Pharmacological facilitation of fear extinction and the search for adjunct treatments for anxiety disorders--the case of yohimbine

Abstract

There is current interest in identifying drugs that facilitate fear extinction, as this form of learning is the basis of certain cognitive therapies for anxiety disorders. Following an initial report several years ago that the alpha2-adrenoreceptor antagonist yohimbine facilitated extinction in mice, more recent studies have shown mixed effects or even impairment. It has become clear that the effect of yohimbine on extinction depends on a number of factors, including genetic background, contextual variables and the presence of competing behaviors. To what extent theses effects of yohimbine are mediated through the alpha2-adrenoreceptor, as opposed to other sites of action, is also uncertain. More work is needed before this drug can be approved as a pharmacological adjunct for extinction-based therapies. More generally, the case of yohimbine may serve as a model for the development of other extinction facilitators.

Figure 1

A commonly employed procedure for testing the effects of putative extinction-facilitating drugs such as yohimbine in rodents. On Day 1, subjects undergo Pavlovian fear conditioning in which a previous innocuous stimulus, for example auditory tone, (conditioned stimulus, CS) is repeatedly paired with an aversive stimulus, for example footshock (unconditioned stimulus, US). The fear response to the tone is often measured by quantifying freezing. On Day 2, subjects are treated with the drug (or an appropriate vehicle control) and then undergo partial fear extinction training in which CS is repeatedly presented in the absence of the US. On Day 3, extinction retrieval is tested. If drug treatment was effective in facilitating fear extinction, the fear response to the CS in drug-treated subjects will be significantly less than in vehicle-treated controls.