Figure 1.

Highly simplified schematic depicting the interactions among the amygdala, infralimbic (IL) region of the medial prefrontal cortex, and hippocampus that are believed to underlie extinction of conditioned fear and, perhaps, extinction of conditioned drug craving and withdrawal as well. The basolateral complex of the amygdala (BLA) is a site of essential plasticity underlying fear memories. BLA receives sensory information about discrete conditioned stimuli, such as lights, tones, and odors, as well as (through the hippocampus) contextual or spatial cues. After acquisition, BLA triggers conditioned fear responses through its projections to the central nucleus of the amygdala (CeA), which in turn innervates hypothalamic and brainstem targets (such as the periaqueductal gray (PAG) and nucleus reticularis pontis caudalis (PnC)) to elicit behavioral indices of fear, including freezing and fear-potentiated startle (FPS). In extinction, the omission of the unconditioned stimulus is detected through a mechanism that is not well understood. CS-related information is relayed to both BLA and IL, and NMDA receptor-dependent synaptic plasticity occurs at both sites. After extinction training is complete, IL contributes to the suppression of fear conditioned responses by inhibiting amygdalar throughput, likely by activating GABAergic interneurons within BLA, GABAergic intercalated cell masses (ICMs) lying between BLA and CeA, or both. A similar scenario may be true for extinction of conditioned drug craving and withdrawal. Drug-related conditioned responses presumably are triggered through different neural intermediaries (such as the ventral tegmental (VTA) or bed nucleus of the stria terminalis (BNST)) than is conditioned fear, but the same basic BLA–mPFC circuitry may be shared, as suggested by findings that NMDA receptor-mediated synaptic plasticity within BLA and mPFC contribute to extinction of cue-induced drug-seeking behavior.