This may result from a decreased protein expression, possibly due to the phosphorylation, and subsequent inactivation of an element of the transcriptional machinery. Alternatively, it may result from the PKG-induced degradation of the proteins. It is also possible that phosphorylation by PKG

of the Selleckchem 5-Fluoracil proteins or of Inhibitors,research,lifescience,medical some partner proteins may have induced the formation of alternate complexes that prevented accessibility of MeCP2 and HDAC2 to their respective antibodies. This latter possibility is particularly attractive as both proteins were similarly regulated. The effect on both proteins was abolished by the injection of the selective PKG inhibitor, KT5823, confirming that the effect was due to PKG-dependent phosphorylation. The effect on MeCP2 expression was greatly potentiated in the three structures examined by the addition and subsequent activation of exogenous overexpressed PKG. Surprisingly, the latter effect was not observed when HDAC2 expression was measured. It is noteworthy that other HDACs, such as HDAC5 or Inhibitors,research,lifescience,medical HDAC11, which belong

to different classes of histone deacetylases that are also regulated by cocaine (Host et al. 2011), were not modulated by PKG (data not shown), Inhibitors,research,lifescience,medical suggesting a unique role of HDAC2 in this process. In contrast, injection of the PKG vector or Br-cG into the VTA failed to alter MeCP2 or HDAC2 levels in any of the brain sites. The data probably underscore a differential action of PKG at the pre- and postsynaptic levels. Effectively, the observation that only intra-CPu infusions produced the effect probably denotes that it results Inhibitors,research,lifescience,medical from a PKG-modified signal transduction pathway taking place in neurons postsynaptic from the dopaminergic neuron. Indeed, in an Inhibitors,research,lifescience,medical electron microscopy study, we showed that PKG was localized mainly in postsynaptic sites (data not shown). These findings are consistent with our previous results that

also failed to find an effect of intra-VTA infusions of Br-cG on cocaine-induced egr-1 expression in the CPu (Jouvert et al. 2004). When the PKG vector was injected into the CPu, overexpression of the kinase was found primarily PD184352 (CI-1040) in GABAergic medium-spiny neurons (Jouvert et al. 2004). Activation of the cGMP pathway in these neurons probably modulates GABA release in many projection areas and therefore disrupts the striato-nigro-thalamic loop. Modulation of neurotransmitter release by cGMP has been demonstrated in many systems; cGMP activators like natriuretic peptides inhibit various secretory responses such as aldosterone and catecholamines (Samson et al. 1993; Babinski et al. 1995), whereas endogenous NO modulates the release of several neurotransmitters, including catecholamines, excitatory and inhibitory amino acids, and serotonin (Guevara-Guzman et al. 1994; Prast and Philippu 2001).