Persistent Disruption of an Established Morphine Conditioned Place Preference

Abstract

In human addicts, craving and relapse are frequently evoked by the recall of memories connected to a drug experience. Established memories can become labile if recalled and can then be disrupted by several interfering events and pharmacological treatments, including inhibition of protein synthesis. Thus, reactivation of mnemonic traces provides an opportunity for disrupting memories that contribute to pathological states. Here, we tested whether the memory of a drug experience can be weakened by inhibiting protein synthesis after the reactivation of its trace. We found that an established morphine conditioned place preference (mCPP) was persistently disrupted if protein synthesis was blocked by either anisomycin or cycloheximide after the representation of a conditioning session. Unlike other types of memories, an established mCPP did not become labile after contextual recall, but required the concomitant re-experience of both the conditioning context and the drug. An established mCPP was disrupted after the conditioning session if protein synthesis was blocked selectively in the hippocampus, basolateral amygdala, or nucleus accumbens but not in the ventral tegmental area. This disruption seems to be permanent, because the preference did not return after further conditioning. Thus, established memories induced by a drug of abuse can be persistently disrupted after reactivation of the conditioning experience.

Disrupting the memory of places induced by drugs of abuse weakens motivational withdrawal in a context-dependent manner

“…This effect is likely to be caused by the disruption of the reconsolidation of the memory (12), as the impairment of both place conditioning and withdrawal are dependent on the reactivation of mCPP. This is in agreement with the results of our previous study (14) that also demonstrated that reexperiencing morphine in a different context or in the home cage does not evoke any lability in mCPP. Furthermore, we show that the disruption of mCPP is persistent and the memory does not return after further conditioning or testing in the presence of morphine, suggesting that the disruption is not caused by state dependency.…”

“…Given the relevant contribution of the contextual representation in both mCPP and withdrawal, we tested whether the hippocampus, a brain region known to process contextual and place memories (20), including mCPP, is involved in linking memories to withdrawal. Dorsal or complete hippocampal lesions impair rat mCPP (21), and we have previously shown that an injection of the protein synthesis inhibitor anisomycin into the dorsal hippocampus following mCPP reactivation persistently disrupts an established mCPP memory (14). Here we tested whether blocking protein synthesis in the dorsal hippocampus affects the link between mCPP and withdrawal evoked as in the previous experiments.…”

“…One week later, mCPP memory was reactivated with a single 10-mg/kg conditioning trial (1XRC), and immediately after, half the animals received two systemic cycloheximide (CXM) injections at 2.2 mg/kg, 5 h apart, and the other half received two injections of vehicle solution. This cycloheximide treatment has been shown to block more than 70% of protein synthesis in the rat brain for at least 6 h and to persistently disrupt mCPP reconsolidation (14). The next day, both groups of rats were divided in two subgroups, which underwent 0.3 mg/kg naltrexone (NTX)-precipitated withdrawal or a control vehicle treatment (see Materials and Methods for details) (17).…”

“…Thus, the disruption of these mechanisms following memory reactivation represents a strategy for weakening pathogenic memories including those involved in drug conditioning (12). Morphine-or cocaine-conditioned place preference, as well as the conditioned reinforcing properties of a cocaine-associated stimulus, can be disrupted by postreactivation inhibition of protein synthesis, ERK, or of the expression of the immediate-early gene Zif268 (13)(14)(15)(16). We previously showed that, in rats, a conditioned place preference evoked by morphine [m-chlorophenylpiperazine (mCPP)] is persistently disrupted by systemic or stereotactic injections of protein synthesis inhibitors into the hippocampus, amygdala, or nucleus accumbens following its reactivation by a conditioning trial (14).…”

Intrahippocampal infusions of anisomycin produce amnesia: Contribution of increased release of norepinephrine, dopamine, and acetylcholine

“…In addition to amnesias produced by anisomycin injections into the amygdala, as above, anisomycin also impairs memory when administered to other memory systems, including the hippocampus, where anisomycin impairs inhibitory avoidance memory (Quevedo et al 1999;Debiec et al 2002;Milekic et al 2006). The present study extends the prior findings ) in several respects.…”