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...

ABSTRACT:Studies were designed to quantitatively assess the mRNA expression of 1) 10 cytochrome P450 (P450) enzymes in human cornea, iris-ciliary body (ICB), and retina/choroid relative to their levels in the liver, and of 2) 21 drug transporters in these tissues relative to their levels in human small intestine, liver, or kidney. Potential species differences in mRNA expression of PEPT1, PEPT2, and MDR1 were also assessed in these ocular tissues from rabbit, dog, monkey, and human. P450 expression was either absent or marginal in human cornea, ICB, and retina/choroid, suggesting a limited role for P450-mediated metabolism in ocular drug disposition. In contrast, among 21 key drug efflux and uptake transporters, many exhibited relative expression levels in ocular tissues comparable with those observed in small intestine, liver, or kidney. This robust ocular transporter presence strongly suggests a significant role that transporters may play in ocular barrier function and ocular pharmacokinetics. The highly expressed efflux transporter MRP1 and uptake transporters PEPT2, OCT1, OCTN1, and OCTN2 may be particularly important in absorption, distribution, and clearance of their drug substrates in the eye. Evidence of cross-species ocular transporter expression differences noted in these studies supports the conclusion that transporter expression variability, along with anatomic and physiological differences, should be taken into consideration to better understand animal ocular pharmacokinetic and pharmacodynamic data and the scalability to human for ocular drugs.

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NCX 125, a compound targeting 2 different mechanisms, is endowed with potent ocular hypotensive effects. This may lead to potential new perspectives in the treatment of patients at risk of glaucoma.

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