The histone demethylase KDM6B in the medial prefrontal cortex epigenetically regulates cocaine reward memory

Zhang, Yu-Xiang; Akumuo, Rita; España, Rodrigo A.; Yan, Cheng; Gao, Wen-Jun; Li, Yanchun

doi:10.1016/j.neuropharm.2018.08.030

Cited by 32 publications

(22 citation statements)

References 63 publications

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“…The lysine demethylase 6B (KDM6B) is upregulated in the mPFC during cocaine withdrawal and is known to regulate drug-associated reward memory. KDM6B inhibition disrupts both, reconsolidation of cocaine-conditioned memory and reinstatement, suggesting dual effects of KDM6B in cocaine drug-seeking behaviour [179]. In alcohol dependence, the upregulation of KDM6B is associated with epigenetic regulation of signalling pathways by a decrease in the H3K27me3 level, consistent with its known demethylase function [180].…”

Section: Addiction and Epigeneticsmentioning

confidence: 68%

Epigenetic Regulation of Circadian Clocks and Its Involvement in Drug Addiction

Saad

Zwiller

Kalsbeek

et al. 2021

Genes

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Based on studies describing an increased prevalence of addictive behaviours in several rare sleep disorders and shift workers, a relationship between circadian rhythms and addiction has been hinted for more than a decade. Although circadian rhythm alterations and molecular mechanisms associated with neuropsychiatric conditions are an area of active investigation, success is limited so far, and further investigations are required. Thus, even though compelling evidence connects the circadian clock to addictive behaviour and vice-versa, yet the functional mechanism behind this interaction remains largely unknown. At the molecular level, multiple mechanisms have been proposed to link the circadian timing system to addiction. The molecular mechanism of the circadian clock consists of a transcriptional/translational feedback system, with several regulatory loops, that are also intricately regulated at the epigenetic level. Interestingly, the epigenetic landscape shows profound changes in the addictive brain, with significant alterations in histone modification, DNA methylation, and small regulatory RNAs. The combination of these two observations raises the possibility that epigenetic regulation is a common plot linking the circadian clocks with addiction, though very little evidence has been reported to date. This review provides an elaborate overview of the circadian system and its involvement in addiction, and we hypothesise a possible connection at the epigenetic level that could further link them. Therefore, we think this review may further improve our understanding of the etiology or/and pathology of psychiatric disorders related to drug addiction.

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Section: Addiction and Epigeneticsmentioning

confidence: 68%

Epigenetic Regulation of Circadian Clocks and Its Involvement in Drug Addiction

Saad

Zwiller

Kalsbeek

et al. 2021

Genes

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“…Another outstanding question is the exact mechanisms by which ACA CaMKII neurons drive the long-term effect of enhanced drug-seeking induced by concurrent Meth and sex, during which we hypothesize key molecular events occur to induce long-term plasticity associated with habitual, dysregulated drug-seeking (Nestler, 2008 , 2014 ; Perrotti et al, 2008 ; Li et al, 2011 ; Muschamp et al, 2012 ; Godino et al, 2015 ; Zhang et al, 2018 ). Previously, we showed that concurrent Meth and sex experience induced long term increases in expression of phosphorylation of MAP kinase (pERK) in ACA CaMKII neurons (Kuiper et al, 2017 ), consistent with long term plasticity.…”

Section: Discussionmentioning

confidence: 99%

“…This plasticity may be a reflection of alterations in afferent signaling to the CaMKII cells, including local inhibitory interneurons (Morshedi and Meredith, 2007 ; Wearne et al, 2017 ). Cellular and epigenetic alterations have been observed in mPFC following chronic Meth (Howell and Kimmel, 2008 ; Shibasaki et al, 2011 ; Li et al, 2014 ) or other psychostimulants (Mychasiuk et al, 2013 ; Zhang et al, 2018 ). Since sexual behavior and drug exposure lead to similar molecular and plasticity mechanisms within NAc and VTA (Beloate and Coolen, 2017 , 2018 ), it is interesting to test if concurrent Meth and sex may cause either additive or synergistic effects on such cellular alterations.…”

Section: Discussionmentioning

confidence: 99%

Enhancement of Drug Seeking Following Drug Taking in a Sexual Context Requires Anterior Cingulate Cortex Activity in Male Rats

Kuiper

Lucas

Mai

et al. 2020

Front. Behav. Neurosci.

