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Adolescents are more to susceptible to microglial activation by nicotine as compared to adults which results in long term effects in terms of nicotine induced neuropathology and addiction (101, 108). Microglial activation phenotypes are described as (1) classic activation (M1 phenotype), (2) alternative activation (M2a phenotype), (3) alternative type II activation (M2b phenotype), and (4) acquired deactivation (M2c phenotype) (113, 114).

The M1 phenotype is commonly referred to as neurotoxic (116, 117). M1 microglia regulate synaptic pruning (118) and exhibit limited phagocytic activity (119). These microglia can stimulate tissue regeneration and can eliminate cellular debris. M2b microglia show increased IL-12, IL-10, and HLA-DR expression.

M2b microglia also have significant phagocytic activity and an increased expression of CD32 and CD64. M2c also known as acquired Repronex (Menotropins for Injection)- FDA phenotype is acquired as a result of stimulation with the anti-inflammatory cytokine IL-10 or glucocorticoids, shows increased expression of transforming growth factor (TGF), sphingosine kinase (SPHK1), and CD163 Repronex (Menotropins for Injection)- FDA. Nicotine induces both immunosuppressive and immuno-stimulatory effects in problem drug CNS (126, 127).

The translocator protein (TSPO) is used as a neuro-inflammatory marker as its expression is upregulated in reactive glial cells during CNS pathologies. However, it remains unclear in which microglial phenotypes TSPO levels are upregulated, as microglia can display a plethora of activation states that can be protective or detrimental to the brain.

TSPO expression johnson boys selectively increased in M1 microglia but not M2 microglia. TSPO imaging reveals microgliosis in non-neurodegenerative brain pathologies, and this is perhaps reflected in the observation that cigarette smokers have decreased levels of TSPO suggesting that neuroprotective properties of nicotine and the anti-inflammatory responses of nicotine may be responsible for the decreased incidence in neurological diseases in smokers (128).

Nicotine induced increases in brain inflammatory markers which are not only dose-dependent, but are also related to smoking intensity and time since smoking cessation (126). Additional studies are needed to examine nicotine induced inflammatory responses and TSPO binding in human smokers during acute nicotine withdrawal in order to evaluate the Repronex (Menotropins for Injection)- FDA potential of microglial modulators as smoking cessation aids.

The NADPH oxidase (Nox) system is a major source of intracellular ROS production in the adult brain and the nicotine withdrawal induced activation of the Nox isoform-Nox-2 expression in microglia, which is believed to be the primary mechanism that results Repronex (Menotropins for Injection)- FDA increased ROS generation and pro-inflammatory response to nicotine Repronex (Menotropins for Injection)- FDA (131, 132).

Synaptic cues specific to the NAc during exposure to chronic nicotine or withdrawal from chronic nicotine distinctly influence the phenotype of its resident microglia.

Microglia play a critical role in synaptic remodeling and plasticity that underlies drug addiction (133, 134). Activated microglia produce and release a variety of pro-inflammatory cytokines and augmenting the production of free radicals (143). Microglial cells express innate immune receptors, Toll like Receptors (TLRs) and cytoplasmic NOD-like immune receptors (NLRs) (144, 145), which react not only to pathogens (PAMPs, pathogen associated molecular patterns), but also to stress conditions, and to cell damage (DAMPS Repronex (Menotropins for Injection)- FDA damage-associated molecular patterns) (146).

Several studies demonstrate the participation of these receptors in neuroinflammation and associated neuropathology is induced by nicotine abuse, particularly in adolescence (147). Significant morphological differences exist between adult microglia and adolescent microglia, adult microglia were larger and have more complex morphology than adolescent microglia. The transcriptional profile associated with immune activation is significantly different in adolescent microglia as compared to adult microglia (148).

Nicotine treatment showed age-dependent effects on microglial marker Iba1 expression in the NAc and BLA which are actively maturing brain region during adolescence responsible for reward (66). Microglia express the receptor CX3CR1, which mediates developmental synaptic pruning through the neuronal ligand CX3CL1 (111). Nicotine decreased overall expression of genes associated with microglial activation and nicotine alters the expression of these transcripts in an age-dependent manner which suggests that microglia are not fully mature by adolescence (101).

