Abstract
Chromatin remodelling is integral to the formation of long-term memories. Recent evidence suggests that histone modification may play a role in the persistence of memories associated with drug use. The present series of experiments aimed to examine the effect of histone deacetylase (HDAC) inhibition on the extinction and reinstatement of nicotine self-administration. Rats were trained to intravenously self-administer nicotine for 12 days on a fixed-ratio 1 schedule. In Experiment 1, responding was then extinguished through removal of nicotine and response-contingent cues. After each extinction session, the HDAC inhibitor, sodium butyrate (NaB), was administered immediately, or six hours after each session. In Experiment 2, response-contingent cues remained available across extinction to increase rates of responding during this phase, and NaB was administered immediately after the session. Finally, in Experiment 3, the effect of NaB treatment on extinction of responding for sucrose pellets was assessed. Across all experiments reinstatement to the cue and/or the reward itself was then tested. In the first experiment, treatment with NaB significantly attenuated nicotine and nicotine + cue reinstatement when administered immediately, but not six hours after each extinction session. When administered after cue-extinction (Expt. 2), NaB treatment specifically facilitated the rate of extinction across sessions, indicating that HDAC inhibition enhanced consolidation of the extinction memory. In contrast, there was no effect of NaB on the extinction and reinstatement of sucrose-seeking (Expt. 3), indicating that the observed effects are specific to a drug context. These results provide the first demonstration that HDAC inhibition facilitates the extinction of responding for an intravenously self-administered drug of abuse and further highlight the potential of HDAC inhibitors in the treatment of drug addiction.
Highlights
Tobacco addiction is a major cause of preventable ill health and death in western countries
Histone acetylation has been implicated in learning about Pavlovian context-drug associations. Both the acquisition and extinction of a conditioned place preference (CPP) for cocaine [10,11,12] and morphine [13, 14] are facilitated by histone deacetylase (HDAC) inhibition, these effects appear to be both dose and timing dependent [15, 16]
Parameters for sucrose self-administration were identical to those for nicotine with three exceptions: (1) rats did not undergo surgery; (2) active nose-pokes were reinforced with a 45 mg sucrose pellet (AIN-76A; TestDiet, MO, USA) delivered into the magazine; and (3) sessions lasted until a maximum of 30 pellets were earned or 30 minutes had elapsed
Summary
Tobacco addiction is a major cause of preventable ill health and death in western countries. Histone acetylation has been implicated in learning about Pavlovian context-drug associations Both the acquisition and extinction of a conditioned place preference (CPP) for cocaine [10,11,12] and morphine [13, 14] are facilitated by HDAC inhibition, these effects appear to be both dose and timing dependent [15, 16]. Extending the results of Pavlovian conditioning to an instrumental paradigm is important in the study of drug addiction, as this type of procedure has higher face validity, more closely approximating drug taking behaviour in humans [18] To this end, several recent studies have implicated histone acetylation in the rewarding properties of cocaine [19,20,21,22] and alcohol [23]. Detected effects were specific to nicotine-seeking, or are a property of reward-related learning more generally (Experiment 3)
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