DAT isn’t all that: cocaine reward and reinforcement require Toll-like receptor 4 signaling

Northcutt, Alexis L.; Hutchinson, Mark R.; Wang, X; Baratta, Michael V.; Hiranita, Takato; Cochran, Thomas A.; Pomrenze, Matthew B.; Galer, Erika L.; Kopajtic, Theresa; Li, C M; Amat, José; Larson, Gaynor A.; Cooper, Donald; Huang, Yong; O’Neill, Casey E.; Yin, Hang; Zahniser, Nancy R.; Katz, Jonathan L.; Rice, Kenner C.; Maier, Steven F.; Bachtell, Ryan K.; Watkins, Linda R.

doi:10.1038/mp.2014.177

Cited by 180 publications

(297 citation statements)

References 63 publications

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“…Though we were not in a position to address the identity of c-Fos-positive neurons in TLR4 -/-mice in the current study, we think these neurons may be D2-MSNs as activation of these neurons mainly controls aversive behaviors [37][38][39]. It is well-known that D2-MSNs are inhibited by DA [40], and xenobiotic activation of TLR4 results in an increase in DA in the NAc [20,33]. This may explain why TLR4 deficiency enhanced neuronal activity in the NAcSh after the novelty-seeking test.…”

Section: Discussionmentioning

confidence: 80%

“…In particular, it has recently been shown that substances of abuse such as opioids [33] and cocaine [20] function as xenobiotic ligands for TLR4 [34]. Xenobiotic activation of TLR4 increases the DA level in the NAc [20,33]. We do not know if endogenous opioids are capable of activating TLR4 directly, nevertheless we speculate that TLR4 deficiency may lead to a decreased level of DA in the NAc, an area important in motivational conflict.…”

Section: Discussionmentioning

confidence: 84%

“…All these TLR4-mediated molecular and cellular consequences are pivotal to relevant neuropsychiatric diseases. In particular, it has recently been shown that substances of abuse such as opioids [33] and cocaine [20] function as xenobiotic ligands for TLR4 [34]. Xenobiotic activation of TLR4 increases the DA level in the NAc [20,33].…”

Section: Discussionmentioning

confidence: 99%

“…It functions in neurogenesis, axonal growth, and structural plasticity [12,14,15], and regulates the cognitive and affective behaviors associated with depression [16,17] and drug addiction [18,19]. Notably, TLR4 can be activated directly by opioids [19] and cocaine [20], and this activation contributes to drug reinforcement via increasing the level of extracellular dopamine (DA) in the nucleus accumbens (NAc) [20]. It is well established that the mesolimbic DA system is closely associated with approach-avoidance behavior [21,22].…”

Section: Introductionmentioning

confidence: 99%

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Toll-Like Receptor 4 Deficiency Causes Reduced Exploratory Behavior in Mice Under Approach-Avoidance Conflict

Yan

Cheng

et al. 2016

Neurosci. Bull.

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Abnormal approach-avoidance behavior has been linked to deficits in the mesolimbic dopamine (DA) system of the brain. Recently, increasing evidence has indicated that toll-like receptor 4 (TLR4), an important pattern-recognition receptor in the innate immune system, can be directly activated by substances of abuse, resulting in an increase of the extracellular DA level in the nucleus accumbens. We thus hypothesized that TLR4-dependent signaling might regulate approach-avoidance behavior. To test this hypothesis, we compared the novelty-seeking and social interaction behaviors of TLR4-deficient (TLR4 -/-) and wild-type (WT) mice in an approach-avoidance conflict situation in which the positive motivation to explore a novel object or interact with an unfamiliar mouse was counteracted by the negative motivation to hide in exposed, large spaces. We found that TLR4 -/-mice exhibited reduced novelty-seeking and social interaction in the large open spaces. In less stressful test apparatuses similar in size to the mouse cage, however, TLR4 -/-mice performed normally in both novelty-seeking and social interaction tests. The reduced exploratory behaviors under approachavoidance conflict were not due to a high anxiety level or an enhanced fear response in the TLR4 -/-mice, as these mice showed normal anxiety and fear responses in the open field and passive avoidance tests, respectively. Importantly, the novelty-seeking behavior in the large open field induced a higher level of c-Fos activation in the nucleus accumbens shell (NAcSh) in TLR4 -/-mice than in WT mice. Partially inactivating the NAcSh via infusion of GABA receptor agonists restored the novelty-seeking behavior of TLR4 -/-mice. These data suggested that TLR4 is crucial for positive motivational behavior under approach-avoidance conflict. TLR4-dependent activation of neurons in the NAcSh may contribute to this phenomenon.

