Effects of a histone deacetylase 3 inhibitor on extinction and reinstatement of cocaine self-administration in rats

Abstract

Rationale: A challenge in treating substance use disorder is that successful treatment often does not persist, resulting in relapse and continued drug seeking. One approach to persistently weaken drug-seeking behaviors is to pair exposure to drug-associated cues or behaviors with delivery of a compound that may strengthen the inhibition of the association between drug cues and behavior. Objectives: We evaluated whether a selective histone deacetylase 3 (HDAC3) inhibitor could promote extinction and weaken contextual control of operant drug-seeking after intravenous cocaine self-administration. Methods: Male Long Evans rats received a systemic injection of the HDAC3 inhibitor RGFP966 either before or immediately after the first extinction session. Persistence of extinction was tested over subsequent extinction sessions, as well as tests of reinstatement that included cue-induced reinstatement, contextual renewal, and cocaine-primed reinstatement. Additional extinction sessions occurred between each reinstatement test. We also evaluated effects of RGFP966 on performance and motivation during stable fixed ratio operant responding for cocaine and during a progressive ratio of reinforcement. Results: RGFP966 administered before the first extinction session led to significantly less responding during subsequent extinction and reinstatement tests compared to vehicle-injected rats. Follow-up studies found that these effects were not likely due to a performance deficit or a change in motivation to self-administer cocaine, as injections of RGFP966 had no effect on stable responding during a fixed or progressive ratio schedule. In addition, RGFP966 administered just after the first extinction session had no effect during early extinction and reinstatement tests, but weakened long-term responding during later extinction sessions. Conclusions: These results suggest that a systemic injection of a selective HDAC3 inhibitor can enhance extinction and suppress reinstatement after cocaine self-administration. The finding that behavioral and pharmacological manipulations can be combined to decrease drug-seeking provides further potential for treatment by epigenetic modulation.

Sensory cortical and subcortical auditory neurophysiological changes predict cue-specific extinction behavior enabled by the pharmacological inhibition of an epigenetic regulator during memory formation

“…Present results support this fundamental role for HDAC3-mediated regulation of memory consolidation. Previous literature has focused on the ability of HDAC3 inhibition to enhance the formation, strength, or persistence of long-term memory (Vecsey et al, 2007;Stefanko et al, 2009), including extinction memory (Wang et al, 2010;Malvaez et al, 2013;Castino et al, 2015;Hitchcock et al, 2019). Yet, some studies failed to find effects on memory strength without consideration of memory specificity first (Bieszczad et al, 2015, Shang et al, 2019, Rotondo & Bieszczad, 2020, including in auditory fear extinction memory (Bredy et al, 2007;Bowers et al, 2015).…”

“…Epigenetic mechanisms are now known to be ubiquitous in long-term memory processes. Previous investigations have shown one variety of epigenetic regulation by class I histone deacetylases (HDACs)including the most prominent HDAC expressed in the adult brain, HDAC3-can enable long-term memory (LTM) formation in a variety of behavioral tasks and species (Bredy et al, 2007;Lattal et al, 2007;Stefanko et al, 2009;Malvaez et al, 2010;Wang et al, 2010;Malvaez et al, 2013;Raybuck et al, 2013;Bowers et al, 2015;Hitchcock et al, 2019;Phan et al, 2017) including humans (Gervain et al, 2013). However, recent work using a sensory model of learning, memory and experience-dependent sensory neuroplasticity has shown a much more significant role of HDAC3 on LTM beyond facilitating its formation per se.…”

The Emerging Role of ATP-Dependent Chromatin Remodeling in Memory and Substance Use Disorders

“…These cocaine-induced changes in acetylation strongly implicate HDAC and HAT enzymes in cocaine-associated behaviors. Indeed, disengagement of Class I HDACs significantly alters behavioral strategies used in cocaine self-administration [126][127][128][129].…”

Editorial: the psychopharmacology of extinction—from theory to therapy

“…Indeed, there are similarities between fear memory and drug memory extinction at the molecular level. Lattal and colleagues (Hitchcock et al 2019) investigate the requirement for epigenetic modifications in the extinction and reinstatement of cocaine self-administration, allowing parallels to be drawn to fear memory extinction (as reviewed earlier in the issue by Marshall and Bredy 2019). Similarly, differences in the molecular mechanisms underlying fear extinction and fear memory reconsolidation can also be observed in the reconsolidation and extinction of drug-associated memories, as reviewed by Taylor and colleagues (Torregrossa et al 2019).…”