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Individual variance in vulnerability to develop addictions is influenced by social factors. Specifically, drug-taking in a sexual context appears to enhance further drug-seeking behavior in human users, as these users identify the effects of drugs to enhance sexual pleasure as a primary reason for continued drug use. Methamphetamine (Meth) is commonly used in this context. Similarly, male rats that self-administered Meth immediately followed by sexual behavior display enhanced drug-seeking behavior, including attenuation of extinction and increased reinstatement to seeking of Meth-associated cues. Hence, drug-taking in a sexual context enhances vulnerability for addiction. However, the neural mechanisms by which this occurs are unknown. Here the hypothesis was tested that medial prefrontal cortex is essential for this effect of Meth and sex when experienced concurrently. First it was shown that CaMKII neurons in the anterior cingulate area (ACA) were co-activated by both Meth and sex. Next, chemogenetic inactivation of ACA CaMKII cells using AAV5-CaMKIIa-hM4Di-mCherry was shown not to affect Meth-induced locomotor activity or sexual behavior. Subsequently, chemogenetic inactivation of ACA CaMKII neurons during Meth self-administration followed by sexual behavior was shown to prevent the effects of Meth and sex on enhanced reinstatement of Meth-seeking but did not affect enhanced drug-seeking during extinction tests. These results indicate that ACA CaMKII cell activation during exposure to Meth in a sexual context plays an essential role in the subsequent enhancement of drug-seeking during reinstatement tests.

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“…Rats went through procedures in Figure 1 without cannula placement, microinjection or locomotion test. Western blotting was performed as previously described ( Zhang et al, 2018 ). Briefly, brain tissue containing the VLO was rapidly collected after animal anesthesia and decapitation.…”

Section: Methodsmentioning

confidence: 99%

The 5-HT6 Receptors in the Ventrolateral Orbital Cortex Attenuate Allodynia in a Rodent Model of Neuropathic Pain

Zhang

Yang

et al. 2020

Front. Neurosci.

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Mechanical allodynia, characterized by a painful sensation induced by innocuous stimuli, is thought to be caused by disruption in pain-related regions. Identification and reversal of this pathologic neuroadaptation are therefore beneficial for clinical treatment. Previous evidence suggests that 5-HT 6 receptors in the ventrolateral orbital cortex (VLO) are involved in neuropathic pain, but their function is poorly understood. The aim of the present study is to unveil the role of 5-HT 6 receptors in the VLO and the underlying mechanisms in pain modulation. Here, by using the spared nerve injury (SNI) pain model, first, we report that 5-HT 6 receptor protein decreased in the contralateral VLO compared with the ipsilateral VLO in rats with allodynia. Second, microinjection of the selective 5-HT 6 receptor agonists EMD-386088 and WAY-208466 into the contralateral VLO consistently and significantly depressed allodynia. Third, microinjection of the selective antagonist SB-258585 blocked the agonist-induced anti-allodynic effect, while the antagonist applied alone to the VLO had no effect. Furthermore, the anti-nociceptive effect of EMD-386088 on neuropathic pain was prevented by the adenylate cyclase (AC) inhibitor SQ-22536, and protein kinase A (PKA) inhibitor H89, suggesting that AC/PKA signaling might underlie the antinociception of agonists. Finally, the 5-HT 6 receptors were found to be colocalized with a glutamate transporter (EAAC1) by immunofluorescent staining, and the glutamate receptor antagonist kynurenic acid was found to completely block antinociception. These findings indicated that the antinociceptive effect of 5-HT 6 receptor agonists might occur via interaction with the glutamatergic system. Altogether, the agonists activated 5-HT 6 receptors present in the glutamatergic neurons in the VLO to facilitate the AC/PKA cascade, which subsequently might evoke glutamate release, thus depressing allodynia. These findings suggest a potential therapeutic role of 5-HT 6 receptor agonists in treating neuropathic pain.

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The histone demethylase KDM6B in the medial prefrontal cortex epigenetically regulates cocaine reward memory

Cited by 32 publications

References 63 publications

Epigenetic Regulation of Circadian Clocks and Its Involvement in Drug Addiction

Epigenetic Regulation of Circadian Clocks and Its Involvement in Drug Addiction

Enhancement of Drug Seeking Following Drug Taking in a Sexual Context Requires Anterior Cingulate Cortex Activity in Male Rats

The 5-HT6 Receptors in the Ventrolateral Orbital Cortex Attenuate Allodynia in a Rodent Model of Neuropathic Pain

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