Discriminative stimuli are sufficient for incubation of cocaine craving

Abstract

In abstinent drug addicts, cues formerly associated with drug-taking experiences gain relapse-inducing potency (‘incubate’) over time. Animal models of incubation may help develop treatments to prevent relapse, but these models have ubiquitously focused on the role of conditioned stimuli (CSs) signaling drug delivery. Discriminative stimuli (DSs) are unique in that they exert stimulus-control over both drug taking and drug seeking behavior and are difficult to extinguish. For this reason, incubation of the excitatory effects of DSs that signal drug availability, not yet examined in preclinical studies, could be relevant to relapse prevention. We trained rats to self-administer cocaine (or palatable food) under DS control, then investigated DS-controlled incubation of craving, in the absence of drug-paired CSs. DS-controlled cocaine (but not palatable food) seeking incubated over 60 days of abstinence and persisted up to 300 days. Understanding the neural mechanisms of this DS-controlled incubation holds promise for drug relapse treatments.

Sex differences in opioid and psychostimulant craving and relapse: a critical review

“…However, these results should be interpreted with caution because in both sexes, the incubation effect was variable and statistically non-significant, likely due to the use of the limited access procedure (incubation is less robust with this procedure 112 ). Madangopal 113 reported that incubation of the response to cocaine discriminative cues is more persistent in female rats and last for up to 200 abstinence days. However, these results should also be interpreted with caution because the study was not powered to detect sex differences.…”

Trial-based Discrimination Procedure for Studying Drug Relapse in Rats

“…Please refer to the original article (Madangopal et al, 2019) for behavioral measures used for different phases of the study, recommended sample sizes, and statistical tests employed for analysis.…”

“…All work was conducted at the National Institute on Drug Abuse (NIDA) and was supported by the NIDA Intramural Research Program funds to the lab of Dr. Bruce T. Hope. The procedures described here are also detailed in the original study published in eLife (Madangopal et al, 2019). We thank Dr. Bruce T. Hope for thoughtful comments during the writing of this manuscript and M. Raley (NIDA IRP Visual Media) for assistance with illustrations.…”

“…We recently developed a trial-based procedure (Madangopal et al, 2019) to train male and female rats to discriminatively self-administer cocaine (0.75 mg/kg/infusion) during trials in which a positive discriminative stimulus (DS+) signaled cocaine availability, while suppressing responding on the same lever during trials in which a negative discriminative stimulus (DS-) signaled cocaine unavailability during the same session. Drug infusions were not paired with CSs (Madangopal et al, 2019).…”

“…We recently developed a trial-based procedure (Madangopal et al, 2019) to train male and female rats to discriminatively self-administer cocaine (0.75 mg/kg/infusion) during trials in which a positive discriminative stimulus (DS+) signaled cocaine availability, while suppressing responding on the same lever during trials in which a negative discriminative stimulus (DS-) signaled cocaine unavailability during the same session. Drug infusions were not paired with CSs (Madangopal et al, 2019). Following training, we tested for the ability of DSs to control cocaine seeking at multiple time points extending to 400 days of abstinence and observed that cocaine seeking during DS+, but not DS-, presentations was maximal after 60 days of abstinence (reflecting incubation of DS-controlled cocaine-seeking) and persisted for up to 200 days despite repeated testing under extinction conditions.…”