Cocaine self-administration by rats is inhibited by cyclic GMP-elevating agents: involvement of epigenetic markers.

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.

Overexpression of cyclic GMP-dependent protein kinase reduces MeCP2 and HDAC2 expression.

Nitric oxide (NO) and the C-type natriuretic peptide (CNP) exert their action via stimulation of the cyclic GMP (cGMP)-signaling pathway, which includes the activation of cGMP-dependent protein kinases (PKG). The present report shows that the activation of PKG by local application of 8-bromo-cGMP in the caudate-putamen reduced the expression of the epigenetic markers, methyl-CpG-binding protein 2 (MeCP2) and histone deacetylase 2 (HDAC2), in dopaminergic projection areas of cocaine-treated rats. An effect of lesser amplitude was observed when rats were not injected with cocaine.

The inhibition of histone deacetylases reduces the reinstatement of cocaine-seeking behavior in rats.

Drug addiction is a chronic brain disease characterized by a persistent risk of relapse, even after a long period of abstinence. A current hypothesis states that relapse results from lasting neuroadaptations that are induced in response to repeated drug administration. The adaptations require gene expression, some of which being under the control of stable epigenetic regulations.