The NMDA antagonist MK-801 disrupts reconsolidation of a cocaine-associated memory for conditioned place preference but not for self-administration in rats

Abstract

Recent research suggests that drug-related memories are reactivated after exposure to environmental cues and may undergo reconsolidation, a process that can strengthen memories. Conversely, reconsolidation may be disrupted by certain pharmacological agents such that the drug-associated memory is weakened. Several studies have demonstrated disruption of memory reconsolidation using a drug-induced conditioned place preference (CPP) task, but no studies have explored whether cocaine-associated memories can be similarly disrupted in cocaine self-administering animals after a cocaine priming injection, which powerfully reinstates drug-seeking behavior. Here we used cocaine-induced CPP and cocaine self-administration to investigate whether the N-methyl-D-aspartate receptor antagonist (+)-5methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) given just prior to reactivation sessions would suppress subsequent cocaine-primed reinstatement (disruption of reconsolidation). Systemic injection of MK-801 (0.05 or 0.20 mg/kg administered intraperitoneally) in rats just prior to reactivation of the cocaine-associated memory in the CPP context attenuated subsequent cocaine-primed reinstatement, while no disruption occurred in rats that did not receive reactivation in the CPP context. However, in rats trained to self-administer cocaine, systemic administration of MK-801 just prior to either of two different types of reactivation sessions had no effect on subsequent cocaine-primed reinstatement of lever-pressing behavior. Thus, systemic administration of MK-801 disrupted the reconsolidation of a cocaine-associated memory for CPP but not for self-administration. These findings suggest that cocaine-CPP and self-administration do not use similar neurochemical processes to disrupt reconsolidation or that cocaine-associated memories in self-administering rats do not undergo reconsolidation, as assessed by lever-pressing behavior under cocaine reinstatement conditions.

Figure 1.

MK-801 prior to two reactivation sessions in the CPP chamber suppresses subsequent cocaine-primed reinstatement. Data are mean ± SEM of preference score. Preference score = day being tested minus initial preference day. (Top) The protocol for results shown in A–C. Init Pref = initial preference for cocaine-paired chamber prior to training; Test = test day for place preference in cocaine-paired chamber in which no cocaine was administered; Last Ext = Last Extinction Day; Reinstate = cocaine-primed reinstatement using 10 mg/kg i.p. cocaine. Rats were tested immediately after injection for reinstatement. Only the last extinction day is shown for clarity. N = 12 for Saline group; N = 7 for 0.05 mg/kg MK-801 group; N = 8 for 0.20 mg/kg MK-801 group. ⁺P < 0.05, compared within groups to their Init Pref Day; *P < 0.05, compared with saline group on the same day. (B) Locomotor activity during the Reinstatement Day. Data are mean ± SEM photocell beam breaks per minute of time spent in the cocaine-paired compartment. (C) Preference scores during the two reactivation days in the presence of saline or MK-801. Data are mean ± SEM of preference score. The 0.20 mg/kg MK-801 dose suppressed the preference scores on both reactivation days.

Figure 2.

MK-801 prior to two reactivation sessions in the home cage does not suppress subsequent cocaine-primed reinstatement. Data are mean ± SEM of preference score. (Top) The protocol for results shown in A and B. See Figure 1 legend for full explanation of terminology. Drugs were administered in the home cage on Reactivation Days 1 and 2 instead of in the CPP apparatus. N = 7 for Saline group; N = 8 for 0.20 mg/kg MK-801 group. ⁺P < 0.05, compared within groups to their Init Pref Day. (B) Locomotor activity during the Reinstatement Day. Data are mean ± SEM photocell beam breaks per minute of time spent in the cocaine-paired compartment.

Figure 3.

MK-801 prior to two 15-min noncontingent cocaine presentations in the self-administration chamber does not suppress subsequent cocaine-primed reinstatement. Data are mean ± SEM of active lever presses (A) and inactive lever presses (B). (Top) The protocol for results shown in A–C. For clarity, only the last 3 d of the self-administration maintenance phase are shown (Maint 1–3). Maint = Active lever presses during maintenance training; Last Ext = Last Extinction Day; Reinstate = cocaine-primed reinstatement using 10 mg/kg i.p. cocaine. Rats were tested in a 2-h session immediately after injection for reinstatement. Only the last extinction day is shown for clarity. (A) N = 17 for Saline group; N = 10 for 0.05 mg/kg MK-801 group; N = 16 for 0.20 mg/kg MK-801 group. (B) N = 15 for the 0.20 mg/kg MK-801 group because of one rat that pressed over 2300 times on the inactive lever during the third maintenance day and was removed from the analysis and the figure. ⁺P < 0.05, compared within groups between Last Extinction Day and the Reinstatement Day (for clarity, only significant differences between these two days are indicated). (C) Active lever presses during the two reactivation days in the presence of saline or MK-801. Data are mean ± SEM of active lever presses.

Figure 4.

MK-801 prior to two 2-h cocaine self-administration reactivation sessions in the self-administration chamber does not suppress subsequent cocaine-primed reinstatement. Data are mean ± SEM of active lever presses (A) and inactive lever presses (B). (Top) The protocol for results shown in A–C. See Figure 3 legend for full explanation of terminology. Rats were tested in a 2-h session immediately after injection for reinstatement. (A,B) N = 8 for each group. ⁺P < 0.05, compared within groups between Last Extinction Day and the Reinstatement Day (for clarity, only significant differences between these two days are indicated). (C) Active lever presses during the two reactivation days in the presence of saline or MK-801. Data are mean ± SEM of active lever presses. MK-801 suppressed lever pressing on both reactivation days.