32,40,41 Conversely, reducing histone acetylation by overexpressing certain HDACs, or knockdown of the HAT, CBP, results in less sensitivity to cocaine.32,34,40 Two reports have extended these findings in rat models of cocaine self-administration, where animals are trained to press levers to receive the drug. Interestingly, delivery of the HDAC inhibitor, sodium butyrate, potentiates drug-taking42 while delivery of the HDAC inhibitor, trichostatin Inhibitors,research,lifescience,medical A, attenuates it.43 The explanation for these different observations is unclear, but it may involve experimental differences with the self-administration paradigm

or the HDAC inhibitor used. Cocaine alters histone acetylation through many enzymes in the NAc, but one particular HDAC, HDAC5, responds uniquely to chronic cocaine administration, raising the interesting 3-MA concentration possibility Inhibitors,research,lifescience,medical that this HDAC is involved in the behavioral transitions which occur between acute and chronic cocaine exposure (eg, drug experimentation to compulsive

drug use). Chronic cocaine administration increases the phosphorylation Inhibitors,research,lifescience,medical of IIDAC5 and shuttles it out of the nucleus, permitting hyperacetylation of histones at target genes for HDACS (Figure 2).40 This phosphorylation reaction may be mediated by Ca2+/calmodulin-dependent protein kinase II (CaMKII), since ex vivo inhibition of CaMKII reduces the activity-induced phosphorylation of HDAC5. Consistent with its regulation by cocaine, mice deficient for HDACS display normal rewarding responses to initial cocaine exposures, but become hypersensitive when treated with a Inhibitors,research,lifescience,medical chronic course of cocaine.40 Thus, pharmacological and genetic manipulations that increase histone acetylation Inhibitors,research,lifescience,medical appear to potentiate behavioral responses to cocaine and suggest that altered histone acetylation may contribute to establishment of an addicted state. Histone H3 phosphorylation and phosphoacetylation also appear to play key roles in drug-regulated behaviors. Global levels of

histone H3 phosphorylation at serine 10 are induced by acute Sclareol cocaine in striatum, a process which requires the kinase MSKl.19,32 The function of MSK1 is behaviorally important, as mice lacking this kinase have attenuated locomotor responses to cocaine. Cocaine-induced inhibition of protein phosphatase-1 also plays an important role in IB phosphorylation in striatum (Figure 2). Dopamine D1 receptor activation alters the phosphorylation of dopamine-regulated and cyclic-AMP-regulated phosphoprotein of 32kD (DARPP-32) at particular serine residues; the protein then accumulates in the nucleus to inhibit protein phosphatase-1 from dephosphorylating histone H3.20 The simultaneous activation of an H3 kinase and inhibition of an H3 phosphatase results in the robust increase in H3 phosphorylation after acute cocaine exposure.