D-cycloserine, sarcosine and D-serine diminish the expression of cocaine-induced conditioned place preference.

Reactivation of cocaine-associated memories plays a critical role in reinstating the cocaine-seeking behavior and causing relapse. Cocaine-induced conditioned place preference (CPP) was used as a behavioral paradigm indicative of cocaine-associated memory and repeated cocaine-free preference tests served as a behavioral procedure to retrieve such a memory in this study. Since D-cycloserine was reported to eradicate drug-associated memories, two other N-methyl-D-aspartate (NMDA) receptor agonists were assessed for their efficacy on facilitating the extinction of cocaine-induced CPP. Although D-cycloserine (30 mg/kg) abolished cocaine (10 mg/kg)-induced CPP, sarcosine (300 and 600 mg/kg) and D-serine (600 mg/kg) diminished the expression of such a cocaine memory. Sarcosine (600 mg/kg) and D-serine (600 mg/kg) did not affect the storage of this cocaine memory. It was of interest to note that D-cycloserine facilitated the extinction of cocaine-induced CPP in a fast and early-onset manner, while sarcosine and D-serine decreased cocaine-induced CPP expression in a delay-onset manner. D-cycloserine (30 mg/kg), D-serine (600 mg/kg) and sarcosine (600 mg/kg) did not affect the consolidation of cocaine (5 mg/kg)-induced CPP. Finally, sarcosine (at 600 mg/kg/day for 3 consecutive days) and D-serine (at 600 mg/kg/day for 3 consecutive days) did not produce observable aversive effect associated with their administration in a conditioned place aversion paradigm. Likewise, a similar dosing regimen of sarcosine or D-serine did not cause evident activity-impairing effect. In addition to D-cycloserine treatment, our results indicate that long-term treatment with D-serine and sarcosine may afford a therapeutic advance in suppressing the expression of cocaine-associated memory.

Systemic treatment with protein synthesis inhibitors attenuates the expression of cocaine memory.

It has been proposed that a memory trace enters a labile phase each time it is retrieved. A reactivated memory relies on de novo protein synthesis to be faithfully reconsolidated and restored. Thus, in theory, a long-lasting and pathological memory associated with drug use may be disrupted by inhibiting its reconsolidation through use of protein synthesis inhibitors administered immediately following the memory retrieval. However, effective and efficient strategies to reactivate drug memory remained elusive. This study was undertaken to examine the effects of systemic cycloheximide and anisomycin treatment on the reconsolidation and maintenance of a reactivated cocaine-conditioned place preference (CPP) in mice using several strategies designed to reactivate the previously acquired memory. We found that anisomycin (50 mg/kg/injection) and cycloheximide (15 mg/kg/injection) administered immediately after the reactivation of cocaine-CPP ameliorated subsequent expression and maintenance of this memory. Likewise, when anisomycin and cycloheximide were administered immediately after additional cocaine and saline conditioning trials, the reactivated memory engendered by those extra training trials was also diminished. However, a similar anisomycin dosing regimen failed to affect subsequent expression of cocaine-CPP when additional cocaine conditioning trial was used in the absence of additional saline trial. Finally, cocaine and saline administration to mice in their home cages with or without anisomycin treatment had no effect on later cocaine-CPP expression. Taken together, these findings suggest that systemic treatment with protein synthesis inhibitors immediately after the reactivation of cocaine-CPP effectively diminished the reconsolidation and maintenance of such a cocaine memory. More importantly, reactivation of cocaine-CPP could be achieved by presentation of cocaine-conditioned cues as well as by administering additional cocaine and saline conditioning trials in a balanced fashion.