Interaction between the basolateral amygdala and dorsal hippocampus is critical for cocaine memory reconsolidation and subsequent drug context-induced cocaine-seeking behavior in rats

ABSTRACTContextual drug-associated memories precipitate craving and relapse in cocaine users. Such associative memories can be weakened through interference with memory reconsolidation, a process by which memories are maintained following memory retrieval-induced destabilization. We hypothesized that cocaine-memory reconsolidation requires cannabinoid type 1 receptor (CB1R) signaling based on the fundamental role of the endocannabinoid system in synaptic plasticity and emotional memory processing. Using an instrumental rat model of cocaine relapse, we evaluated whether systemic CB1R antagonism (AM251; 3 mg/kg, I.P.) during memory reconsolidation alters (a) subsequent drug context-induced cocaine-seeking behavior, as well as (b) cellular adaptations and (c) excitatory synaptic physiology in the basolateral amygdala (BLA). Systemic CB1R antagonism – during, but not after, cocaine-memory reconsolidation – reduced drug context-induced cocaine-seeking behavior three days, but not three weeks, later. CB1R antagonism also inhibited memory retrieval-associated increases in BLA zinc finger 268 (zif268) and activity regulated cytoskeletal-associated protein (Arc) immediate-early gene expression and changes in BLA α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and N-methyl-D-aspartate receptor (NMDAR) subunit phosphorylation that likely contribute to increased receptor membrane trafficking and synaptic plasticity during memory reconsolidation. Furthermore, CB1R antagonism increased memory reconsolidation-associated spontaneous excitatory post-synaptic current frequency in BLA principal neurons during memory reconsolidation. Together, these findings suggest that CB1R signaling modulates cellular and synaptic mechanisms in the BLA during cocaine-memory reconsolidation, thereby facilitating cocaine-memory maintenance. These findings identify the CB1R as a potential therapeutic target for relapse prevention.SIGNIFICANCE STATEMENTDrug relapse can be triggered by the retrieval of context-drug memories upon re-exposure to a drug-associated environment. Context-drug associative memories become destabilized upon retrieval and must be reconsolidated into long-term memory stores in order to persist. Hence, targeted interference with memory reconsolidation can weaken maladaptive context-drug memories and reduce the propensity for drug relapse. Our findings indicate that cannabinoid type 1 receptor (CB1R) signaling is critical for context-cocaine memory reconsolidation and subsequent drug context-induced reinstatement of cocaine-seeking behavior. Furthermore, cocaine-memory reconsolidation is associated with CB1R-dependent immediate-early gene expression and changes in excitatory synaptic proteins and physiology in the basolateral amygdala. Together, our findings provide initial support for CB1R as a potential therapeutic target for relapse prevention.

Download Full-text

Basolateral amygdala CB1 receptors modulate HPA axis activation and context-cocaine memory strength during reconsolidation

10.1101/2020.07.18.209932 ◽

2020 ◽

Author(s):

Jessica A. Higginbotham ◽

Nicole M. Jones ◽

Rong Wang ◽

Ryan J. McLaughlin ◽

Rita A. Fuchs

Keyword(s):

Memory Retrieval ◽

Basolateral Amygdala ◽

Memory Reconsolidation ◽

Long Term Memory ◽

Memory Strength ◽

Corticosterone Concentration ◽

Cannabinoid Type 1 Receptor ◽

Cocaine Seeking ◽

Seeking Behavior ◽

The Impact

ABSTRACTRe-exposure to a cocaine-associated context triggers craving and relapse through the retrieval of salient context-drug memories. Upon retrieval, context-drug memories become labile and temporarily sensitive to modification before they are reconsolidated into long-term memory stores. Cannabinoid type 1 receptor (CB1R) signaling is necessary for cocaine-memory reconsolidation and associated glutamatergic plasticity in the basolateral amygdala (BLA); however, it remains unclear whether CB1Rs in the BLA mediate this phenomenon. To investigate this question, we examined whether CB1R antagonist or agonist administration into the BLA immediately after cocaine-memory retrieval (i.e., during memory reconsolidation) alters cocaine-memory strength and subsequent drug context-induced cocaine-seeking behavior in an instrumental rodent model of cocaine relapse. Intra-BLA administration of the CB1R antagonist, AM251 (0.3 µg/hemisphere) – during, but not after, memory reconsolidation – increased drug context-induced cocaine-seeking behavior three days later, while the CB1R agonist, WIN55,212-2 (0.5 µg/hemisphere) failed to alter this behavior. Furthermore, AM251 administration into the posterior caudate putamen (anatomical control region) during memory reconsolidation did not alter subsequent context-induced cocaine-seeking behavior. In a follow-up experiment, cocaine-memory retrieval elicited robust hypothalamic-pituitary-adrenal axis activation, as indicated by an increase in blood serum corticosterone concentration, and this response was selectively extended by intra-BLA AM251 administration during the putative time of memory reconsolidation relative to all control conditions. Together, these findings suggest that CB1R populations in the BLA gate memory strength or interfere with memory maintenance, possibly by diminishing the impact of cue-induced arousal on the integrity of the reconsolidating memory trace or on the efficiency of the memory reconsolidation process.

Download Full-text