ReviewExtinction of drug seeking
Research highlights
▶The expression of extinction of drug seeking is dependent upon IL, AcbSh, and MDH. ▶ Extinction training induces plasticity in glutamatergic signaling in AcbSh and AcbC. ▶ The actions of glutamate, GABA, and dynorphin in these pathways are critical. ▶ The expression of extinction of drug seeking depends on parallel pathways. ▶ The neural circuits of extinction expression overlap with those for reinstatement.
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).
Section snippets
Prefrontal cortex
The prefrontal cortex (PFC) has long been implicated in reinstatement of drug seeking (for review see [4], [7]). These studies have emphasized the specific role for the prelimbic (PL) region in reinstatement of drug seeking. For example, reversible inactivation of PL prevents cocaine priming [62] and stress [8], [9] induced reinstatement of cocaine seeking. Moreover a similar prevention of cocaine priming reinstatement of cocaine seeking is observed after microinjections of D1-like or D2-like
Nucleus accumbens
A variety of lines of evidence implicatenucleus accumbens (Acb) in extinction of drug self-administration. Here we briefly review the relevant neuroanatomical properties of Acb followed by evidence from molecular, electrophysiological, and reversible inactivation studies that Acb contributes to extinction of drug self-administration.
Acb is the ventral extension of the striatum. It receives direct glutamatergic inputs from limbic sites including hippocampus, medial prefrontal cortex, entorhinal
Medial dorsal hypothalamus
Hypothalamus has long been implicated in regulating primary reward and feeding [98], [99] and, more recently, responding to drug associated stimuli [35], [36]. Moreover, the neuropeptide orexin, which is expressed solely in hypothalamic neurons, plays an important role in reinstatement of drug seeking. Stimulation of orexin receptors can reinstate conditioned place preference [35] whereas the orexin antagonist SB 334867 prevents cue or yohimbine induced reinstatement of extinguished alcohol
Neural circuit level mechanisms for extinction of drug seeking
As reviewed above, IL, AcbSh, and MDH have each been implicated in expression of extinction of drug seeking from studies using intravenous cocaine or alcoholic beer reinforcers. There are at least two important questions regarding neural circuit level mechanisms for extinction expression. The first is the nature of the connectivity between these regions. The second is how these structures interface with the circuits mediating reinstatement. There are strong theoretical and empirical reasons for
Conclusions
Extinction produces a significant reduction in drug seeking. The literature reviewed here shows that this reduction in drug seeking is dependent upon cortical, striatal, and hypothalamic regions that include IL, AcbSh, and MDH. Studies of the connectivity and functional interaction between these regions suggest that the expression of extinction of drug seeking depends, in part, on cortico-striatal–hypothalamic and cortico-hypothalalmic–thalamic pathways. Within these pathways the actions of the
Acknowledgements
Preparation of this manuscript was supported by Australian Postgraduate Awards to EZM and NJM as well as grants (510199 and 630406) from the National Health and Medical Research Council to GPM. GPM is an Australian Research Council QEII Fellow (DP0877430).
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