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. 2010 Jul 6;107(27):12345-50.
doi: 10.1073/pnas.1003152107. Epub 2010 Jun 21.

Disrupting the Memory of Places Induced by Drugs of Abuse Weakens Motivational Withdrawal in a Context-Dependent Manner

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Disrupting the Memory of Places Induced by Drugs of Abuse Weakens Motivational Withdrawal in a Context-Dependent Manner

Stephen M Taubenfeld et al. Proc Natl Acad Sci U S A. .
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Abstract

Addicts repeatedly relapse to drug seeking even after years of abstinence, and this behavior is frequently induced by the recall of memories of the rewarding effects of the drug. Established memories, including those induced by drugs of abuse, can become transiently fragile if reactivated, and during this labile phase, known as reconsolidation, can be persistently disrupted. Here we show that, in rats, a morphine-induced place preference (mCPP) memory is linked to context-dependent withdrawal as disrupting the reconsolidation of the memory leads to a significant reduction of withdrawal evoked in the same context. Moreover, the hippocampus plays a critical role in linking the place preference memory with the context-conditioned withdrawal, as disrupting hippocampal protein synthesis and cAMP-dependent-protein kinase A after the reactivation of mCPP significantly weakens the withdrawal. Hence, targeting memories induced by drugs may represent an important strategy for attenuating context-conditioned withdrawal and therefore subsequent relapse in opiate addicts.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Disrupting mCPP reconsolidation disrupts subsequent NTX-precipitated withdrawal. Experimental timelines are shown above each experiment. The score values are shown in Table S1. Values of preference or avoidance are expressed in seconds as differences (test vs. pretest) and shown as means ± SEM (A) Cycloheximide significantly disrupts mCPP compared with vehicle (tests 1–4, n = 6–8; *P < 0.05, **P < 0.01). The animals with disrupted CPP also show a significantly disrupted NTX-precipitated withdrawal (tests 1 and 2, n = 7–8; **P < 0.01, ***P < 0.001). (B) Same as in A, except that 1XRC was omitted and testing was completed at test 1; n = 8 per group.
Fig. 2.
Fig. 2.
The contextual conditioning to morphine is necessary for linking a context-precipitated withdrawal. Experimental timelines are shown above each experiment. The score values are shown in Table S1. Preference or avoidance are expressed in seconds as differences (test vs. pretest) and shown as means ± SEM (A) Cycloheximide treatment following a single morphine conditioning (n = 7–8 per group) shows no effect on withdrawal. (B) Four vehicle-context exposures were experienced instead of morphine conditioning. One week later, one morphine conditioning was administered in one context (context A); 24 h later, the withdrawal protocol was carried out in the same context. No effect on withdrawal is found; n = 6–8 per group. (C) Morphine conditioning (4×) 1 wk later: 1XRC was administered following cycloheximide or vehicle treatment. Twenty-four hours later 1× conditioning followed 4 h later by NTX was performed in the vehicle-paired (unpaired) context. Cycloheximide significantly disrupts mCPP (n = 7–8; **P < 0.01), but no effect on withdrawal was found.
Fig. 3.
Fig. 3.
Inhibition of hippocampal protein synthesis significantly disrupts both mCPP and subsequent withdrawal. Experimental timelines are shown above each experiment. Scores are shown in Table S1. Values of preference or avoidance are expressed in seconds as differences (test vs. pretest) and shown as means ± SEM. (A) Anisomycin injected into the dorsal hippocampus significantly disrupts NTX-precipitated withdrawal (n = 7–8 per group; ***P < 0.001). (B) The effect of anisomycin is contingent upon reactivation: same as in A, except that 1XRC was omitted and testing was completed after the first test. Anisomycin did not affect withdrawal (n = 8 per group).
Fig. 4.
Fig. 4.
Hippocampal PKA is required for the link between mCPP memory and NTX-precipitated withdrawal. Experimental timelines are shown above each experiment. Scores are shown in Table S1. Values of preference or avoidance are expressed in seconds as differences (test vs. pretest) and shown as means ± SEM. (A) Bilateral hippocampal injections of Rp-cAMP significantly disrupts mCPP (n = 8 per group; **P < 0.01, *P < 0.05). These rats also showed a significant reduction in NTX-precipitated withdrawal (n = 8 per group; ***P < 0.001, **P < 0.01). (B) The Rp-cAMP effect is contingent upon reactivation. Same as in A, except that 1XRC was omitted and testing was completed after the first test (n = 8 per group).

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