Prior alcohol use enhances vulnerability to compulsive cocaine self-administration by promoting degradation of HDAC4 and HDAC5

Griffin, Edmund A.; Melas, Philippe A.; Zhou, Royce W.; Li, Yang; Mercado, Peter; Kempadoo, Kimberly A.; Stephenson, Stacy; Colnaghi, Luca; Taylor, Kathleen; Hu, Mei‐Chen; Kandel, Eric R.; Kandel, Denise B.

doi:10.1126/sciadv.1701682

Cited by 47 publications

(34 citation statements)

References 55 publications

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“…To this end, we first confirmed the presence of crosssensitization between WIN and cocaine only in adolescent (and not in adult) rats. Our previous studies on other "gateway" drugs, such as nicotine and alcohol (41,42), suggested that drugpriming properties are mediated by epigenetic mechanisms (e.g., HDACs and histone acetylation) in line with the epigeneticpriming hypothesis in addiction (43). In agreement with this hypothesis, we found that WIN preexposure resulted in cocaineinduced global histone hyperacetylation in the adolescent PFC.…”

Section: Discussionsupporting

confidence: 89%

Cannabinoid exposure in rat adolescence reprograms the initial behavioral, molecular, and epigenetic response to cocaine

Scherma

Qvist

Asok

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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The initial response to an addictive substance can facilitate repeated use: That is, individuals experiencing more positive effects are more likely to use that drug again. Increasing evidence suggests that psychoactive cannabinoid use in adolescence enhances the behavioral effects of cocaine. However, despite the behavioral data, there is no neurobiological evidence demonstrating that cannabinoids can also alter the brain’s initial molecular and epigenetic response to cocaine. Here, we utilized a multiomics approach (epigenomics, transcriptomics, proteomics, and phosphoproteomics) to characterize how the rat brain responds to its first encounter with cocaine, with or without preexposure to the synthetic cannabinoid WIN 55,212-2 (WIN). We find that in adolescent (but not in adult) rats, preexposure to WIN results in cross-sensitization to cocaine, which correlates with histone hyperacetylation and decreased levels of HDAC6 in the prefrontal cortex (PFC). In the PFC, we also find that WIN preexposure blunts the typical mRNA response to cocaine and instead results in alternative splicing and chromatin accessibility events, involving genes such as Npas2. Moreover, preexposure to WIN enhances the effects of cocaine on protein phosphorylation, including ERK/MAPK-targets like gephyrin, and modulates the synaptic AMPAR/GluR composition both in the PFC and the nucleus accumbens (NAcc). PFC–NAcc gene network topological analyses, following cocaine exposure, reveal distinct top nodes in the WIN preexposed group, which include PACAP/ADCYAP1. These preclinical data demonstrate that adolescent cannabinoid exposure reprograms the initial behavioral, molecular, and epigenetic response to cocaine.

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Section: Discussionsupporting

confidence: 89%

Cannabinoid exposure in rat adolescence reprograms the initial behavioral, molecular, and epigenetic response to cocaine

Scherma

Qvist

Asok

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Also, given that several epigenetic mechanisms regulate transcription, it is possible that other mechanisms are contributing to gene expression, such as DNA methylation or microRNA interactions. Nonetheless, we found an association between histone acetylation and gene expression after repeated METH treatment for Hdac2 (decreased promoter H3/H4ac and mRNA levels) and Hdac4 (increased promoter H4ac and mRNA levels), which is in agreement with the proposed role of gene targets of class IIa HDACs in chronic responses to addictive drugs …”

Section: Discussionsupporting

confidence: 89%

“…It is noteworthy that increased H4ac at Hdac4 and Hdac5 after repeated METH occurred in parallel with decreased H3/H4ac at class I Hdac1 , Hdac2 , and Hdac8 . It has been proposed that behavioral responses to chronic exposure to addictive drugs may involve class IIa HDAC gene targets . HDAC4 and 5 appear to have specific roles in synaptic plasticity, memory formation, and spatial learning, and they have been implicated in cocaine reward and METH craving .…”

