Review. Context-induced relapse to drug seeking: a review

Abstract

In humans, exposure to environmental contexts previously associated with drug intake often provokes relapse to drug use, but the mechanisms mediating this relapse are unknown. Based on early studies by Bouton & Bolles on context-induced 'renewal' of learned behaviours, we developed a procedure to study context-induced relapse to drug seeking. In this procedure, rats are first trained to self-administer drug in one context. Next, drug-reinforced lever responding is extinguished in a different (non-drug) context. Subsequently, context-induced reinstatement of drug seeking is assessed by re-exposing rats to the drug-associated context. Using variations of this procedure, we and others reported reliable context-induced reinstatement in rats with a history of heroin, cocaine, heroin-cocaine combination, alcohol and nicotine self-administration. Here, we first discuss potential psychological mechanisms of context-induced reinstatement, including excitatory and inhibitory Pavlovian conditioning, and occasion setting. We then summarize results from pharmacological and neuroanatomical studies on the role of several neurotransmitter systems (dopamine, glutamate, serotonin and opioids) and brain areas (ventral tegmental area, accumbens shell, dorsal striatum, basolateral amygdala, prefrontal cortex, dorsal hippocampus and lateral hypothalamus) in context-induced reinstatement. We conclude by discussing the clinical implications of rat studies on context-induced reinstatement of drug seeking.

Figure 1

Context-induced reinstatement of drug seeking. Data are mean±s.e.m. number of non-reinforced lever or nose-poke responses on the previously active manipulandum (previously paired with drug delivery) during tests for context-induced reinstatement of drug seeking; non-reinforced responses on the previously active manipulandum serve as the operational measure of drug seeking during testing. The rats were previously trained to self-administer (a) speedball (a heroin–cocaine combination), (b) heroin, (c) nicotine, (d) cocaine or (e) alcohol. The rats were trained in one context (drug context). Next, lever or nose-poke responding in the presence of a discrete cue was extinguished in a second non-drug context (extinction context). The rats were then tested either in the drug context or in the extinction context. For comparison purposes, the mean±s.e.m. number of non-reinforced responding during the first extinction session is also depicted. Data were adapted from Crombag & Shaham (2002), Bossert et al. (2004), Marinelli et al. (2007), Diergaarde et al. (in press) and Hamlin et al. (2008) for (a–e), respectively. ^*Different from the extinction context, p<0.05.

Figure 2

A model of dopamine–glutamate interaction in the accumbens shell that mediates context-induced reinstatement of heroin seeking. (a) Exposure to heroin-associated contexts activates both dopamine and glutamate neurons that project to accumbens shell. Glutamate activation of shell medium spiny neurons increases the number of up-state neurons, which is further potentiated via D₁ receptor (D1R) activation by dopamine, resulting in the activation of downstream targets, which leads to the reinstatement of drug seeking. (b) Blockade of either glutamate transmission in accumbens shell by LY379268 (an agonist of inhibitory mGluR₂ located on presynaptic glutamatergic neurons) or dopamine transmission by SCH 23390 (an antagonist of postsynaptic D₁ receptors) prevents context-induced transition to the neuronal up-state, resulting in decreased activity of accumbens shell medium spiny output neurons, which in turn leads to the inhibition of context-induced reinstatement of heroin seeking. Blue: dopamine neurons; green: glutamate neurons; red: medium spiny accumbens projection neurons.