Extinction of drug- and withdrawal-paired cues in animal models: relevance to the treatment of addiction

Abstract

Conditioned drug craving and withdrawal elicited by cues paired with drug use or acute withdrawal are among the many factors contributing to compulsive drug taking. Understanding how to stop these cues from having these effects is a major goal of addiction research. Extinction is a form of learning in which associations between cues and the events they predict are weakened by exposure to the cues in the absence of those events. Evidence from animal models suggests that conditioned responses to drug cues can be extinguished, although the degree to which this occurs in humans is controversial. Investigations into the neurobiological substrates of extinction of conditioned drug craving and withdrawal may facilitate the successful use of drug cue extinction within clinical contexts. While this work is still in the early stages, there are indications that extinction of drug- and withdrawal-paired cues shares neural mechanisms with extinction of conditioned fear. Using the fear extinction literature as a template, it is possible to organize the observations on drug cue extinction into a cohesive framework.

Figure 1

Schematic representation of the drug self-administration paradigm. Panel A, left. In this paradigm, animals (often rats) learn to emit an operant response (typically a lever press) that is reinforced by an intravenous infusion of a drug of abuse. Drug cues can introduced into this paradigm in two ways. In the more common method (top), a discrete cue such as a multi-modal stimulus consisting of visual (light) and auditory (tone) components is triggered simultaneously with drug infusions when the animal completes a required schedule of responding. In the second, less common method (bottom), animals first are trained to lever press for drug administration only (no cues), and then in a separate session in which the manipulandum (lever) is not available, the animal is presented several times with cues followed by drug administered by the experimenter. Panel A, center. Following lever press/cue training, lever pressing is extinguished by allowing the animal to lever press but withholding both the drug and the cues. Panel A, right. Finally, the response-reinstating value of the cues is assessed in test sessions in which the cues are reintroduced in the absence of drug. At the outset of testing, there is typically a transient increase in the rate of lever pressing following exposure to the cues. Cue extinction occurs over the course of multiple cue presentations and is assessed as a lessening of the ability of the cues to maintain responding in the continued absence of drug. Panel B. The rate of lever pressing tends to increase during lever press training until it reaches a maximal value, and then tends to decline during lever press extinction (after an initial “extinction burst”). During a test, lever pressing is reinstated when the drug-paired cues are reintroduced. This response-reinstating ability of the cues extinguishes over the course of the test in the continued absence of drug.

Figure 2

Simplified depiction of how conditioning contributes to the development and maintenance of fear- and addiction-related behaviors. A Pavlovian conditioned stimulus (CS) is a cue that signals impending delivery of an innately appetitive or aversive unconditioned stimulus (US). In the fear conditioning paradigm, a CS such as a tone is paired with a US such as foot shock. After training, the tone elicits a conditioned response (CR), fear, which can be defined operationally in rodents as freezing (cessation of all bodily movements except those required for respiration). In an analogous manner, a CS such as a light that is paired with administration of a drug such as morphine (US) acquires the ability to elicit drug craving and withdrawal CRs, which can be defined operationally as drug-seeking behavior (e.g., pressing a lever for delivery of morphine).

Figure 3

Highly simplified schematic depicting hypothetical mechanisms by which extinction of conditioned fear relies on interactions between the amygdala and the infralimbic (IL) region of medial prefrontal cortex. The basolateral complex of the amygdala (BLA) is a site of essential plasticity underlying conditioned fear memories. BLA triggers fear responses via its projections to the central nucleus of the amygdala (CeA), and also projects to IL. In extinction, the omission of the US 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 CRs by inhibiting amygdalar throughput, likely by activating GABAergic interneurons within BLA, GABAergic intercalated cell masses (ICMs) lying between BLA and CeA, or both. Other brain areas (including the hippocampus; not pictured) likely also play important roles in extinction. There is accumulating evidence that analogous mechanisms are involved in extinction of drug-related cues.