HDAC3-selective inhibitor enhances extinction of cocaine-seeking behavior in a persistent manner - PubMed (original) (raw)

HDAC3-selective inhibitor enhances extinction of cocaine-seeking behavior in a persistent manner

Melissa Malvaez et al. Proc Natl Acad Sci U S A. 2013.

Abstract

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.

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Conflict of interest statement

Conflict of interest statement: G.A.R. and M.A.W. received research support from a Sponsored Research Agreement from Repligen Corp. V.J., S.C., and J.R.R. are employed by Repligen Corp. M.M. and S.C.M. report no financial disclosures.

Figures

Fig. 1.

Fig. 1.

HDAC3 inhibition enhances the rate and persistence of extinction of cocaine-CPP. (A) Schematic of cocaine-CPP training and extinction. (B) Treatment with RGFP966 (10 mg/kg) after posttest 1 significantly reduced cocaine-CPP, and the effect was maintained in subsequent CPP tests. Vehicle, n = 12; RGFP966 3 mg/kg, n = 12; RGFP966 10 mg/kg, n = 12. (C) Mice treated with RGFP966 (10 mg/kg) during extinction consolidation did not reinstate cocaine-seeking behavior; Vehicle, n = 8; RGFP966 3 mg/kg, n = 7; RGFP966 10 mg/kg, n = 8. Data are expressed as mean ± SEM. †Significantly different from 0. *Significantly different from vehicle; P < 0.05.

Fig. 2.

Fig. 2.

HDAC3 inhibition simultaneously reduces drug-seeking behavior and enhances memory. (A) Schematic of cocaine-CPP training and extinction, followed in parallel with OLM training. RGFP966 was administered immediately after extinction training, 1 h before OLM training in the same mice. Vehicle, n = 6; RGFP966 10 mg/kg; n = 6. (B) RGFP966 administered immediately after a nonreinforced exposure resulted in loss of CPP the next day. (C) RGFP966 treatment resulted in significantly enhanced object location memory. Data are expressed as mean ± SEM. *Significantly different from vehicle; P < 0.05.

Fig. 3.

Fig. 3.

HDAC3 inhibition promotes histone acetylation and gene expression during extinction consolidation. (A) RGFP966 treatment promoted acetylation of H4K8 in the IFC (vehicle, n = 5; RGFP966, n = 5), but not in the HIPP (vehicle, n = 3; RGFP966, n = 3) or NAc (vehicle, n = 3; RGFP966, n = 3). (B and C) RGFP966 treatment increased acetylation of H3K14 in the IFC (vehicle, n = 5; RGFP966, n = 5), HIPP (vehicle, n = 5; RGFP966, n = 5), and NAc (vehicle, n = 5; RGFP966, n = 6) during extinction consolidation (B), with no difference in acetylation of H2BK12 (vehicle, n = 6; RGFP966, n = 5 for each brain region) (C). (D) c-FOS expression was significantly increased in the IFC (vehicle, n = 6; RGFP966, n = 5), but not in the HIPP (vehicle, n = 7; RGFP966, n = 6) or NAc (vehicle, n = 9; RGFP966, n = 7), of mice treated with RGFP966. (E) NR4A2 expression was significantly increased in the HIPP (vehicle, n = 5; RGFP966, n = 5), but not in the IFC (vehicle, n = 6; RGFP966, n = 5) or NAc (vehicle, n = 6; RGFP966, n = 5), after RGFP966 treatment during extinction consolidation. (F and G) RGFP966 treatment led to decreased HDAC3 occupancy at the c-fos promoter (vehicle, n = 6; RGFP966, n = 7) (F), with a corresponding increase in acetylation of H4K8 (vehicle, n = 6; RGFP966, n = 8) (G). Data are expressed as mean ± SEM. *Significantly different from vehicle; P < 0.05.

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