Section: Discussionmentioning

confidence: 99%

HDAC superfamily promoters acetylation is differentially regulated by modafinil and methamphetamine in the mouse medial prefrontal cortex

et al. 2019

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Dysregulation of histone deacetylases (HDAC) has been proposed as a potential contributor to aberrant transcriptional profiles that can lead to changes in cognitive functions. It is known that METH negatively impacts the prefrontal cortex (PFC) leading to cognitive decline and addiction whereas modafinil enhances cognition and has a low abuse liability. We investigated if modafinil (90 mg/kg) and methamphetmine (METH)(1 mg/kg) may differentially influence the acetylation status of histones 3 and 4 (H3ac and H4ac) at proximal promoters of class I, II, III, and IV HDACs. We found that METH produced broader acetylation effects in comparison with modafinil in the medial PFC.For single dose, METH affected H4ac by increasing its acetylation at class I Hdac1 and class IIb Hdac10, decreasing it at class IIa Hdac4 and Hdac5. Modafinil increased H3ac and decreased H4ac of Hdac7. For mRNA, single-dose METH increased Hdac4 and modafinil increased Hdac7 expression. For repeated treatments (4 d after daily injections over 7 d), we found specific effects only for METH. We found that METH increased H4ac in class IIa Hdac4 and Hdac5 and decreased H3/H4ac at class I Hdac1, Hdac2, and Hdac8. At the mRNA level, repeated METH increased Hdac4 and decreased Hdac2. Class III and IV HDACs were only responsive to repeated treatments, where METH affected the H3/H4ac status of Sirt2, Sirt3, Sirt7, and Hdac11.Our results suggest that HDAC targets linked to the effects of modafinil and METH may be related to the cognitive-enhancing vs cognitive-impairing effects of these psychostimulants.

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“…In summary, we report that homozygous Hdac4 A778T mice on a nearly isogenic C57BL/6 background exhibit certain metabolic and behavioral phenotypes relevant to EDs in a sexdependent manner, including altered feeding and body weight, reduced motivation for palatable food and social subordination, which may be influenced by complicated environmental factors. Since HDAC4 has been implicated in many different brain functions, including learning and memory (Kim et al, 2012;Sando et al, 2012;Fitzsimons et al, 2013;Makinistoglu and Karsenty, 2015;Wu et al, 2016), neurodegeneration (Majdzadeh et al, 2008;Li et al, 2012;Mielcarek et al, 2013Mielcarek et al, , 2015Whitehouse et al, 2015;Wu et al, 2017;Federspiel et al, 2019), drug addiction (Griffin et al, 2017;Penrod et al, 2018;Gonzalez et al, 2019), PTSD (Maddox et al, 2018;Saha et al, 2019), and major depressive disorder (Hobara et al, 2010;Sarkar et al, 2014;Higuchi et al, 2016), future mechanistic investigations in homozygous Hdac4 A778T mice at molecular, cellular and circuit levels will not only provide novel insight into the neurobiological basis of an ED, but also advance our knowledge about the underlying mechanisms of other neuropsychiatric disorders.…”

Section: Discussionmentioning

confidence: 99%

Behavioral Alterations in Mice Carrying Homozygous HDAC4A778T Missense Mutation Associated With Eating Disorder

et al. 2020

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Prior alcohol use enhances vulnerability to compulsive cocaine self-administration by promoting degradation of HDAC4 and HDAC5

Abstract: Prior alcohol use increases vulnerability to cocaine addiction by promoting degradation of HDAC4 and HDAC5.

Cited by 47 publications

References 55 publications

Cannabinoid exposure in rat adolescence reprograms the initial behavioral, molecular, and epigenetic response to cocaine

Cannabinoid exposure in rat adolescence reprograms the initial behavioral, molecular, and epigenetic response to cocaine

HDAC superfamily promoters acetylation is differentially regulated by modafinil and methamphetamine in the mouse medial prefrontal cortex

Behavioral Alterations in Mice Carrying Homozygous HDAC4A778T Missense Mutation Associated With Eating Disorder

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