Biology subjects

Fuchs, R. A.

Publications and source records attributed to Fuchs, R. A..

5 recordsLinked to original sources

bioRxiv2024

Dorsal Raphe to Basolateral Amygdala Corticotropin-Releasing Factor Circuit Regulates Cocaine-Memory Reconsolidation

Environmental stimuli elicit drug craving and relapse in cocaine users by triggering the retrieval of strong cocaine-related contextual memories. Retrieval can also destabilize drug memories, requiring reconsolidation, a protein synthesis-dependent storage process, to maintain memory strength. Corticotropin-releasing factor (CRF) signaling in the basolateral amygdala (BLA) is necessary for cocaine-memory reconsolidation. We have hypothesized that a critical source of CRF in the BLA is the dorsal raphe nucleus (DR) based on its neurochemistry, anatomical connectivity, and requisite involvement in cocaine-memory reconsolidation. To test this hypothesis, male and female Sprague-Dawley rats received adeno-associated viruses to express Gi-coupled designer receptors exclusively activated by designer drugs (DREADDs) selectively in CRF neurons of the DR and injection cannulae directed at the BLA. The rats were trained to self-administer cocaine in a distinct environmental context then received extinction training in a different context. They were then briefly re-exposed to the cocaine-predictive context to destabilize (reactivate) cocaine memories. Intra-BLA infusions of the DREADD agonist deschloroclozapine (DCZ; 0.1 mM, 0.5 L/hemisphere) after memory reactivation attenuated cocaine-memory strength, relative to vehicle infusion. This was indicated by a selective, DCZ-induced and memory reactivation-dependent decrease in drug-seeking behavior in the cocaine-predictive context in DREADD-expressing males and females at test compared to respective controls. Notably, BLA-projecting DR CRF neurons that exhibited increased c-Fos expression during memory reconsolidation co-expressed glutamatergic and serotonergic neuronal markers. Together, these findings suggest that the DRCRF [->] BLA circuit is engaged to maintain cocaine-memory strength after memory destabilization, and this phenomenon may be mediated by DR CRF, glutamate, and/or serotonin release in the BLA.

neuroscience↗

bioRxiv2021

Optogenetic inhibition of the dorsal hippocampus CA3 region during early-stage cocaine-memory reconsolidation disrupts subsequent context-induced cocaine seeking in rats

The dorsal hippocampus (DH) is key to the long-term maintenance of cocaine memories following retrieval-induced memory destabilization; even though, it is not the site of protein synthesis-dependent memory reconsolidation. Here, we took advantage of the temporal and spatial specificity of an optogenetic manipulation to examine the role of the cornu ammonis 3 subregion of the DH (dCA3) in early-stage cocaine-memory reconsolidation. Male Sprague-Dawley rats expressing eNpHR3.0 in the DH were trained to self-administer cocaine in a distinct context and underwent extinction training in a different context. Rats then received a 15-min memory-reactivation session, to destabilize cocaine memories and trigger reconsolidation, or remained in their home cages (no-reactivation controls). Optogenetic inhibition of the dCA3 for 1 h immediately, but not 1 h, after memory reactivation resulted in cocaine-memory impairment as indicated by reduction in drug-seeking behavior selectively in the cocaine-paired context 3 d later, at test, relative to responding in no-inhibition, no-reactivation, and no-eNpHR3.0 controls. Cocaine-memory impairment was associated with reduced c-Fos expression, an index of neuronal activation, in the dCA3 stratum lucidum (SL) and stratum pyramidale (SP) at test. Based on these observations and extant literature, we postulate that recurrent circuits in the SP are activated during early-stage memory reconsolidation to maintain labile cocaine memories prior to protein synthesis-dependent restabilization in another brain region, such as the basolateral amygdala. Furthermore, SL and SP interneurons may enhance memory reconsolidation by limiting synaptic noise in the SP and also contribute to recall as elements of the updated cocaine engram or retrieval links.

neuroscience↗

bioRxiv2020

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

Re-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 {micro}g/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 {micro}g/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.

neuroscience↗

bioRxiv2020

CB1 receptor signaling modulates amygdalar plasticity during context-cocaine memory reconsolidation to promote subsequent cocaine seeking

Contextual 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 -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.

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bioRxiv2019

Vaporized cannabis extracts have reinforcing properties and support conditioned drug-seeking behavior in rats

Recent trends in cannabis legalization have increased the necessity to better understand the effects of cannabis use. Animal models involving traditional cannabinoid self-administration approaches have been notoriously difficult to establish and differences in the drug employed and its route of administration have limited the translational value of preclinical studies. To address this challenge in the field, we have developed a novel method of cannabis self-administration using response-contingent delivery of vaporized {Delta}9-tetrahydrocannabinol-rich (CANTHC) or cannabidiol-rich (CANCBD) complete cannabis extracts. Male Sprague Dawley rats were trained to nosepoke for discrete puffs of CANTHC, CANCBD, or vehicle (VEH) in daily one-hour sessions. Cannabis vapor reinforcement resulted in strong discrimination between active and inactive operanda. CANTHC maintained higher response rates under fixed ratio schedules and higher break points under progressive ratio schedules compared to CANCBD or VEH, and the number of vapor deliveries positively correlated with plasma THC concentrations. Moreover, metabolic phenotyping studies revealed alterations in locomotor activity, energy expenditure, and daily food intake that are consistent with effects in human cannabis users. Furthermore, both cannabis regimens produced ecologically relevant brain concentrations of THC and CBD and CANTHC administration decreased hippocampal CB1 receptor binding. Removal of CANTHC reinforcement (but not CANCBD) resulted in a robust extinction burst and an increase in cue-induced cannabis-seeking behavior relative to VEH. These data indicate that volitional exposure to THC-rich cannabis vapor has bona fide reinforcing properties and collectively support the utility of the vapor self-administration model for the preclinical assessment of volitional cannabis intake and cannabis-seeking behaviors.

neuroscience↗