Abstract
Drug addiction is considered maladaptive learning, and drug-related memories aroused by the presence of drug related stimuli (drug context or drug-associated cues) promote recurring craving and reinstatement of drug seeking. The mammalian target of rapamycin signaling pathway is involved in reconsolidation of drug memories in conditioned place preference and alcohol self-administration (SA) paradigms. Here, we explored the effect of mTOR inhibition on reconsolidation of addiction memory using cocaine self-administration paradigm. Rats received intravenous cocaine self-administration training for 10 consecutive days, during which a light/tone conditioned stimulus was paired with each cocaine infusion. After acquisition of the stable cocaine self-administration behaviors, rats were subjected to nosepoke extinction (11 days) to extinguish their behaviors, and then received a 15 min retrieval trial with or without the cocaine-paired tone/light cue delivery or without. Immediately or 6 h after the retrieval trial, rapamycin (10 mg/kg) was administered intraperitoneally. Finally, cue-induced reinstatement, cocaine-priming-induced reinstatement and spontaneous recovery of cocaine-seeking behaviors were assessed in rapamycin previously treated animals, respectively. We found that rapamycin treatment immediately after a retrieval trial decreased subsequent reinstatement of cocaine seeking induced by cues or cocaine itself, and these effects lasted at least for 28 days. In contrast, delayed intraperitoneal injection of rapamycin 6 h after retrieval or rapamycin injection without retrieval had no effects on cocaine-seeking behaviors. These findings indicated that mTOR inhibition within the reconsolidation time-window impairs the reconsolidation of cocaine associated memory, reduces cocaine-seeking behavior and prevents relapse, and these effects are retrieval-dependent and temporal-specific.
Highlights
Drug addiction is defined as a chronic psychiatric disease with a high rate of relapse even after a long period of withdrawal
The main findings of this study are following: 1) Systemic administration of rapamycin immediately after retrieval of cocaine cue memory effectively reduced the cocaine-seeking behavior induced by drug-associated cues and the reinstatement of cocaine seeking induced by cocaine in rats; 2) The inhibitory effect of systemic rapamycin administration immediately after retrieval of cocaine cue memory on cocaineseeking behavior persisted for least 28 days; 3) rapamycin when administered intraperitoneally with a 6 h delay or without a retrieval trial had no effects on cue-induced and cocainepriming-induced reinstatement of cocaine-seeking behavior, indicating that the inhibitory effects of rapamycin on cocaineseeking behavior is retrieval-dependent and temporal-specific
We have demonstrated that intraperitoneal injection of rapamycin immediately after memory retrieval inhibits mammalian target of rapamycin (mTOR) activity
Summary
Drug addiction is defined as a chronic psychiatric disease with a high rate of relapse even after a long period of withdrawal. Addicted individuals experience intense drug craving that can persist long after withdrawal, leading to high relapse rates. They exert compulsive seeking and drugtaking behaviors that are difficult to control despite the serious adverse consequences of drug abuse. Much evidence shows that the persistence of drug memory and the difficulty in eliminating are the root causes of compulsive drug use behavior, drug-seeking behavior, and relapse after withdrawal (Childress et al, 1986; Kelley, 2004; Torregrossa et al, 2011). Elucidating the neurobiological mechanisms of drug memory and disrupting it through various interventions seem to be an effective way to treat drug addiction and prevent relapse after withdrawal
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