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Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Toll-Like Receptor 4 Deficiency Causes Reduced Exploratory Behavior in Mice Under Approach-Avoidance Conflict

Yan

Cheng

et al. 2016

Neurosci. Bull.

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“…In the brain, acute cocaine results in increased IL-1β mRNA in the NAc and cortex (Cearley et al, 2011), while methamphetamine leads to increased IL-6 and TNFα in hippocampus and frontal cortex (Gonçalves et al, 2008). Similarly, acute injections of cocaine results in elevated IL-1β mRNA in the VTA, an effect that is blocked with (+)-naloxone treatment (Northcutt et al, 2015). These data are supported by in vitro preparations, as cultured microglia exposed to cocaine upregulate transcription of TNFα, IL-6, and CCL2 (Liao et al, 2016) as well as IL-1β (Northcutt et al, 2015).…”

Section: Psychostimulants Glia and Neuroimmune Signalingmentioning

confidence: 92%

Glial and Neuroimmune Mechanisms as Critical Modulators of Drug Use and Abuse

Lacagnina

Rivera

Bilbo

2016

Neuropsychopharmacol

212

170

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Drugs of abuse cause persistent alterations in synaptic plasticity that may underlie addiction behaviors. Evidence suggests glial cells have an essential and underappreciated role in the development and maintenance of drug abuse by influencing neuronal and synaptic functions in multifaceted ways. Microglia and astrocytes perform critical functions in synapse formation and refinement in the developing brain, and there is growing evidence that disruptions in glial function may be implicated in numerous neurological disorders throughout the lifespan. Linking evidence of function in health and under pathological conditions, this review will outline the glial and neuroimmune mechanisms that may contribute to drug-abuse liability, exploring evidence from opioids, alcohol, and psychostimulants. Drugs of abuse can activate microglia and astrocytes through signaling at innate immune receptors, which in turn influence neuronal function not only through secretion of soluble factors (eg, cytokines and chemokines) but also potentially through direct remodeling of the synapses. In sum, this review will argue that neural-glial interactions represent an important avenue for advancing our understanding of substance abuse disorders.

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The HMGB1–RAGE axis in nucleus accumbens facilitates cocaine‐induced conditioned place preference via modulating microglial activation

Ye,

Gao,

Liu

et al. 2024

Brain and Behavior

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IntroductionRepeated exposure to cocaine induces microglial activation. Cocaine exposure also induces a release of high mobility group box‐1 (HMGB1) from neurons into the extracellular space in the nucleus accumbens (NAc). HMGB1 is an important late inflammatory mediator of microglial activation. However, whether the secretion of HMGB1 acts on microglia or contributes to cocaine addiction is largely unknown.MethodsRats were trained by intraperitoneal cocaine administration and cocaine‐induced conditioned place preference (CPP). Expression of HMGB1 was regulated by viral vectors. Activation of microglia was inhibited by minocycline. Interaction of HMGB1 and the receptor for advanced glycation end products (RAGE) was disrupted by peptide.ResultsCocaine injection facilitated HMGB1 signaling, together with the delayed activation of microglia concurrently in the NAc. Furthermore, the inhibition of HMGB1 or microglia activation attenuated cocaine‐induced CPP. Box A, a specific antagonist to interrupt the interaction of HMGB1 and RAGE, abolished the expression of cocaine reward memory. Meanwhile, the inhibition of HMGB1–RAGE interaction suppressed cocaine‐induced microglial activation, as well as the consolidation of cocaine‐induced memory.ConclusionAll above results suggest that the neural HMGB1 induces activation of microglia through RAGE, which contributes to the consolidation of cocaine reward memory. These findings offer HMGB1–RAGE axis as a new target for the treatment of drug addiction.

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DAT isn’t all that: cocaine reward and reinforcement require Toll-like receptor 4 signaling

Cited by 180 publications

References 63 publications

Toll-Like Receptor 4 Deficiency Causes Reduced Exploratory Behavior in Mice Under Approach-Avoidance Conflict

Toll-Like Receptor 4 Deficiency Causes Reduced Exploratory Behavior in Mice Under Approach-Avoidance Conflict

Glial and Neuroimmune Mechanisms as Critical Modulators of Drug Use and Abuse

The HMGB1–RAGE axis in nucleus accumbens facilitates cocaine‐induced conditioned place preference via modulating microglial activation

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