A single exposure to cocaine during development elicits regionally-selective changes in basal basic Fibroblast Growth Factor (FGF-2) gene expression and alters the trophic response to a second injection

Giannotti, Giuseppe; Caffino, Lucia; Malpighi, Chiara; Melfi, Simona; Racagni, Giorgio; Fumagalli, Fabio

doi:10.1007/s00213-014-3708-x

Cited by 15 publications

(13 citation statements)

References 32 publications

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“…Our previous study found that adolescent cocaine exposure results in a prolonged modification on synapses in adult medial prefrontal cortex (mPFC) (6). A single cocaine injection could produce changes in the mPFC of adolescent rather than adult animals (7,8), indicating that adolescent mPFC is more sensitive to cocaine experience than that of adults (9,10). Subregions of mPFC, mainly including cingulate cortex, prelimbic cortex (PrL), and infralimbic cortex, demonstrate distinct connectivity and regulate different behavioral outcomes (11).…”

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Adolescent cocaine exposure enhances the GABAergic transmission in the prelimbic cortex of adult mice

et al. 2019

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We have recently shown in rats that adolescent cocaine exposure induces prolonged modifications on synapses in medial prefrontal cortex (mPFC), which might contribute to long‐term behavioral outcomes in adulthood. In this study, we further investigated the molecular mechanisms underlying adolescent cocaine exposure‐related psychiatric problems in adulthood, especially focusing on the alterations of GABAergic transmission in prelimbic cortex (PrL), 1 subregion of mPFC. Consistent with a previous study, adolescent cocaine‐exposed mice exhibited enhanced anxiety‐like behaviors in their adulthood. In the same mice models, depression‐like behaviors increased as well, but the conditioned place preference formed normally. In parallel, activities of pyramidal neurons at layer V of PrL were reduced after adolescent cocaine exposure, accompanied by an increase in the percentage of symmetric synapses in PrL of adult mice. Additionally, miniature inhibitory postsynaptic currents rather than miniature excitatory postsynaptic currents were increased on these pyramidal neurons, and increased levels of GABA were found in adult PrL. The molecules in the GABAergic system in adult PrL were also changed by adolescent cocaine use, as indicated by increased glutamate decarboxylase 67kDa, GAB AA‐αl, and decreased GABA transporter 1. In the same mice, some regulators to GABAergic transmission such as neuregulin l/ErbB4 signals were heightened as well. Collectively, these findings revealed that adolescent cocaine exposure results in permanent enhancement of GABAergic transmission on pyramidal neurons in PrL, which subsequently attenuate the activities of these neurons and ultimately contributes to the development of psychiatric disorders in later life.—Shi, P., Nie, J., Liu, H., Li, Y., Lu, X., Shen, X., Ge, F., Yuan, T.‐F., Guan, X. Adolescent cocaine exposure enhances the GABAergic transmission in the prelimbic cortex of adult mice. FASEB J. 33, 8614–8622 (2019). http://www.fasebj.org

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Adolescent cocaine exposure enhances the GABAergic transmission in the prelimbic cortex of adult mice

et al. 2019

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“…These findings add complexity as well as specificity to our previous data and reinforce the notion that a single cocaine exposure during adolescence is sufficient to trigger functional and structural changes in the rat brain. We have previously shown that a single injection of cocaine during adolescence influences the response to a second challenge of the psychostimulant, altering trophic response (Giannotti et al, 2015) as well as actin dynamics (Caffino et al, 2017b) thus suggesting that early cocaine priming might affect plasticity in the developing brain. Further studies will evaluate whether a single exposure to cocaine during adolescence influences addiction liability at adulthood.…”

Section: Resultsmentioning

confidence: 99%

“…Since adolescence is considered a window of vulnerability to drugs of abuse, we have recently investigated whether a single exposure to cocaine during this exquisitely sensitive maturational period would be sufficient to alter brain plasticity. We have found that a single cocaine exposure alters expression of neurotrophic factors such as FGF-2 (Giannotti et al, 2015) and disrupts actin dynamics (Caffino et al, 2017b). Based on these lines of evidence, we hypothesized that a single injection of cocaine during adolescence would be sufficient to trigger enduring morphological changes in the developing brain, altering the glutamate synapse.…”

Section: Introductionmentioning

confidence: 99%

“…Rats were sacrificed at PND 42, i.e. 7 days after the drug exposure: the choice of this time point derives from previous evidence from our laboratory showing molecular changes indicative of cortical reorganization 7 days after a single administration of cocaine (Caffino et al, 2017b;Giannotti et al, 2015). Moreover, in order to investigate whether a single injection of cocaine during adolescence might impact the glutamate synapse differently from adulthood, we exposed adult rats to the same treatment schedule and sacrificed them 7 days after treatment, i.e.…”

Section: Introductionmentioning

confidence: 99%

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A single cocaine administration alters dendritic spine morphology and impairs glutamate receptor synaptic retention in the medial prefrontal cortex of adolescent rats

