The basolateral amygdala and nucleus accumbens core mediate dissociable aspects of drug memory reconsolidation

A distributed limbic-corticostriatal circuitry is implicated in cue-induced drug craving and relapse. Exposure to drug-paired cues not only precipitates relapse, but also triggers the reactivation and reconsolidation of the cue-drug memory. However, the limbic cortical-striatal circuitry underlying drug memory reconsolidation is unclear. The aim of this study was to investigate the involvement of the nucleus accumbens core and the basolateral amygdala in the reconsolidation of a cocaine-conditioned stimulus-evoked memory. Antisense oligodeoxynucleotides (ASO) were infused into each structure to knock down the expression of the immediate-early gene zif268, which is known to be required for memory reconsolidation. Control infusions used missense oligodeoxynucleotides (MSO). The effects of zif268 knockdown were measured in two complementary paradigms widely used to assess the impact of drug-paired CSs upon drug seeking: the acquisition of a new instrumental response with conditioned reinforcement and conditioned place preference. The results show that both intranucleus accumbens core and intrabasolateral amygdala zif268 ASO infusions at memory reactivation impaired the reconsolidation of the memory underlying a cocaine-conditioned place preference. However, knockdown of zif268 in the nucleus accumbens at memory reactivation had no effect on the memory underlying the conditioned reinforcing properties of the cocaine-paired CS measured subsequently, and this is in contrast to the marked impairment observed previously following intrabasolateral amygdala zif268 ASO infusions. These results suggest that both the basolateral amygdala and nucleus accumbens core are key structures within limbic cortical-striatal circuitry where reconsolidation of a cue-drug memory occurs. However reconsolidation of memory representations formed during Pavlovian conditioning are differentially localized in each site.Through Pavlovian association with the effects of addictive drugs, a conditioned stimulus (CS) acquires both general motivational and sensory-specific conditioned reinforcing properties (Everitt et al. 2000). These associations contribute to the high likelihood of relapse in addicted individuals, yet the extinction of drug CSs by nonreinforced exposure has proved to be of limited therapeutic utility (Conklin and Tiffany 2002). In abstinent humans, drug CSs evoke salient and persistent memories of drug-taking experiences, inducing craving and relapse (Childress et al. 1988; O''Brien et al. 1992), while in animals they also precipitate relapse to, or reinstatement of, drug-seeking behavior (de Wit and Stewart 1981; Meil and See 1996; Fuchs et al. 1998; Weiss 2000). Thus, disrupting drug-related memories might significantly diminish relapse propensity on subsequent exposure to drug-paired CSs, and thereby promote abstinence.Exposure to a drug-associated CS also triggers a process of memory reconsolidation, which restabilizes the reactivated and labile memory (Nader 2003). While reconsolidation may adaptively update memories (Dudai 2006; Hupbach et al. 2007; Rossato et al. 2007; Lee 2009), its disruption may reduce the impact of intrusive or aberrant memories on behavior subsequently (Lee et al. 2005, 2006; Brunet et al. 2008; Kindt et al. 2009; Taubenfeld et al. 2009). The reconsolidation of CS–cocaine memories has been shown to depend upon protein synthesis and expression of the plasticity-associated immediate-early gene, zif268, in the basolateral amygdala (BLA), since zif268 knockdown at memory reactivation disrupted the acquired conditioned reinforcing properties of the CS measured in drug-seeking tasks days or weeks later (Lee et al. 2005, 2006).Although the BLA has an established role in CS-drug memory reconsolidation, it remains unclear whether other sites within limbic cortical-ventral striatal circuitry participate in this process. The nucleus accumbens core (AcbC) is a primary candidate, as zif268 is up-regulated in the AcbC as well as in the BLA following exposure to cocaine CSs (Thomas et al. 2003). Furthermore, the AcbC, which is strongly implicated in Pavlovian influences on drug seeking and relapse (Cardinal et al. 2002; Kalivas and McFarland 2003), has been shown to be a site where the reconsolidation of a drug conditioned place preference (CPP) memory can be disrupted (Miller and Marshall 2005).Given the evidence of increased zif268 expression in the AcbC following CS-drug memory reactivation, we investigated its requirement in the reconsolidation of cocaine-associated memories. To address this issue, we employed two different but complementary paradigms widely used to measure the conditioned effects of CSs associated with drugs of abuse: the acquisition of a new instrumental response with conditioned reinforcement (ANR) and CPP. These procedures have been used successfully to investigate the mechanisms underlying the reconsolidation of appetitive Pavlovian memories, but it is likely that they depend upon different associative mechanisms (Everitt et al. 1991; White and McDonald 1993) that in turn depend upon different neural loci within limbic cortical-striatal circuitry (Cardinal et al. 2002). Therefore, to enable a full comparison with the functional involvement of the BLA, we investigated the necessity for BLA zif268 expression in drug memory reconsolidation as assessed in the CPP paradigm.     

Dissociable learning processes,associative theory,and testimonial reviews: A comment on Smith and Church (2018)

Psychonomic Bulletin & Review - Smith and Church (Psychonomic Bulletin & Review, 25, 1565–1584 2018) present a “testimonial” review of dissociable learning processes...     

Was Hirschi Right?: A National-Level Longitudinal Examination of Religion as a Social Bond

The current research re-examines Hirschi’s (1969) omission of religion as a social bond by examining the impact of religious commitment and religious salience on substance use in National Youth Survey Family Study respondents, both in adolescence/early adulthood, and again in middle adulthood. This approach allows for a longitudinal examination of a large, nationally representative sample of respondents. Results challenge Hirschi’s decision, and suggest that, particularly in adolescence, a person’s religious service attendance, and belief in religion, do affect their likelihood of substance use. Further research is suggested.     

Intensive OutPatient Therapy for Clergy Burnout: How Much Difference Can a Week Make?

A pre-test and post-test quasi-experimental matched pairs design was used to assess the effectiveness of a week-long multi-therapist intensive outpatient intervention process with clergy suffering from depression and burnout. Participants (n = 23) in the “Clergy in Kairos” program of the Pastoral Institute (Muse in J Pastor Care Couns 61(3):183–195, 2007) constituted the experimental variable. Clergy surveyed from United Methodist and Presbyterian denominations (n = 121) provided a control group from which 23 respondents were selected whose pre-test scores in depression and burnout were statistically equivalent to those in the experimental group. The treatment group consisted of clergy from three denominations who self-selected (or in some cases were referred by denominational officials) into the program. At the outset, clergy in both groups reported equivalent levels of conflict, emotional exhaustion, depersonalization, and depression. At the 6-months follow-up, clergy in the experimental group showed significant improvement of depression, emotional exhaustion, and depersonalization scores. By contrast, there was no change in the burnout and depression scores in the control group at 6-months post-test. Findings suggest the usefulness of a week-long multi-therapist intensive outpatient intervention in reducing burnout and depression.     

Some further tests of the constant-ratio rule

Five experiments sought to test the constant-ratio rule (CRR) with single dimensional ensembles composed of 2, 4, or 8 stimulus objects. Each S attempted to identify stimuli which varied in weight or in visual size or brightness. The results demonstrated: (a) The CRR predicts equally well the response proportions of single dimensional visual, kinesthetic, and auditory stimulus ensembles, but less well than those for multidimensional auditory stimuli. (b) Better predictions are obtained with four than with two stimulus objects.(c) The CRR is sensitive to variations in the spacing and range of the stimulus ensembles and to practice on the task. It is concluded that the rule tends to fail whenever stimulus conditions elicit differential amounts of stimulus and response confusion.