Yohimbine stress potentiates conditioned cue-induced reinstatement of heroin-seeking in rats

Abstract

Stress and drug-associated cues can trigger craving and relapse in abstinent drug-dependent individuals. Although the role of these two critical factors in relapse has been extensively studied, the interaction between stress and drug-associated cues in relapse has been less well characterized. Using an animal model of relapse, we assessed the effects of the pharmacological stressor, yohimbine (1.25 or 2.5mg/kg), on reinstatement of extinguished heroin-seeking in rats either in the presence or absence of heroin-associated cues. Yohimbine, in the absence of heroin-associated cues, and cues by themselves reliably reinstated heroin-seeking over extinction levels. Notably, animals showed significantly potentiated responding when yohimbine preceded cue-induced reinstatement (3-4x higher over cues or yohimbine alone). These results demonstrate that exposure to heroin-paired cues during yohimbine-induced stress greatly potentiates heroin-seeking, and support the simultaneous targeting of both stress and cue activation during relapse intervention.

Fig. 1

Average active and inactive lever responses (mean ± SEM) per session over the last 3 days of heroin self-administration (Panel A) and during the first 7 days of extinction (Panel B).

Fig. 2

Lever responding during reinstatement tests (mean ± SEM) on active and inactive levers. Test sessions occurred after yohimbine pretreatment (0, 1.25, or 2.50 mg/kg) in the absence (No Cues) or presence (Cues) of previously paired heroin cues. Significant differences from the No Cues condition (*p < 0.05) and Cues alone (†p < 0.05) are indicated.