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Figure 2.
Regulation of chromatin structure by drugs of abuse. Drug-induced signaling events are depicted for psychostimulants such as cocaine and amphetamine. These drugs increase cAMP levels in striatum, which activates protein kinase A (PKA) and leads to phosphorylation of its targets. This includes the cAMP response element binding protein (CREB), the phosphorylation of which induces its association with the histone acetyltransferase, CREB binding protein (CBP) to acetylate histones and facilitate gene activation. This is known to occur on many genes including fosB and c-fos in response to psychostimulant exposure. AFosB is also upregulated by chronic psychostimulant treatments, and is known to activate certain genes (eg, cdk5) and repress others (eg, c-fos) where it recruits HDAC1 as a corepressor. This repression of c-fos also involves increased repressive histone methylation, which is thought to occur via the induction of specific histone methyltransferases (HMTs). In addition, cocaine regulates the HMT, KMT1 C/G9a, which alters histone H3 methylation on K9. It is not yet known how cocaine regulates histone demethylases (HDM) or DNA methyltransferases (DNMTs). Cocaine also activates the mitogen activated protein kinase (MAPK) cascade, which through MSK1 can phosphorylate CREB and histone H3 at serine 10. Cocaine promotes H3 phosphorylation via a distinct pathway, whereby PKA activates protein phosphatase 2A, leading to the dephosphorylation of serine 97 of DARPP32. This causes DARPP32 to accumulate in the nucleus and inhibit protein phosphatase-1 (PP1) which normally dephosphorylates H3. Chronic exposure to psychostimulants increases glutamatergic stignaling from the prefrontal cortex to the NAc. Glutamatergic signaling elevates Ca2+ levels in NAc postsynaptic elements where it activates CaMK (calcium/calmodulin protein kinases) signaling, which, in addition to phosphorylating CREB, also phosphorylates HDAC5. This results in nuclear export of HDAC5 and increased histone acetylation on its target genes (eg, NK1R[NK1 or substance P receptor]). From ref 8: Tsankova N, Renthal W, Kumar A, Nestler EJ. Epigenetic regulation in psychiatric disorders. Nat Rev Neurosci. 2007;8:355-367.
