Context-induced relapse to cocaine seeking after punishment-imposed abstinence is associated with activation of cortical and subcortical brain regions

We recently developed a rat model of context-induced relapse to alcohol seeking after punishment-imposed abstinence to mimic relapse after self-imposed abstinence due to adverse consequences of drug use. Here, we determined the model's generality to cocaine and have begun to explore brain mechanisms of context-induced relapse to cocaine seeking after punishment-imposed abstinence, using the activity marker Fos. In exp. 1, we trained rats to self-administer cocaine (0.75 mg/kg/infusion, 6 hours/day, 12 days) in context A. Next, we transferred them to context B where for the paired group, but not unpaired group, 50 percent of cocaine-reinforced lever presses caused aversive footshock. We then tested the rats for cocaine seeking under extinction conditions in contexts A and B. We also retested them for relapse after retraining in context A and repunishment in context B. In exp. 2, we used Fos immunoreactivity to determine relapse-associated neuronal activation in brain regions of rats exposed to context A, context B or neither context. Results showed the selective shock-induced suppression of cocaine self-administration and context-induced relapse after punishment-imposed abstinence in rats exposed to paired, but not unpaired, footshock. Additionally, context-induced relapse was associated with selective activation of dorsal and ventral medial prefrontal cortex, anterior insula, dorsal striatum, basolateral amygdala, paraventricular nucleus of the thalamus, lateral habenula, substantia nigra, ventral subiculum, and dorsal raphe, but not nucleus accumbens, central amygdala, lateral hypothalamus, ventral tegmental area and other brain regions. Together, context-induced relapse after punishment-imposed abstinence generalizes to rats with a history of cocaine self-administration and is associated with selective activation of cortical and subcortical regions

Role of ventral subiculum neuronal ensembles in incubation of oxycodone craving after electric barrier-induced voluntary abstinence

We recently developed a rat model of incubation of oxycodone craving after electric barrier-induced voluntary abstinence, and showed time-dependent increases in drug seeking on abstinence days 15 and 30 compared to day 1. Here, we studied the role of ventral subiculum (vSub) neuronal ensembles in incubation of oxycodone seeking after electric barrier-induced abstinence using the activity marker Fos, and inactivation of vSub neurons using muscimol+baclofen (GABAA+B receptor agonists) or the Daun02 chemogenetic inactivation procedure. We trained Sprague Dawley or Fos-lacZ transgenic rats to self-administer oxycodone (0.1 mg/kg/infusion, 6-h/d) for 14 days. We then introduced an electric barrier of increasing shock intensity (0.1 to 0.4 mA) near the drug-paired lever that led to cessation of oxycodone self-administration. We tested Sprague Dawley rats (n=6-7/group) for relapse to oxycodone seeking (extinction tests) in the absence of shock and drug on abstinence day 15, and extracted the brains for Fos immunohistochemistry or tested the rats (n=10-12/group) after vSub injections of vehicle or muscimol+baclofen. We then tested Fos-lacZ transgenic rats (n=10-11/group) for relapse to oxycodone seeking on abstinence day 18 after selective Daun02 induced chemogenetic inactivation of relapse-activated Fos neurons in vSub on abstinence day 15. Relapse after electric barrier-induced abstinence was associated with increased Fos expression in vSub, and both local and selective inactivation of vSub Fos-expressing neuronal ensembles decreased “incubated” oxycodone seeking. Together, these data demonstrate a role of vSub neuronal ensembles in incubation of oxycodone craving after cessation of drug taking due to adverse consequences of drug seeking

Role of ventral subiculum neuronal ensembles in incubation of oxycodone craving after electric barrier-induced voluntary abstinence

High relapse rate is a key feature of opioid addiction. In humans, abstinence is often voluntary due to negative consequences of opioid seeking. To mimic this human condition, we recently introduced a rat model of incubation of oxycodone craving after electric barrier-induced voluntary abstinence. Incubation of drug craving refers to time-dependent increases in drug seeking after cessation of drug self-administration. Here, we used the activity marker Fos, muscimol-baclofen (GABAa + GABAb receptor agonists) global inactivation, Daun020-selective inactivation of putative relapse-associated neuronal ensembles, and fluorescence-activated cell sorting of Fos-positive cells and quantitative polymerase chain reaction to demonstrate a key role of vSub neuronal ensembles in incubation of oxycodone craving after voluntary abstinence, but not homecage forced abstinence. We also used a longitudinal functional magnetic resonance imaging method and showed that functional connectivity changes in vSub-related circuits predict opioid relapse after abstinence induced by adverse consequences of opioid seeking.Funding Agencies|Intramural Research Program of the NIDA-NIH [ZIA-DA000434-22]; Swedish Research Council International Postdoc grant [2019-00658]</p