Fear extinction is a form of inhibitory learning that allows for the adaptive control of conditioned fear responses. Although fear extinction is an active learning process that eventually leads to the formation of a consolidated extinction memory, it is a fragile behavioural state. Fear responses can recover spontaneously or subsequent to environmental influences, such as context changes or stress. Understanding the neuronal substrates of fear extinction is of tremendous clinical relevance, as extinction is the cornerstone of psychological therapy of several anxiety disorders and because the relapse of maladaptative fear and anxiety is a major clinical problem. Recent research has begun to shed light on the molecular and cellular processes underlying fear extinction. In particular, the acquisition, consolidation and expression of extinction memories are thought to be mediated by highly specific neuronal circuits embedded in a large-scale brain network including the amygdala, prefrontal cortex, hippocampus and brain stem. Moreover, recent findings indicate that the neuronal circuitry of extinction is developmentally regulated. Here, we review emerging concepts of the neuronal circuitry of fear extinction, and highlight novel findings suggesting that the fragile phenomenon of extinction can be converted into a permanent erasure of fear memories. Finally, we discuss how research on genetic animal models of impaired extinction can further our understanding of the molecular and genetic bases of human anxiety disorders.

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Pathological fear and anxiety are highly debilitating and, despite considerable advances in psychotherapy and pharmacotherapy they remain insufficiently treated in many patients with PTSD, phobias, panic and other anxiety disorders. Increasing preclinical and clinical evidence indicates that pharmacological treatments including cognitive enhancers, when given as adjuncts to psychotherapeutic approaches [cognitive behavioral therapy including extinction-based exposure therapy] enhance treatment efficacy, while using anxiolytics such as benzodiazepines as adjuncts can undermine long-term treatment success. The purpose of this review is to outline the literature showing how pharmacological interventions targeting neurotransmitter systems including serotonin, dopamine, noradrenaline, histamine, glutamate, GABA, cannabinoids, neuropeptides (oxytocin, neuropeptides Y and S, opioids) and other targets (neurotrophins BDNF and FGF2, glucocorticoids, L-type-calcium channels, epigenetic modifications) as well as their downstream signaling pathways, can augment fear extinction and strengthen extinction memory persistently in preclinical models. Particularly promising approaches are discussed in regard to their effects on specific aspects of fear extinction namely, acquisition, consolidation and retrieval, including long-term protection from return of fear (relapse) phenomena like spontaneous recovery, reinstatement and renewal of fear. We also highlight the promising translational value of the preclinial research and the clinical potential of targeting certain neurochemical systems with, for example d-cycloserine, yohimbine, cortisol, and L-DOPA. The current body of research reveals important new insights into the neurobiology and neurochemistry of fear extinction and holds significant promise for pharmacologically-augmented psychotherapy as an improved approach to treat trauma and anxiety-related disorders in a more efficient and persistent way promoting enhanced symptom remission and recovery.

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