Regulation of Gene Expression by Chronic Morphine and Morphine Withdrawal in the Locus Ceruleus and Ventral Tegmental Area

McClung, Colleen A.; Nestler, Eric J.; Zachariou, Venetia

doi:10.1523/jneurosci.0062-05.2005

Cited by 149 publications

(155 citation statements)

References 46 publications

(48 reference statements)

Supporting

Mentioning

137

Contrasting

Unclassified

Order By: Relevance

“…Thus, our microarray analysis, in addition to confirm a number of transcriptional targets of morphine (Korostynski et al, 2007;McClung et al, 2005) and reveal novel ones, provided a short list of candidate genes to have a function in HDACimediated enhancement of non-homeostatic behavioral responses to morphine. Particularly remarkable is the case of circadian clock genes.…”

Section: Discussionmentioning

confidence: 86%

“…Although circadian clock genes are appealing candidates for mediating the interaction between sodium butyrate and morphine, the transcriptional program activated by chronic morphine is broad (Korostynski et al, 2007;McClung et al, 2005) and its interaction with sodium butyrate complex ( Figure 5; Supplementary Figure S5). Besides circadian genes, our results show that morphine and sodium butyrate interact on the regulation of the expression of several other transcription factors that may lead to further transcriptional changes, such as fosB, the activity-regulated transcription factors Npas4 and Nr4al, and the transcriptional repressor Zbtb16 that positively regulates the ERK pathway and can potentially enhance drug effects.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Selective Boosting of Transcriptional and Behavioral Responses to Drugs of Abuse by Histone Deacetylase Inhibition

Sanchis‐Segura

López‐Atalaya

Barco

2009

Neuropsychopharmacol

121

View full text Add to dashboard Cite

Histone acetylation and other modifications of the chromatin are important regulators of gene expression and, consequently, may contribute to drug-induced behaviors and neuroplasticity. Earlier studies have shown that a reduction in histone deacetylase (HDAC) activity results in the enhancement of some psychostimulant-induced behaviors. In this study, we extend those seminal findings by showing that the administration of the HDAC inhibitor sodium butyrate enhances morphine-induced locomotor sensitization and conditioned place preference. In contrast, this compound has no effects on the development of morphine tolerance and dependence. Similar effects were observed for cocaine and ethanol-induced behaviors. These behavioral changes were accompanied by a selective boosting of a component of the transcriptional program activated by chronic morphine administration that included circadian clock genes and other genes relevant to addictive behavior. Our results support a specific function for histone acetylation and the epigenetic modulation of transcription at a reduced number of biologically relevant loci on non-homeostatic, long-lasting, drug-induced behavioral plasticity.

show abstract

Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Selective Boosting of Transcriptional and Behavioral Responses to Drugs of Abuse by Histone Deacetylase Inhibition

Sanchis‐Segura

López‐Atalaya

Barco

2009

Neuropsychopharmacol

121

View full text Add to dashboard Cite

show abstract

“…Genome-wide mRNA analysis has identified many potential gene targets for drugs of abuse in distinct brain reward regions (Freeman et al, 2001;McClung and Nestler, 2003;McClung et al, 2005;Winstanley et al, 2007;Yao et al, 2004). Therefore, it is of great interest to identify the underlying mechanisms by which chronic cocaine experience promote Histone acetylation, motivation, and self-administration L Wang et al sustained changes in gene expression.…”

Section: Discussionmentioning

confidence: 99%

Chronic Cocaine-Induced H3 Acetylation and Transcriptional Activation of CaMKIIα in the Nucleus Accumbens Is Critical for Motivation for Drug Reinforcement

