Nonspecific histone deacetylase (HDAC) inhibition has been shown to facilitate the extinction of drug-seeking behavior in a manner resistant to reinstatement. A key open question is which specific HDAC is involved in the extinction of drug-seeking behavior. Using the selective HDAC3 inhibitor RGFP966, we investigated the role of HDAC3 in extinction and found that systemic treatment with RGFP966 facilitates extinction in mice in a manner resistant to reinstatement. We also investigated whether the facilitated extinction is related to the enhancement of extinction consolidation during extinction learning or to negative effects on performance or reconsolidation. These are key distinctions with regard to any compound being used to modulate extinction, because a more rapid decrease in a defined behavior is interpreted as facilitated extinction. Using an innovative combination of behavioral paradigms, we found that a single treatment of RGFP966 enhances extinction of a previously established cocaine-conditioned place preference, while simultaneously enhancing long-term object-location memory within subjects. During extinction consolidation, HDAC3 inhibition promotes a distinct pattern of histone acetylation linked to gene expression within the infralimbic cortex, hippocampus, and nucleus accumbens. Thus, the facilitated extinction of drug-seeking cannot be explained by adverse effects on performance. These results demonstrate that HDAC3 inhibition enhances the memory processes involved in extinction of drug-seeking behavior.long-term memory | epigenetics | chromatin N umerous studies have demonstrated that long-term memory mechanisms require transcription (1), likely because gene expression is necessary for the stable changes in neuronal plasticity ultimately driving long-term changes in behavior. A key mechanism by which gene expression profiles are regulated is chromatin modification. One of the best-studied chromatin modifying mechanisms is histone acetylation, carried out by histone acetyltransferases and histone deacetylases (HDACs), which in general facilitate and repress gene expression, respectively (2-4). Several studies have demonstrated that manipulating histone acetyltransferases and HDACs can alter memory processes during initial memory formation (5-13) as well as extinction memory processes (14-17). Extinction is a transcription-dependent process (18-20) through which a previously held conditioned response (such as drug-seeking) is reduced or eliminated.Recently, it was reported that pharmacologic inhibition of HDACs facilitates extinction of drug-seeking, resulting in rapid and persistent loss of a previously established behavior that is resistant to reinstatement (16,21). One interpretation of this action is that HDAC inhibition robustly enhances consolidation of extinction memory, suggesting that HDACs normally function as negative regulators of extinction learning, similar to their role in initial memory consolidation. However, the finding that inhibition of HDACs during consolidation of extinction p...

A cyclic peptide specific for type I collagen is derivatized with three {Gd(dtpa)} moieties to create a molecular MRI contrast agent for fibrosis imaging. In a mouse model of myocardial infarction (heart attack), collagen levels are elevated in the infarct zone. MRI after injection of the contrast agent selectively enhances and delineates the infarct zone (see preinjection and postinjection images); dtpa=diethylenetriaminepentaacetate.

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Use of the gadolinium-based collagen-targeting contrast agent, EP-3533, enabled in vivo molecular MR imaging of fibrosis in a mouse model of healed postinfarction myocardial scarring.

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