2018

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The brain is still maturing during adolescence and interfering with such a vulnerable period may lead to structural and functional consequences. We investigated the effect of a single cocaine exposure on dendritic spine structure and glutamate dynamics in the medial prefrontal cortex (mPFC) of adolescent rats 7 days after a single cocaine administration. We found a reduced number of dendritic spines, suggesting that cocaine lowers the density of dendritic spines in the mPFC of adolescent rats. Since dendritic spines are postsynaptic glutamatergic protrusions, we investigated the main determinants of glutamate postsynaptic responsiveness. In the postsynaptic density, cocaine reduced the expression of the NMDA receptor subunits GluN1, GluN2A and GluN2B as well as of the AMPA GluA1 and GluA2 subunits. Cocaine also impaired their synaptic stability since the expression of the scaffolding proteins SAP102 and SAP97, critical for the anchoring of such receptors at the postsynaptic membrane, was reduced as well. The expression of PSD-95 and Arc/Arg3.1, which play structural and functional roles in glutamate neurons, was also similarly reduced. Such changes were not found in the whole homogenate, ruling out a translational effect of cocaine and implying, rather, an impaired synaptic retention at the active zones of the synapse. Notably, neither these critical glutamate determinants nor the density and morphology of the dendritic spines were altered in the mPFC of adult animals, suggesting that a single cocaine exposure selectively impairs the developmental trajectory of the glutamate synapse. These results indicate a dynamic impairment of mPFC glutamate homeostasis during a critical developmental window that persists for at least one week after a single cocaine administration. Our results identify dysfunctional glutamate synapse as a major contributor to the mechanisms that distinguish adolescent vs. adult outcomes of a single cocaine exposure.

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“…Indeed, some genes involved in compensatory adaptive changes might display gene priming, reflecting graded levels of epigenetic regulation, and transcription-based changes in protein abundance might modify the redox-regulated pathways indicated in Figure 2 . Recent advancements (Anker and Carroll, 2011 ; Robison and Nestler, 2011 ; Schwarz et al, 2011 ; Feng and Nestler, 2013 ; Giannotti et al, 2014 ; Li et al, 2014 ) clearly indicate the potential value of investigating the various mechanisms that modulate the reversible transitions between chromatin states under the influence of drug exposure, including gene priming and desensitization.…”

Section: Gene Primingmentioning

confidence: 99%

Redox-based epigenetic status in drug addiction: a potential contributor to gene priming and a mechanistic rationale for metabolic intervention

Trivedi

Deth

2015

Front. Neurosci.

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Alcohol and other drugs of abuse, including psychostimulants and opioids, can induce epigenetic changes: a contributing factor for drug addiction, tolerance, and associated withdrawal symptoms. DNA methylation is a major epigenetic mechanism and it is one of more than 200 methylation reactions supported by methyl donor S-adenosylmethionine (SAM). Levels of SAM are controlled by cellular redox status via the folate and vitamin B12-dependent enzyme methionine synthase (MS). For example, under oxidative conditions MS is inhibited, diverting its substrate homocysteine (HCY) to the trans sulfuration pathway. Alcohol, dopamine, and morphine, can alter intracellular levels of glutathione (GSH)-based cellular redox status, subsequently affecting SAM levels and DNA methylation status. Here, existing evidence is presented in a coherent manner to propose a novel hypothesis implicating the involvement of redox-based epigenetic changes in drug addiction. Further, we discuss how a “gene priming” phenomenon can contribute to the maintenance of redox and methylation status homeostasis under various stimuli including drugs of abuse. Additionally, a new mechanistic rationale for the use of metabolic interventions/redox-replenishers as symptomatic treatment of alcohol and other drug addiction and associated withdrawal symptoms is also provided. Hence, the current review article strengthens the hypothesis that neuronal metabolism has a critical bidirectional coupling with epigenetic changes in drug addiction exemplified by the link between redox-based metabolic changes and resultant epigenetic consequences under the effect of drugs of abuse.

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A single exposure to cocaine during development elicits regionally-selective changes in basal basic Fibroblast Growth Factor (FGF-2) gene expression and alters the trophic response to a second injection

Abstract: These findings show that a single cocaine injection is sufficient to produce enduring changes in the adolescent brain and indicate that early cocaine priming alters the mechanisms regulating the trophic response in a brain region-specific fashion.

Cited by 15 publications

References 32 publications

Adolescent cocaine exposure enhances the GABAergic transmission in the prelimbic cortex of adult mice

Adolescent cocaine exposure enhances the GABAergic transmission in the prelimbic cortex of adult mice

A single cocaine administration alters dendritic spine morphology and impairs glutamate receptor synaptic retention in the medial prefrontal cortex of adolescent rats

Redox-based epigenetic status in drug addiction: a potential contributor to gene priming and a mechanistic rationale for metabolic intervention

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