A Basolateral Amygdala Microcircuit for Drug Craving: Is There a Craving Engram?

Abstract

The basolateral amygdala is a subdivision of the amygdala that is located in the medial temporal lobe (1). The basolateral complex can be divided into lateral and basal nuclei of the amygdala, which receive inputs from the prefrontal cortex, auditory cortex, thalamus, ventral pallidum, ventral tegmental area, locus coeruleus, dorsal raphe, and stria terminalis and send prominent outputs to the central nucleus of the amygdala, the prelimbic and infralimbic prefrontal cortices, the entorhinal cortex, the bed nucleus of the stria terminalis, the hippocampus, and the nucleus accumbens (1). The central nucleus of the amygdala can be divided into lateral and medial divisions. The basolateral amygdala has long been associated with connecting salient stimuli to behavioral outputs in the domain of fear conditioning (2). As such, the basolateral amygdala plays a key role in the formation, storage, and retrieval of conditioned fear memories (2). However, the basolateral amygdala also plays a role in mediating appetitive conditioning. Neural connections between the lateral and basolateral amygdala and the nucleus accumbens have been hypothesized to generate goal-directed behavior in response to conditioned reward-predictive cues. Particularly compelling have been the data showing that the basolateral amygdala mediates conditioning associated with the rewarding effects of drugs of abuse. Neuropharmacological disconnection studies implicated the basolateral amygdala connection to the nucleus accumbens core in cocaine seeking. The removal of a small population of neurons by ablating or silencing neurons that overexpress cyclic adenosine monophosphate response element binding protein in the lateral amygdala (i.e., neurons that are recruited during conditioning) blocked the expression and consolidation of cocaine-induced conditioned place preference (3). As discussed by Hsiang et al. (3), functional magnetic resonance imaging studies in humans with a history of cocaine use showed that the presentation of cues that were previously associated with cocaine craving also increased activity in the amygdala. In the current issue of Biological Psychiatry, Puaud et al. (4) used a projection-specific Cre-dependent DREADD (designer receptor exclusively activated by designer drugs)-mediated causal approach in Sprague Dawley rats to test the hypothesis that direct projections from the basolateral amygdala to the nucleus accumbens core are required for the acquisition of cue-controlled cocaine-seeking behavior. The authors used a sophisticated behavioral task that measures drug-seeking behavior, combined with a chemogenetic microcircuit approach to show that a specific pathway from the basolateral