Drug-Induced Epigenetic Changes Produce Drug Tolerance

Abstract

Tolerance to drugs that affect neural activity is mediated, in part, by adaptive mechanisms that attempt to restore normal neural excitability. Changes in the expression of ion channel genes are thought to play an important role in these neural adaptations. The slo gene encodes the pore-forming subunit of BK-type Ca2+-activated K+ channels, which regulate many aspects of neural activity. Given that induction of slo gene expression plays an important role in the acquisition of tolerance to sedating drugs, we investigated the molecular mechanism of gene induction. Using chromatin immunoprecipitation followed by real-time PCR, we show that a single brief sedation with the anesthetic benzyl alcohol generates a spatiotemporal pattern of histone H4 acetylation across the slo promoter region. Inducing histone acetylation with a histone deacetylase inhibitor yields a similar pattern of changes in histone acetylation, up-regulates slo expression, and phenocopies tolerance in a slo-dependent manner. The cAMP response element binding protein (CREB) is an important transcription factor mediating experience-based neuroadaptations. The slo promoter region contains putative binding sites for the CREB transcription factor. Chromatin immunoprecipitation assays show that benzyl alcohol sedation enhances CREB binding within the slo promoter region. Furthermore, activation of a CREB dominant-negative transgene blocks benzyl alcohol–induced changes in histone acetylation within the slo promoter region, slo induction, and behavioral tolerance caused by benzyl alcohol sedation. These findings provide unique evidence that links molecular epigenetic histone modifications and transcriptional induction of an ion channel gene with a single behavioral event.

Selective Boosting of Transcriptional and Behavioral Responses to Drugs of Abuse by Histone Deacetylase Inhibition

“…Conversely, acetylation-related processes seem less relevant in the development of drug tolerance and dependence (as measured by the intensity of drug withdrawal), which result from transient homeostatic adaptations occurring within the cells and circuits directly stimulated by each drug and are not considered core symptoms of addiction (Hyman et al, 2006). This view is in agreement with earlier pharmacological and genetic studies on psychostimulants-induced sensitization and CPP (Bilbao et al, 2008;Kalda et al, 2007;Kumar et al, 2005;Levine et al, 2005;Renthal et al, 2007), as well as with the few preceding studies indicating that HDACis do not facilitate the development of tolerance (Wang et al, 2007) and that histone acetylation might be more involved in the expression than in the induction of drug dependence (Pandey et al, 2008). Future studies should further explore this intriguing dissociation.…”

SWI/SNF chromatin remodeling regulates alcohol response behaviors in Caenorhabditis elegans and is associated with alcohol dependence in humans

“…Modification of gene expression is associated with the progression to addiction (9,10). Epigenetic changes have been implicated in alcohol-dependent gene regulation (11), in the development of rapid tolerance to ethanol in a variety of model systems (12)(13)(14), and in alcohol-drinking behaviors in mammals (11,15). Epigenetic factors also may modify the basal LR to alcohol.…”

The Relationship between Duration of Initial Alcohol Exposure and Persistence of Molecular Tolerance Is Markedly Nonlinear

“…Examples of potential drug-activated molecular switches include transcription factors such as ␦fosB and CREB (Kelz et al, 1999;Nestler et al, 2001;Hyman et al, 2006;Renthal et al, 2008) and secondary signaling molecules such as PKA (Coe et al, 1996;Pandey et al, 2001;Lin et al, 2006). In flies, CREB, which is activated by PKA, mediates upregulation of dslo during rapid tolerance to benzyl alcohol (Wang et al, 2007).…”

“…However, other mechanisms also play a role in BK acute tolerance. These include short-duration posttranscriptional changes such as phosphorylation/dephosphorylation, as well as more lasting alterations such as membrane lipid modification (Yuan et al, 2008;Treistman and Martin, 2009), and epigenetic phenomena such as chromatin remodeling (Wang et al, 2007(Wang et al, , 2009. Why do multiple and seemingly redundant BK adaptive mechanisms, such as both desensitization and subsequent internalization exist?…”