Wang

et al. 2009

Neuropsychopharmacol

160

156

View full text Add to dashboard Cite

The regulation of gene expression in the brain reward regions is known to contribute to the pathogenesis and persistence of drug addiction. Increasing evidence suggests that the regulation of gene transcription is mediated by epigenetic mechanisms that alter the chromatin structure at specific gene promoters. To better understand the involvement of epigenetic regulation in drug reinforcement properties, rats were subjected to cocaine self-administration paradigm. Daily histone deacetylase (HDAC) inhibitor infusions in the shell of the nucleus accumbens (NAc) caused an upward shift in the dose-response curve under fixed-ratio schedule and increased the break point under progressive-ratio schedule, indicating enhanced motivation for self-administered drug. The effect of the HDAC inhibitor is attributed to the increased elevation of histone acetylation induced by chronic, but not acute, cocaine experience. In contrast, neutralizing the chronic cocaine-induced increase in histone modification by the bilateral overexpression of HDAC4 in the NAc shell reduced drug motivation. The association between the motivation for cocaine and the transcriptional activation of addiction-related genes by H3 acetylation in the NAc shell was analyzed. Among the genes activated by chronic cocaine experiences, the expression of CaMKIIa, but not CaMKIIb, correlated positively with motivation for the drug. Lentivirus-mediated shRNA knockdown experiments showed that CaMKIIa, but not CaMKIIb, in the NAc shell is essential for the maintenance of motivation to self-administered cocaine. These findings suggest that chronic drug-use-induced transcriptional activation of genes, such as CaMKIIa, modulated by H3 acetylation in the NAc is a critical regulatory mechanism underlying motivation for drug reinforcement. Neuropsychopharmacology (2010) 35, 913-928; doi:10.1038/npp.2009; published online 9 December 2009 Keywords: histone acetylation; nucleus accumbens; motivation; cocaine self-administration; addiction; CaMKIIa INTRODUCTIONDrug addiction is a debilitating psychiatric disorder characterized by (1) a compulsion to seek and take the drug, (2) a loss of control in limiting intake, and (3) the emergence of a negative emotional state when access to the drug is prevented (Hyman et al, 2006;Kalivas et al, 2005;Koob and Kreek, 2007). The complex behavioral changes leading to drug addiction are thought to result from molecular and cellular adaptation in specific brain regions (Brami-Cherrier et al, 2005). One area of intensive research to clarify neuroadaptation addresses the regulation of gene expression induced by the drug (Nestler, 2001). The drug induces changes in gene expression in key brain reward regions, such as the nucleus accumbens (NAc), prefrontal cortex (PFC), and ventral tegmental area (VTA). For instance, the expression of the immediate early gene c-Fos and several other Fos family proteins is upregulated in the nucleus accumbens, striatum (Courtin et al, 2006) and frontal cortex (Thiriet et al, 2000) after acute cocaine treatment. T...

show abstract

“…The adrenergic fibers arising from medullary A1-A2 neuron groups projecting to the bed nucleus of the stria terminalis may also contribute to the opioid withdrawal syndrome (Delfs et al, 2000). Rebound of adenylyl cyclase activity in these parts of the brain (Punch et al, 1997;Williams et al, 2001;McClung et al, 2005) may constitute the molecular correlate of withdrawal.…”

Section: Discussionmentioning

confidence: 99%

Absence and Rescue of Morphine Withdrawal in GIRK/Kir3 Knock-out Mice

Cruz¹,

Berton²,

Sollini³

et al. 2008

J. Neurosci.

View full text Add to dashboard Cite

Although morphine induces both analgesia and dependence through -opioid receptors (MORs), the respective contributions of the intracellular effectors engaged by MORs remain unknown. To examine the contribution of G-protein-gated inwardly rectifying K ϩ (GIRK, Kir3) channels to morphine dependence and analgesia, we quantified naloxone-precipitated withdrawal behavior and morphine analgesia using GIRK knock-out ( Ϫ/Ϫ ) mice. The morphine withdrawal syndrome was strongly attenuated, whereas morphine analgesia was mostly preserved in mice lacking both GIRK2 and GIRK3 (GIRK2/3 Ϫ/Ϫ mice). In acute slices containing the locus ceruleus (LC) from GIRK2/3 Ϫ/Ϫ mice, the increase in spontaneous firing typically associated with morphine withdrawal was absent. Moreover, although morphine elicited normal presynaptic inhibition in the LC, postsynaptic GIRK currents were completely abolished in GIRK2/3 Ϫ/Ϫ mice. Altogether, these data suggested that morphine-evoked postsynaptic inhibition of the LC was required for the induction of dependence. Consistent with this hypothesis, morphine withdrawal behavior was rescued in GIRK2/3 Ϫ/Ϫ mice by ablation of adrenergic fibers using the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine. Our data suggest that inhibition of adrenergic tone is required for the induction of dependence, and that channels containing GIRK2 and GIRK3 serve as an inhibitory gate.

show abstract

Regulation of Gene Expression by Chronic Morphine and Morphine Withdrawal in the Locus Ceruleus and Ventral Tegmental Area

Cited by 149 publications

References 46 publications

Selective Boosting of Transcriptional and Behavioral Responses to Drugs of Abuse by Histone Deacetylase Inhibition

Selective Boosting of Transcriptional and Behavioral Responses to Drugs of Abuse by Histone Deacetylase Inhibition

Chronic Cocaine-Induced H3 Acetylation and Transcriptional Activation of CaMKIIα in the Nucleus Accumbens Is Critical for Motivation for Drug Reinforcement

Absence and Rescue of Morphine Withdrawal in GIRK/Kir3 Knock-out Mice

Contact Info

Product

Resources

About