title: Cocaine self-administration by rats is inhibited by cyclic GMP-elevating agents: involvement of epigenetic markers.
abstract: The C-type natriuretic peptide (CNP) exerts its action via stimulation of the cyclic GMP (cGMP) signalling pathway, which includes the activation of cGMP-dependent protein kinases. The pathway can also be activated by inhibitors of phosphodiesterases (PDE) that hydrolyse cGMP. The present report shows that activation of the cGMP pathway by CNP, by bromo-cGMP, a cell-permeant cGMP analogue, or by the PDE inhibitor zaprinast dose dependently reduces intravenous cocaine self-administration by rats. The effect was found when the compounds were injected in situ into the prefrontal cortex, but not when they were injected into the nucleus accumbens. A decrease in the number of cocaine infusions performed by rats was obtained under the fixed ratio-1 schedule of reinforcement as well as under a progressive ratio schedule, which evaluates the motivation of the animals for the drug. Decrease in cocaine self-administration was accompanied with reduced expression of the epigenetic markers methyl-CpG-binding protein 2 (MeCP2) and histone deacetylase 2 (HDAC2) in dopaminergic projection areas. An increase in the acetylation level of histone H3, but not of histone H4, was also noticed. Since MeCP2 and HDAC2 are known to modulate dynamic functions in the adult brain, such as synaptic plasticity, our results showing that activation of the cGMP signal transduction pathway decreased both cocaine intake and expression of the epigenetic markers strongly suggest that the MeCP2/HDAC2 complex is involved in the analysis of the reinforcing properties of cocaine in the prefrontal cortex.
authors: Laboratoire de Neurosciences Cognitives et Adaptatives, Université de Strasbourg, Strasbourg, France.
authors: Elodie
authors: E
authors: Deschatrettes
authors: Pascal
authors: P
authors: Romieu
authors: Jean
authors: J
authors: Zwiller
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D003042:Cocaine / Q000008:administration & dosage*; D003216:Conditioning, Operant / Q000187:drug effects; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D005786:Gene Expression Regulation / Q000187:drug effects; D056464:Histone Deacetylase 2 / Q000378:metabolism*; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000378:metabolism*; D020098:Natriuretic Peptide, C-Type / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011688:Purinones / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012055:Reinforcement Schedule; D012646:Self Administration
chemical_list: D018765:Dopamine Uptake Inhibitors; D051783:Methyl-CpG-Binding Protein 2; D010726:Phosphodiesterase Inhibitors; D011688:Purinones; D020098:Natriuretic Peptide, C-Type; C016276:8-bromocyclic GMP; D017346:Protein Serine-Threonine Kinases; C551435:CDKL5 protein, rat; D056464:Histone Deacetylase 2; C011145:zaprinast; D006152:Cyclic GMP; D003042:Cocaine