A recent study showed that microglia are essential regulators of nicotine induced increases in cocaine seeking behavior (101) in adolescent microglia. Nicotine-induces microglial Repronex (Menotropins for Injection)- FDA in the Repronex (Menotropins for Injection)- FDA regions such as NAc, basolateral amygdala (BLA) which are responsible for reward (41, 66). The nicotine induced changes to microglial activation is mediated via the NAc localized D2 receptors and CX3CL1 signaling cascade suggesting that nicotine can induces significant changes to adolescent brain Repronex (Menotropins for Injection)- FDA behavior, and that microglial activation is a critical to this regulation (149).

CX3CL1 not only mediates nicotine-induced increase in microglial activation, but increases the neuronal-microglial communication pathway via the CX3CL1-CX3CR1 interaction, after adolescent-nicotine exposure (149, 150). The adolescence period is therefore a particularly vulnerable period during which, nicotine withdrawal induces microglial morphological changes in the nucleus Repronex (Menotropins for Injection)- FDA (NAc) promoting microglial activation via Nox2-mediated increases in ROS.

The increase in the pro-inflammatory cytokines occurs in both adolescents as well as adults, however, the increase in inflammatory cytokines in adolescents is significantly higher than that in adults (101, carnicor (Figure penile fracture. Schematic that illustrates the effect of nicotine on microglial activation in adult microglia vs.

M1 microglia represent a neurotoxic environment Repronex (Menotropins for Injection)- FDA increased levels of Repronex (Menotropins for Injection)- FDA cytokines while Repronex (Menotropins for Injection)- FDA microglia are neuroprotective.

Adolescent-nicotine exposed microglia show an increased reactive M1 activation and a pro-inflammatory response. Targeting the microglial potassium (KATP) channels has been shown to be effective in controlling inflammatory microglia activation, avoiding its toxic phenotype though a mitochondria-dependent mechanism (155). Such a strategy of modulating microglial activation and consequent neuroinflammation may be a novel therapeutic approach for treatment of nicotine withdrawal symptoms. Nicotine withdrawal is associated with cognitive deficits including attention and episodic memory impairments.

The role of microglia in response to nicotine is further consolidated by experiments that show that microglial depletion reversed the microglial- related Nox2 and associated aberrant ROS production and also decreased anxiety-like behavior that is typical response to nicotine withdrawal (156).

Research investigating the role of microglia in nicotine dependence is limited and still novel, however, has potential implications in the development of more potent therapeutics to treat nicotine dependence and withdrawal. Identification of Repronex (Menotropins for Injection)- FDA involved in the inheritance of specific smoking phenotypes may strengthen the selection of treatment options tailored to individual genotype (157). Although evidence for associations of CYP2A6 with smoking behavior and for the nicotine-metabolite ratio as a predictor of relapse are promising, cost effectiveness of implementing pharmacogenomics therapy would depend on the distribution of the relevant genetic polymorphisms in all smoking individuals (158).

Pharmacogenomics and nicotine dependence is still an emerging science. We speculate that neurodevelopmental changes may be modulated by pharmacotherapy targeted to activate change in microglial phenotype which may promote brain homeostasis and a neuro-adaptation that favors decreased dependence on nicotine thus microglia are a promising therapeutic target that need to be explored.

Currently, data on role of microglial activation in nicotine cravings, withdrawal and tolerance is limited. Repronex (Menotropins for Injection)- FDA sensitization-homeostasis model is unique in its extensive integration of clinical observations and basic science and its attribution of dependence to craving suppression and suggests that separate homeostatic mechanisms are responsible for abstinence, withdrawal, and tolerance (162).

Studies show that behavioral treatments particularly in adolescents are effective, whereas pharmacotherapies have only marginal success (28, 29, 32, 33). The side effect profiles for nicotine replacement therapy, bupropion, and varenicline in adolescents are similar to those reported in adult studies and none of these medications were efficacious in promoting long-term smoking cessation among adolescent smokers.

The decision to use pharmacotherapy in adolescents should be individualized and should be administered in addition to cognitive-behavioral counseling and support. Nicotine dependence over time can result in neuro-plastic changes in the brain (163), and therefore there is a possible concern for nicotine replacement therapy use during adolescence, which is that nicotine can change the neurodevelopmental trajectory.

Therefore, understanding how nicotine affects the adolescent brain, and identifying novel therapeutics is essential to treating nicotine addiction in adolescents.

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