Dopamine in the dorsal hippocampus impairs the late consolidation of cocaine-associated memory

Abstract

Cocaine is thought to be addictive because it elevates dopamine levels in the striatum, reinforcing drug-seeking habits. Cocaine also elevates dopamine levels in the hippocampus, a structure involved in contextual conditioning as well as in reward function. Hippocampal dopamine promotes the late phase of consolidation of an aversive step-down avoidance memory. Here, we examined the role of hippocampal dopamine function in the persistence of the conditioned increase in preference for a cocaine-associated compartment. Blocking dorsal hippocampal D1-type receptors (D1Rs) but not D2-type receptors (D2Rs) 12 h after a single training trial extended persistence of the normally short-lived memory; conversely, a general and a specific phospholipase C-coupled D1R agonist (but not a D2R or adenylyl cyclase-coupled D1R agonist) decreased the persistence of the normally long-lived memory established by three-trial training. These effects of D1 agents were opposite to those previously established in a step-down avoidance task, and were here also found to be opposite to those in a lithium chloride-conditioned avoidance task. After returning to normal following cocaine injection, dopamine levels in the dorsal hippocampus were found elevated again at the time when dopamine antagonists and agonists were effective: between 13 and 17 h after cocaine injection. These findings confirm that, long after the making of a cocaine-place association, hippocampal activity modulates memory consolidation for that association via a dopamine-dependent mechanism. They suggest a dynamic role for dorsal hippocampal dopamine in this late-phase memory consolidation and, unexpectedly, differential roles for late consolidation of memories for places that induce approach or withdrawal because of a drug association.

Figure 1

Temporal duration and dopaminergic modulation of the persistence of a short-lasting cocaine-associated memory. (a) Three doses of cocaine were tested. The dose of 20 mg/kg induced a significant retention of the memory for cocaine–place association when tested 24 h after a one-trial training (n=5–21 per group). Therefore, this dose was used in all the remaining approach experiments. (b) A weak (one-trial training) memory for the cocaine–place association was retained for 24 h but not for 7 or 14 days (n=7–11 per group). (c) A strong (three-trial training) memory for the cocaine–place association was retained for at least 21 days (n=8–10 per group). Asterisks indicate significant differences between cocaine-injected animals and its corresponding saline controls (Newman–Keuls, *p<0.05; **p<0.01). (d–g) Effects of D1-type dopamine agonist (SKF 38393) or antagonist (SCH 23390) injections—given 12 h after the training trial—on the persistence of the memory for cocaine–place associations established by one-trial training. (d) The D1-type agonist had no effect on the 24 h memory for cocaine–place associations established by one-trial training (n=8–10 per group). (e) The D1-type agonist had no effect on the persistence of the memory for cocaine–place associations when tested at 7 days after one-trial training (n=10–12 per group). (f) The D1-type antagonist had no effect on the 24 h memory for cocaine–place associations established by one-trial training (n=16–17 per group). (g) The D1-type antagonist prolonged the duration of the memory for cocaine–place associations after one-trial training (n=11–14 per group). Post hoc analyses demonstrated that the group conditioned with cocaine, infused with SCH 23390 12 h later, and tested at 7 days showed a higher score when compared with the other groups (Newman–Keuls, **p<0.01). Asterisks upon bracket indicate a significant difference between saline- and cocaine-injected animals, collapsed across intracerebral infusion treatments (Newman–Keuls, *p<0.05; **p<0.01). Coc, cocaine; Sal, saline; Veh, vehicle.

