance in depression.”

“In particular, disrupting glucocorticoid signaling in D1+ MSNs by deleting Nr3c1 diminished the motivation these mice display to self-administer cocaine, and this is consistent with previous data where Nr3c1 was deleted from the entire brain (Ambroggi et al., 2009).”

“Chronic stress and glucocorticoid signaling can induce dendritic atrophy and functional changes in microglia which contribute to the deficits of behavior and cognition [50, 51].”

“Glial priming however, has not only been demonstrated after trauma, but also as a consequence of exposure to environmental stressors (Frank et al., 2011).”

“When priming does occur in microglia or peripheral macrophages, these sensitised cells do not produce proinflammatory or antiinflammatory products, but, if further stimulated, they produce high levels of proinflammatory products [69-75].”

“Notably, prior stress has been shown to enhance pro inflammatory cytokine expression and associated neural damage following an immune challenge in adult rats (De Pablos et al. 2006), most likely by sensitizing micro glia (Frank et al. 2011).”

“In addition, sensitization of reward pathways due to aberrant HPA axis activity has been proposed to drive vulnerability to addictive disorders, as GCs promote perseverance of addictive behavior (de Jong and de Kloet 2004; Uhart and Wand 2009; Frank et al. 2011).”

“In addition, there is growing evidence that certain conditions, such as stress (Johnson et al., 2003; Li et al., 2008; Frank et al., 2011; Loram et al., 2011), peripheral inflammation (Perry et al., 2007; Dantzer et al., 2008; Williamson et al., 2011), and advanced age (Barrientos et al., 2006;…”

“This enhancement was reversed by the GR antagonist mifepristone, showing that it was the result of elevated corticosterone (de Pablos et al., 2014); a similar enhancement of microglial activity was observed following corticosterone treat-ment (Frank et al., 2011).”

“Indeed, neuroimmune modulation via microglial and astroglial cells may contribute to stress-induced drug reinstatement (Frank et al., 2011).”

“The immune-priming effect of stress is proposed to mediate stress-induced side effects such as allodynia (Loram et al., 2011), and drug abuse (Frank et al., 2011), and could potentially be involved in MDD as well.”

“The growth in magnitude of the response derives from TDS-based amplifications in the physiological adaptations of the organism, not directly from the size of the initiating stimulus or stressor.”

“Even though GC are known to suppress immune function under some conditions, GC under other conditions can promote immune responsiveness [20; 21; 22; 23; 24].”

“Glucocorticoids potently interact with the inflammatory pathways [297-299] and modify the immune responses to nicotine and alcohol [297, 300].”

“Blockade of glucocorticoid signaling can block stress-induced sensitization of microglial inflammatory responses (Frank et al., 2011), and microglial activation can be primed by in vivo exposure to glucocorticoids (Nair and Bonneau, 2006) or chronic stress (Farooq et al., 2012).”

“However, glucocorticoids may also exert divergent effects to acutely enhance pro-inflammatory cytokine action and chronically potentiate the neuroinflammatory response to stressors (reviewed by Frank et al. 2011).”

“, hypothalamic-pituitary-adrenal axis), and transcription activity within reward neurocircuitry (Allen et al. 2011; Crews and Nixon 2009; Crews et al. 2011; Frank et al. 2011; Kelley and Dantzer 2011; Misra and Pandey 2006; Rosi 2011; Yakovleva et al. 2011).”

“microglial activation state by stress was reported to be associated with elevated glucocorticoids (GCs) [28, 32, 33] caused by alterations in hypothalamic-pituitary-adrenal (HPA) axis”

“Microglia and opioid addiction Similar to psychostimulant addiction, emerging evidences show that opioid-induced morphological and molecular activation in response to opioids is related to the development and maintenance of opioid reward, tolerance, dependence, and withdrawal [96 – 99].”

“An interesting aspect is that drugs of abuse may directly activate microglial and astroglial cells via TLRs, which mediate the innate immune response to pathogens [216].”

“, 2013) and are highly responsive cells that react to stress (Frank et al., 2011), making them suitable candidates to mediate the effects of stress exposure and pediatric mTBI.”

“Frank et al. (2011) review the potential mechanism underlying stress-induced vulnerability to drugs of abuse.”

“In mammals, the integrated response to stress includes a number of neuroendocrine molecules of both the hypothalamic-pituitaryadrenal axis and the sympathetic nervous system, such as catecholamines, adrenocorticotropin and glucocorticoids [19–21].”

“Indeed, modulation of neuroimmune signaling via microglial cells and astrocytes promotes stress-induced drug seeking [98].”

“Although the mechanisms underlying the B.S. in chronic drug use is not well described yet, growing evidence implies the role of neuroinflammatory mediators in the development of drug addiction as well as many other neurological and psychiatric diseases (Frank et al. 2011).”

“CD200 binding its receptor CD200R is thought to constitutively maintain glial cell in a quiescent state (Frank et al., 2011; Yi et al., 2012).”

“Studies have demonstrated that drugs and alcohol interact with the neuroimmune system and alter neuroimmune gene expression and signaling (Frank et al., 2011; Haroon et al., 2012), which in turn contribute to various reinforcing and addictive properties of addiction including reward, stress,…”

“In this context, stress and glucocorticoids have been shown to sensitize neuroinflammatory responses to subsequent drug exposure, indicating that immune mechanisms may play a crucial role in mediating stress-induced vulnerability to addiction [231,272,273].”

“Activation of microglia to a pro-inflammatory immunophenotype can be facilitated by exposure to some stressors.(27) Microglia activation and neuro-inflammatory responses to LPS were found to increase in rats exposed to chronic variable stress.”

“Early developmental insults such as childhood inflammation may have a priming effect on microglia in the brain, which may increase microglial activation and psychosis risk following subsequent infections (Frank et al., 2007; Frank et al., 2011).”

“Interestingly, chronic stress may suppress neuroinflammation in specific brain regions by reducing neuronal activity, impairing astrocytic signaling, or decreasing microglial activation [82,83].”

“Many cytokines may play a role in the biology of addiction (Frank et al., 2011), including those released by microglia (Schwarz & Bilbo, 2013), as a response to neuronal activity changes induced during withdrawal (Parekh et al., 2021).”

“This inflammatory milieu, involving microglial activation, astrocytic dysfunction and peripheral immune cell infiltration [6], disrupts synaptic homeostasis, impairs neuro-plasticity and contributes to the characteristic cognitive and emotional deficits of AUD [7].”

“…Shaw et al. 2024), the induction of neuroinflammatory processes through microglial priming and increased production of pro-inflammatory cytokines (Frank et al. 2011; Munhoz et al. 2006), and the disruption of neurotransmitter systems such as glutamatergic, GABAergic, and monoaminergic…”

“When primingoccurs in microglia or peripheral macrophages, these sensitized cells do not produce inflammatory or anti-inflammatory products, but if further stimulated they turn into a high inflammatory profile ([71-77]).”

“A review of studies focusing on stress and drug misuse concluded that stressors exacerbate a variety of drug-related behaviors (Frank et al., 2011).”