Relapse to opioid seeking in rat models: behavior, pharmacology and circuits

Abstract

Lifetime relapse rates remain a major obstacle in addressing the current opioid crisis. Relapse to opioid use can be modeled in rodent studies where drug self-administration is followed by a period of abstinence and a subsequent test for drug seeking. Abstinence can be achieved through extinction training, forced abstinence, or voluntary abstinence. Voluntary abstinence can be accomplished by introducing adverse consequences of continued drug self-administration (e.g., punishment or electric barrier) or by introducing an alternative nondrug reward in a discrete choice procedure (drug versus palatable food or social interaction). In this review, we first discuss pharmacological and circuit mechanisms of opioid seeking, as assessed in the classical extinction-reinstatement model, where reinstatement is induced by reexposure to the self-administered drug (drug priming), discrete cues, discriminative cues, drug-associated contexts, different forms of stress, or withdrawal states. Next, we discuss pharmacological and circuit mechanisms of relapse after forced or voluntary abstinence, including the phenomenon of "incubation of heroin craving" (the time-dependent increases in heroin seeking during abstinence). We conclude by discussing future directions of preclinical relapse-related studies using opioid drugs.

Fig. 1

Number of empirical papers on relapse to opioid seeking in extinction-based and abstinence-based rodent models. This figure illustrates that most studies on relapse to opioid seeking in rat models have used the classical extinction-reinstatement model.

Fig. 2

Brain areas and pathways involved in relapse to opioid seeking. Coronal sections of the rat brain showing brain areas and pathways implicated in reinstatement/relapse of opioid seeking induced by a drug priming, b discrete cues, c discriminative cues and context, and d different stressors. e Brain areas implicated in relapse to opioid seeking and incubation of opioid craving after forced abstinence. Abbreviations: A1 and A2 noradrenergic cell body nuclei; BLA basolateral amygdala; BNST bed nucleus of stria terminalis; CeA central nucleus of amygdala; dmPFC dorsal medial prefrontal cortex; dDG dorsal dentate gyrus; DLS dorsolateral striatum; EC entorhinal cortex; LDTg lateral dorsal tegmental nucleus; MS medial septum; NE norepinephrine; NAc nucleus accumbens; SN substantia nigra; VP ventral pallidum; vSub ventral subiculum; VTA ventral tegmental area