Extinction of drug seeking

Abstract

Drug seeking behavior can be reduced or inhibited via extinction. The brain mechanisms for extinction of drug seeking are poorly understood but are of significant interest because of their potential to identify novel approaches that promote abstinence from drug taking. Here we review recent literature on the neural mechanisms for extinction in drug self-administration paradigms. First, we consider the brain regions important for extinction of drug seeking. Functional inactivation studies have identified infralimbic prefrontal cortex, nucleus accumbens shell, as well as medial dorsal hypothalamus in the expression of extinction of drug seeking. These structures have been implicated in extinction expression across several reinforcers including cocaine, heroin, and alcohol. Second, we consider molecular studies which show that extinction training is associated with plasticity in glutamatergic signaling in both nucleus accumbens shell and core, and that this training may reverse or ameliorate the neuroadaptations produced by chronic drug exposure and spontaneous withdrawal. Finally, we consider the neural circuitry for extinction of drug seeking. Functional disconnection and neuroanatomical tracing studies show that extinction expression depends, at least in part, on cortico-striatal–hypothalamic and cortico-hypothalalmic–thalamic pathways. Moreover, they indicate that the expression of extinction and reinstatement of drug seeking may depend on parallel pathways that converge within lateral hypothalamus and paraventricular thalamus.

Introduction

Drug addiction is a chronic relapsing condition imposing significant burdens on individual addicts, their families, and communities. Addiction is associated with increased rates of physical health problems including cardiovascular and liver disease; mental health problems including depression and anxiety; reduced levels of productivity, as well as higher utilization of health and social services. Considerable progress has been made in understanding the mechanisms of drug addiction including those contributing to the reinforcing effects of drugs of abuse; the escalation and loss of control over drug intake rendering it compulsive; and, those determining relapse to drug seeking and taking after periods of abstinence. Yet many aspects remain poorly understood. Among these are the mechanisms for extinction of drug seeking.

Extinction is the reduction in drug seeking when the contingency between drug seeking behavior or drug predictive stimuli and the delivery of the drug reward is broken. Extinction is an active learning process. It recruits as yet poorly understood neural circuits to reduce drug seeking. There is evidence that extinction can ameliorate or reverse the neuroadaptations produced by chronic drug self-administration and/or by spontaneous abstinence from drug seeking. Nonetheless, extinction does not erase drug seeking. Rather, it actively inhibits it. This inhibition can be removed in several ways, including via re-presentations of the reinforcer (reinstatement [1]), presentations of a drug-associated stimulus (cue-induced reinstatement) [1], or context-change between extinction and test (context-induced reinstatement) [2]. These restoration or reinstatement phenomena emphasize that at the end of extinction training animals hold conflicting associations: an association from original self-administration training promoting reinstatement of drug seeking and an association from extinction training that opposes or inhibits drug seeking. Despite increasing knowledge regarding neural mechanisms for reinstatement of drug seeking (e.g. [3], [4]), much less is known about the neural mechanisms for extinction of drug self-administration and how extinction inhibits drug seeking. Understanding the mechanisms for extinction of drug self-administration is important because it may help identify, develop, and direct new approaches to promoting abstinence from drug taking and preventing relapse.

Here we review the recent literature on the neural mechanisms for extinction of drug seeking. We focus on findings from self-administration paradigms. The reader is referred to Myers and Carlezon [5] for review of findings from studies using the conditioned place preference procedure. Myers and Davis [6] noted that ‘extinction’ can refer to multiple processes. We follow these authors and use the term ‘extinction’ in reference to the processes underlying loss of responding in drug self-administration paradigms. Likewise, we define the methodological procedure that promotes these losses as ‘extinction training’ and the decrement in responding observed after extinction training as ‘extinction expression’.

Studies of the neural mechanisms of extinction involve a three stage procedure. In initial training, animals are trained to respond (lever press or nose poke) for a drug reward. During extinction training this responding is no longer reinforced. Finally, rats are tested, again under non-reinforcement, for drug seeking. Experimental manipulations or measurements of neural function typically occur at one of three different times during this procedure. Extinction expression studies involve manipulations or measurements prior to test. Extinction learning studies involve manipulations or measurements prior to extinction training. Finally, studies examining consolidation of extinction learning involve manipulations or measurements in the period immediately following extinction training. It is important to note, that in contrast to other preparations for the study of extinction such as fear conditioning, drug self-administration preparations typically involve multiple days of extinction training in relatively long (up to 2 h) sessions. This renders empirical dissociation between extinction learning and extinction expression more difficult because each day of extinction training involves the influences of both extinction learning (from that session) and extinction expression (from previous extinction sessions as well as that session).