Figure 2

Dopaminergic modulation of the persistence of a long-lasting cocaine-associated memory. Effects of D1-type dopamine agonist (SKF 38393) or antagonist (SCH 23390) injections—given 12 h after the training trial—on the persistence of the memory for cocaine–place associations established by 3-trial training. (a) The D1-type agonist (SKF 38393) had no effect on the 24 h memory for cocaine–place associations established by three-trial training (n=9–10 per group). (b) Treatment with the D1-type agonist (SKF 38393) attenuated the 7-day persistence of the memory for cocaine–place associations established by three-trial training (n=7–10 per group). (c) The D1-type antagonist (SCH 23390) had no effect on the 24 h memory for cocaine–place associations established by three-trial training (n=8–10 per group). (d) The D1-type antagonist (SCH 23390) had no effect on the persistence of the memory for cocaine–place associations when tested at 7 days after three-trial training (n=13–15 per group). Post hoc analyses demonstrated that the group conditioned with cocaine, infused with SKF 38393 12 h later, and tested at 7 days showed a higher score when compared with the other groups (Newman–Keuls, **p<0.01). Asterisks upon bracket indicate a significant difference between saline and cocaine-injected animals, collapsed across intracerebral infusion treatments (Newman–Keuls, **p<0.01; ***p<0.001). Coc, cocaine; Sal, saline; Veh, vehicle.

Figure 3

Persistence of cocaine-related memories is regulated by dopaminergic receptors coupled to phospholipase C (PLC) cascade and is not mediated by brain-derived neurotrophic factor (BDNF). (a) Delayed (12 h after conditioning trial) infusion of the adenylyl cyclase (AC)-selective D1-type agonist SKF 83822 had no effect on the 7-day retention of the memory for cocaine–place associations established by three-trial training (n=9–10 per group). (b) Delayed (12 h after conditioning trial) infusion of the PLC-selective D1-type agonist SKF 83959 significantly attenuated 7-day retention of the memory for cocaine–place associations established by three-trial training (n=7–9 per group). Post hoc analyses demonstrated that the group conditioned with cocaine, infused with SKF 83959 12 h later, and tested at 7 days showed a higher score when compared with the other groups (Newman–Keuls, *p<0.05). Asterisks upon bracket indicate a significant difference between saline- and cocaine-injected animals, collapsed across intracerebral infusion treatments (Newman–Keuls, **p<0.01). (c–e) Dorsal hippocampal levels of BDNF of animals administered either saline or 20 mg/kg cocaine. Animals were injected and returned to their home cages (HC groups) or were conditioned as described (C groups). In all the figures, control group is represented by animals injected with saline and left undisturbed in their home cages (Sal/HC groups). (c) Levels of dorsal hippocampal BDNF measured at 12 h after one-trial training. BDNF levels did not vary across treatments (n=5 per group). (d) Levels of dorsal hippocampal BDNF measured at 12 h after three-trial training. BDNF levels did not vary across treatments (n=3–4 per group). (e) SCH 23390 administration did not modify the dorsal hippocampal levels of BDNF measured at 12 h after one-trial training. Animals were conditioned with either saline or cocaine; 11.5 h later they were infused with SCH 23390 or its vehicle and were killed 30 min later (n=15 per group). Coc, cocaine; Sal, saline; Veh, vehicle.

Figure 4

Effects of D1-type dopamine agonist (SKF 38393) on the persistence of the memory for one-trial LiCl–place associations. Infusion of the D1-type agonist (SKF 38393) enhanced the retention of the 7-day memory for the place associations induced by LiCl (n=7–9). Asterisk indicates significant post hoc comparisons (Newman–Keuls, *p<0.05). LiCl, lithium chloride; Sal, saline; Veh, vehicle.

Figure 5

Dopamine (DA) fluctuations in microdialysis samples from the dorsal hippocampus of animals following one-trial training for cocaine–place associations. Cocaine or saline was given at the arrow after the baseline period (B) and hourly samples were taken for the next 24 h. The inset shows the results of four baseline samples pooled together. There were no significant differences in baseline between the two groups (n=7 per group; Student's t-test, t₍₁₂₎=−0.31; p=0.76). There were no significant differences in DA measurements between groups during the first 12-h period of the experiment (main effect of cocaine: F_(1,12)=1.72; p=0.21, NS; main effect of time: F_(11,132)=1.30; p=0.23, NS; cocaine × time interaction: F_(11,132)=0.69; p=0.74, NS). However, during the second 12-h period, there was a significant main effect of time, F_(11,132)=2.04; p=0.03 and a significant cocaine × time interaction, F_(11,132)=4.17; p=0.00003. Asterisks indicate significant post hoc comparisons (Newman–Keuls, **p<0.01; ***p<0.001). The horizontal bar in the bottom of the figure indicates the dark–light cycle (black: lights out).