Exposure to histone deacetylase inhibitors during Pavlovian conditioning enhances subsequent cue-induced reinstatement of operant behavior

Abstract

Histone deacetylase inhibitors (HDACIs) strengthen memory following fear conditioning and cocaine-induced conditioned place preference. Here, we examined the effects of two non-specific HDACIs, valproic acid (VPA) and sodium butyrate (NaB), on appetitive learning measured via conditioned stimulus (CS)-induced reinstatement of operant responding. Rats were trained to lever press for food reinforcement and then injected with VPA (50–200 mg/kg, i.p.), NaB (250–1000 mg/kg, i.p.), or saline vehicle (1.0 ml/kg), 2h before receiving pairings of noncontingent presentation of food pellets preceded by a tone+light cue CS. Rats next underwent extinction of operant responding followed by response-contingent re-exposure to the CS. Rats receiving VPA (100 mg/kg) or NaB (1000 mg/kg) prior to conditioning displayed significantly higher cue-induced reinstatement than did saline controls. Rats that receiving either vehicle or VPA (100 mg/kg) prior to a conditioning session with a randomized relation between presentation of food pellets and the CS failed to show subsequent cue-induced reinstatement with no difference between the two groups. These findings indicate that, under certain contexts, HDACIs strengthen memory formation by specifically increasing the associative strength of the CS, not through an increasing motivation to seek reinforcement.

Inhibition of Histone Deacetylases Facilitates Extinction and Attenuates Reinstatement of Nicotine Self-Administration in Rats

“…Not only did NaB treatment reduce nose-poking on the first session following treatment (when response rates were greatest), but a marked reduction in the number of sessions required for rats to reach the extinction criteria was also detected. The observation that NaB facilitates learning about nicotine-paired discrete cues supports previous research demonstrating that HDAC inhibitors facilitate learning about Pavlovian conditioned stimuli [ 35 ]. The absence of an effect on reinstatement was not surprising, given that several saline rats failed to reach the extinction criteria, as responding did not decline among these animals on the days prior to test.…”

Social defeat stress: Mechanisms underlying the increase in rewarding effects of drugs of abuse

“…These drugs also reverse social avoidance when administered to the amygdala and PFC (Covington, Maze, Vialou, & Nestler, ; Covington et al., ). Inhibition of HDAC with valproic acid not only increases the effects induced by SD (McCann et al., ), but also the conditioning rewarding effects of cocaine because HDAC inhibitors increase associative learning (Montagud‐Romero, Montesinos et al., ; Ploense et al., ). On the contrary, inhibition of HAT activity with the HAT inhibitor curcuma longa, or through viral‐mediated transfer and overexpression of specific HDACs in the NAc, markedly inhibits the increase in cocaine‐induced CPP in defeated animals (Hui, Wang, & Li, ; Renthal et al., ).…”

The effects of valproic acid on appetitive and aversive instrumental learning in adult rats

“…VPA has been shown to strengthen fear-conditioning (Bredy and Barad, 2008 ), extinction of conditioned fear (Bredy and Barad, 2008 ; Heinrichs et al, 2013 ), and reinstatement of cue-induced appetitive operant conditioning (Ploense et al, 2013 ). VPA decreases cellular proliferation while putatively promoting cellular transcription through preventing chromatin compacting associated with deacetylation of lysine residues (Phiel et al, 2001 ).…”