Common neurocircuitry mediating drug and fear relapse in preclinical models

Abstract

Background: Comorbidity of anxiety disorders, stressor- and trauma-related disorders, and substance use disorders is extremely common. Moreover, therapies that reduce pathological fear and anxiety on the one hand, and drug-seeking on the other, often prove short-lived and are susceptible to relapse. Considerable advances have been made in the study of the neurobiology of both aversive and appetitive extinction, and this work reveals shared neural circuits that contribute to both the suppression and relapse of conditioned responses associated with trauma or drug use.

Objectives: The goal of this review is to identify common neural circuits and mechanisms underlying relapse across domains of addiction biology and aversive learning in preclinical animal models. We focus primarily on neural circuits engaged during the expression of relapse.

Key findings: After extinction, brain circuits involving the medial prefrontal cortex and hippocampus come to regulate the expression of conditioned responses by the amygdala, bed nucleus of the stria terminalis, and nucleus accumbens. During relapse, hippocampal projections to the prefrontal cortex inhibit the retrieval of extinction memories resulting in a loss of inhibitory control over fear- and drug-associated conditional responding.

Conclusions: The overlapping brain systems for both fear and drug memories may explain the co-occurrence of fear and drug-seeking behaviors.

Keywords: Addiction; Amygdala; Bed nucleus of the stria terminalis; Extinction; Hippocampus; PTSD; Prefrontal cortex; Reinstatement; Relapse.

Fig. 1

A summary of various drug and fear relapse scenarios, the common and divergent terms used to describe them, and their features

Fig. 2

Arrows indicate common and divergent regions and neural pathways that have been demonstrated as directly engaged by and/or are required for expression of either drug relapse (blue dashed arrows) or for fear relapse (red arrows) after extinction. Relapse circuits are drawn from studies that are not limited to any particular drug type (cocaine, methamphetamine, etc.) or relapse scenario (spontaneous recovery, renewal, etc.). “+” symbols indicate excitatory (glutamatergic) pathways. Arrows labeled with “DA” and “CRF” denote dopaminergic or corticotrophin-releasing factor-releasing relapse circuits, respectively. Region abbreviations: nucleus accumbens core (NAc core); nucleus accumbens shell (NAc shell); ventral tegmental area (VTA); prelimbic cortex (PL); hippocampus (HPC); infralimbic cortex (IL); basolateral amygdala (BLA); central amygdala (CeA); bed nucleus of the stria terminalis (BNST)