Gene expression regulation following behavioral sensitization to cocaine in transgenic mice lacking the glucocorticoid receptor in the brain

doi:10.1016/j.neuroscience.2005.10.006

Neuroscience

Volume 137, Issue 3, 2006, Pages 915-924

https://doi.org/10.1016/j.neuroscience.2005.10.006 Get rights and content

Abstract

Several findings suggest that glucocorticoid hormones influence the propensity of an individual to develop cocaine abuse. These hormones activate two related transcription factors, the glucocorticoid receptor and the mineralocorticoid receptor. We have shown previously that mice carrying a mutation of the glucocorticoid receptor gene specifically in neural cells, glucocorticoid receptor knock-out in the brain, show a dramatic decrease in cocaine-induced self-administration and no behavioral sensitization to this drug, two experimental procedures considered relevant models of addiction. Here, we investigated in glucocorticoid receptor knock-out in the brain mice the consequences of this mutation at the level of the expression of neuropeptide, dopamine receptor and glutamate receptor subunit mRNAs. We quantified mRNA levels in the cortex, striatum and accumbens under basal conditions and following acute or repeated cocaine treatments. Our results show that, under basal conditions, neuropeptide (substance P, dynorphin) and dopamine receptor (D1, D2) mRNAs were decreased in glucocorticoid receptor knock-out in the brain mice in the dorsal striatum but not in the accumbens. However, cocaine-induced changes in the levels of these mRNAs were not modified in glucocorticoid receptor knock-out in the brain mice. In contrast, mutant mice showed altered response in mRNA levels of N-methyl-d-aspartate, GLUR5 and GLUR6 glutamate receptor subunits as well as of enkephalin following cocaine administration. These modifications may be associated to decrease of behavioral effects of cocaine observed in glucocorticoid receptor knock-out in the brain mice.

Section snippets

Mice

Housing of the animals and all animal experimental procedures were carried out in accordance with the guidelines of the French Agriculture and Forestry Ministry (decree 87849) and of European Communities Council Directive (86/609/EEC). All efforts were made to reduce the number of animals used and their suffering. Male Grl1^loxP/loxP NesCre (denominated GR^NesCre, Tronche et al., 1999), bred on a mixed C57B/6–129SveV genetic background and their corresponding controls were used. Mice were

Cocaine-induced behavioral sensitization in GR^NesCre mice

Behavioral results have been previously published (Deroche-Gamonet et al., 2003) and will not be presented here but only briefly summarized.

Behavioral response to cocaine of the acute group did not change between the first (day 3) and second cocaine injection (day 30) demonstrating that control and mutant mice did not behaviorally sensitize between the first and second injection. However, since at day 30, mice already experienced the drug (day 3 injection), the acute group is called here

Discussion

GRs mediate the effects of glucocorticoids on behavioral responses to cocaine (Piazza and Le Moal, 1998). We have previously used conditional mutant mice lacking GR specifically in the brain, GR^NesCre, and have demonstrated that these mice have reduced motivation for cocaine in a self-administration paradigm, and do not develop sensitization to cocaine. Here, we examined basal mRNA levels of various neurotransmission systems in the basal ganglia, and their response to sub-acute cocaine and to a

Acknowledgments

The authors thank Dr. C. Mulle for the gift of the glutamate receptor subunits 5 and 6 cDNA clones. We also would like to thank Dr. M. Solinas for editing the manuscript. This work was supported by Institut National de la Santé et de la Recherche Scientifique (INSERM) and Région Aquitaine grants to P.V.P. F.T. is supported by the CNRS, the Ministère de l’Education Nationale, de la Recherche et de la Technologie, Fondation Recherche Médicale (FRM), and the Mission Interministerielle de Lutta

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¹: The first two authors contributed equally to this work.

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NeuroanatomyGene expression regulation following behavioral sensitization to cocaine in transgenic mice lacking the glucocorticoid receptor in the brain

Abstract

Section snippets

Mice

Cocaine-induced behavioral sensitization in GRNesCre mice

Discussion

Acknowledgments

Mol Brain Res

Brain Res

Cell

Neuropharmacology

Neuroscience

Eur J Pharmacol

Neuroscience

Mol Brain Res

Neuroscience

Neuropharmacology

Pharmacol Biochem Behav

Mol Brain Res

Brain Res

Brain Res

Trends Pharmacol Sci

J Steroid Biochem

Mol Brain Res

Int J Dev Neurosci

Cocaine and methamphetamine differentially affect opioid peptide mRNA expression in the striatum

J Neurochem

Cloning of human mineralocorticoid receptor complementary DNAstructural and functional kinship with gluco-corticoid receptor

Science

Effects of adrenalectomy and glucocorticoids on rat brain dopamine receptors

Neuroendocrinology

Spatial distribution of kainate receptor subunit mRNA in the mouse basal ganglia and ventral mesencephalon

J Comp Neurol

Glucocorticoid regulation of preproenkephalin messenger ribonucleic acid in the rat striatum

J Endocrinol

Neuroanatomy
Gene expression regulation following behavioral sensitization to cocaine in transgenic mice lacking the glucocorticoid receptor in the brain

Cocaine-induced behavioral sensitization in GR^NesCre mice