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

Abstract

Contextual stimulus control over instrumental drug-seeking behavior relies on the reconsolidation of context-responsedrug associative memories into long-term memory storage following retrieval-induced destabilization. According to previous studies, the basolateral amygdala (BLA) and dorsal hippocampus (DH) regulate cocaine-related memory reconsolidation; however, it is not known whether these brain regions interact or independently control this phenomenon. To investigate this question, rats were trained to lever press for cocaine reinforcement in a distinct environmental context followed by extinction training in a different context. Rats were then briefly re-exposed to the cocaine-paired context to destabilize cocaine-related memories, or they were exposed to an unpaired context. Immediately thereafter, the rats received unilateral microinfusions of anisomycin (ANI) into the BLA plus baclofen/muscimol (B/M) into the contralateral (BLA/ DH disconnection) or ipsilateral DH, or they received contralateral or ipsilateral microinfusions of vehicle. They then remained in their home cages overnight or for 21 d, followed by additional extinction training and a test of cocaineseeking behavior (nonreinforced active lever responding). BLA/DH disconnection following re-exposure to the cocainepaired context, but not the unpaired context, impaired subsequent drug context-induced cocaine-seeking behavior relative to vehicle or ipsilateral ANI + B/M treatment. Prolonged home cage stay elicited a time-dependent increase, or incubation, of drug-context-induced cocaine-seeking behavior, and BLA/DH disconnection inhibited this incubation effect despite some recovery of cocaine-seeking behavior. Thus, the BLA and DH interact to regulate the reconsolidation of cocaine-related associative memories, thereby facilitating the ability of drug-paired contexts to trigger cocaine-seeking behavior and contributing to the incubation of cocaine-seeking behavior.

Systems Level Neuroplasticity in Drug Addiction

“…Moreover, permanent lesions or reversible inactivation of the BLA has a number of effects on discrete cueinduced drug seeking, including decreases in responding for stimuli associated with cocaine reinforcement (Whitelaw et al 1996;Meil and See 1997;Grimm and See 2000), and prevention of the acquisition , consolidation (Fuchs et al 2006b;Gabriele and See 2010), and expression Fuchs and See 2002;McLaughlin and See 2003;Rogers et al 2008) of cocaine-or heroin-seeking behavior. A similar role for the BLA in contextual drug seeking has also been found (Fuchs et al 2005), involving interactions with other areas implicated in cue-mediated drug seeking, including prefrontal cortical areas (Fuchs et al 2007;Lasseter et al 2011) and the hippocampus (Fuchs et al 2005;Wells et al 2011).…”

“…It should be noted, however, that recent discoveries have implicated other brain structures and neurotransmitter systems in drug seeking behaviors. As mentioned previously, a considerable amount of research has implicated the dorsal (Fuchs et al 2005(Fuchs et al , 2007Meyers et al 2006;Atkins et al 2008;Ramirez et al 2009;Xie et al 2010;Wells et al 2011) and ventral (Rogers and See 2007;Lasseter et al 2010b) hippocampus in cue-induced relapse, including discrete and contextual forms of associative learning. Additionally, a newly defined region, called the mesopontine rostromedial tegmental nucleus (RMTg; also known as the tail of the VTA) (Jhou et al 2009;Kaufling et al 2009;Lavezzi and Zahm 2011) has been implicated as potentially having a profound role in reward-related behaviors.…”

Inhibition of Hippocampal β-Adrenergic Receptors Impairs Retrieval But Not Reconsolidation of Cocaine-Associated Memory and Prevents Subsequent Reinstatement

“…Alternatively, destabilization of drug-associated memories may be dependent on dHipp b-AR signaling. Evidence supporting this hypothesis reveals that dHipp and basolateral amygdala (BLA) fire synchronously during memory reconsolidation (Narayanan et al, 2007) and disconnection of these structures prevents successful drug-associated memory reconsolidation (Wells et al, 2011). Moreover, synaptic input to BLA during reconsolidation destabilizes BLA synapses (Kim et al, 2010), allowing for subsequent stabilization processes for memory reconsolidation.…”

“…The short CPP tests were chosen to induce reconsolidation while limiting CPP extinction across the initial tests. This length of test is standard for testing reconsolidation of drugassociated memories, and previous investigations using this length of CPP test have revealed a role for dHipp or b-AR signaling in reconsolidation of CPP memories (eg, Bernardi et al, 2009 andOtis et al, 2013) and self-administration memories (eg, Ramirez et al, 2009;Wells et al, 2011 andWouda et al, 2010). A CPP was determined when rats spent significantly more time within the previously cocainepaired chamber than in the saline-paired chamber.…”

Effects of drugs of abuse on hippocampal plasticity and hippocampus-dependent learning and memory: contributions to development and maintenance of addiction

“…For example, permanent lesions of the dorsal, but not ventral hippocampus, as well as temporary inactivation of the dorsal hippocampus by local muscimol infusions impaired cocaine conditioned place preference (CPP; Meyers et al 2003Meyers et al , 2006. Similarly, studies suggest that the dorsal hippocampus controls context-induced reinstatement (Fuchs et al 2005(Fuchs et al , 2007Xie et al 2010;Wells et al 2011). In contrast to the dorsal hippocampus, the ventral hippocampus has been shown to mediate cue-induced and cocaine-primed reinstatement of cocaine self-administration (Rogers and See 2007;Ramirez et al 2009).…”