Dataset Information

Gene expression changes in the medial prefrontal cortex and nucleus accumbens following abstinence from cocaine self-administration.

ABSTRACT:

Background

Many studies of cocaine-responsive gene expression have focused on changes occurring during cocaine exposure, but few studies have examined the persistence of these changes with cocaine abstinence. Persistent changes in gene expression, as well as alterations induced during abstinence may underlie long-lasting drug craving and relapse liability.

Results

Whole-genome expression analysis was conducted on a rat cocaine binge-abstinence model that has previously been demonstrated to engender increased drug seeking and taking with abstinence. Gene expression changes in two mesolimbic terminal fields (mPFC and NAc) were identified in a comparison of cocaine-naïve rats with rats after 10 days of cocaine self-administration followed by 1, 10, or 100 days of enforced abstinence (n = 6-11 per group). A total of 1,461 genes in the mPFC and 414 genes in the NAc were altered between at least two time points (ANOVA, p < 0.05; +/- 1.4 fold-change). These genes can be subdivided into: 1) changes with cocaine self-administration that do not persist into periods of abstinence, 2) changes with cocaine self-administration that persist with abstinence, 3) and those not changed with cocaine self-administration, but changed during enforced abstinence. qPCR analysis was conducted to confirm gene expression changes observed in the microarray analysis.

Conclusions

Together, these changes help to illuminate processes and networks involved in abstinence-induced behaviors, including synaptic plasticity, MAPK signaling, and TNF signaling.

SUBMITTER: Freeman WM

PROVIDER: S-EPMC2837051 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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Publications

Gene expression changes in the medial prefrontal cortex and nucleus accumbens following abstinence from cocaine self-administration.

Freeman Willard M WM Lull Melinda E ME Patel Kruti M KM Brucklacher Robert M RM Morgan Drake D Roberts David C S DC Vrana Kent E KE

BMC neuroscience 20100226

<h4>Background</h4>Many studies of cocaine-responsive gene expression have focused on changes occurring during cocaine exposure, but few studies have examined the persistence of these changes with cocaine abstinence. Persistent changes in gene expression, as well as alterations induced during abstinence may underlie long-lasting drug craving and relapse liability.<h4>Results</h4>Whole-genome expression analysis was conducted on a rat cocaine binge-abstinence model that has previously been demons ...[more]

PMID: 20187946

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Project description:The reinforcing effects and long-term consequences of cocaine self-administration have been associated with brain regions of the mesolimbic dopamine pathway, namely the nucleus accumbens (NAc). Studies of cocaine-induced biochemical adaptations in rodent models have advanced our knowledge; however, unbiased detailed assessments of intracellular alterations in the primate brain are scarce, yet essential, to develop a comprehensive understanding of cocaine addiction. To this end, two-dimensional difference in gel electrophoresis (2D-DIGE) was used to compare changes in cytosolic protein abundance in the NAc between rhesus monkeys self-administering cocaine and controls. Following image normalization, spots with significantly differential image intensities (P<0.05) were identified, excised, trypsin digested and analyzed by matrix-assisted laser-desorption ionization time-of-flight time-of-flight (MALDI-TOF-TOF). In total, 1098 spots were subjected to statistical analysis with 22 spots found to be differentially abundant of which 18 proteins were positively identified by mass spectrometry. In addition, approximately 1000 protein spots were constitutively expressed of which 21 proteins were positively identified by mass spectrometry. Increased levels of proteins in the cocaine-exposed monkeys include glial fibrillary acidic protein, syntaxin-binding protein 3, protein kinase C isoform, adenylate kinase isoenzyme 5 and mitochondrial-related proteins, whereas decreased levels of proteins included beta-soluble N-ethylmaleimide-sensitive factor attachment protein and neural and non-neural enolase. Using a complimentary proteomics approach, the differential expression of phosphorylated proteins in the cytosolic fraction of these subjects was examined. Two-dimensional gel electrophoresis (2DGE) was followed by gel staining with Pro-Q Diamond phosphoprotein gel stain, enabling differentiation of approximately 150 phosphoprotein spots between the groups. Following excision and trypsin digestions, MALDI-TOF-TOF was used to confirm the identity of 15 cocaine-altered phosphoproteins. Significant increased levels were detected for gamma-aminobutyric acid type A receptor-associated protein 1, 14-3-3 gamma-protein, glutathione S-transferase and brain-type aldolase, whereas significant decreases were observed for beta-actin, Rab GDP-dissociation inhibitor, guanine deaminase, peroxiredoxin 2 isoform b and several mitochondrial proteins. Results from these studies indicate coordinated dysregulation of proteins related to cell structure, signaling, metabolism and mitochondrial function. These data extend and compliment previous studies of cocaine-induced biochemical alterations in human postmortem brain tissue, using an animal model that closely recapitulates the human condition and provide new insight into the molecular basis of the disease and potential targets for pharmacotherapeutic intervention.

Project description:Chronic cocaine exposure influences the density and morphology of dendritic spines on medium spiny neurons (MSNs) in the nucleus accumbens (NAc), a critical brain region for cocaine craving. However, the relationship between spine plasticity and craving remains unclear. To study this relationship, we trained rats to self-administer cocaine using an extended-access regimen (6 h per day, 10 days); controls self-administered saline. Previously, a time-dependent intensification (incubation) of cue-induced cocaine craving has been demonstrated after withdrawal from this regimen; furthermore, Ca2+-permeable AMPA receptors (CP-AMPARs) increase in the NAc core after ~1 month of withdrawal and thereafter mediate the expression of incubated craving. Although neither craving nor CP-AMPAR levels were measured in the present study, we killed rats at four withdrawal day (WD) time-points (WD14, WD25, WD36, or WD60) selected to span the rising phase of incubation and the transition from low to high CP-AMPAR levels. MSNs were iontophoretically filled with Lucifer yellow and spines were analyzed with NeuronStudio software. Compared with saline controls, cocaine rats showed no changes in spine density or morphology in the NAc core on WD14 or WD25. On WD36, approximately the withdrawal time when stable elevation of CP-AMPAR levels is detected, the cocaine group exhibited increased density of thin spines in the NAc core. By WD60, however, this effect had reversed: the density of thin spines was lower in cocaine rats compared with saline rats. In contrast, craving and CP-AMPAR levels remain high on WD60. We also assessed spine density on WD36 in the dorsolateral striatum, a region that is not implicated in incubation of cocaine craving and does not undergo CP-AMPAR plasticity. Here, the cocaine group exhibited a small leftward shift in the distribution of spine densities plotted as a cumulative distribution, opposite to the effect found in the NAc core. Overall, our results demonstrate changes in NAc core spines over 2 months of withdrawal but no simple relationship between the time dependency of these spine changes and the previously demonstrated time course of incubation of cocaine craving. However, they raise the possibility that CP-AMPAR accumulation in the NAc core occurs in a population of thin spines that emerges after ~1 month of withdrawal.

Dataset Information

Gene expression changes in the medial prefrontal cortex and nucleus accumbens following abstinence from cocaine self-administration.

Background

Results

Conclusions

Publications

Gene expression changes in the medial prefrontal cortex and nucleus accumbens following abstinence from cocaine self-administration.

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