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

Fredriksson, I.; Shekara, A.; Applebey, S. V.; Minier-Toribio, A.; Altidor, L.; Cifani, C.; Hope, B. T.; Bossert, J. M.; Shaham, Y.

doi:10.1101/2021.03.24.436801

bioRxiv · 10.1101/2021.03.24.436801

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

Fredriksson, I.·Shekara, A.·Applebey, S. V.·Minier-Toribio, A.·Altidor, L.·Cifani, C.·Hope, B. T.·Bossert, J. M.·Shaham, Y.

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Abstract

We recently developed a rat model of incubation of oxycodone craving where opioid seeking progressively increases after voluntary suppression of drug self-administration by adverse consequences of drug seeking. Here, we studied the role of ventral subiculum (vSub) neuronal ensembles in this incubation, using the activity marker Fos, muscimol-baclofen (GABAergic agonists) inactivation, and Daun02 chemogenetic inactivation. We trained Sprague-Dawley or Fos-lacZ transgenic male and female rats to self-administer oxycodone (0.1 mg/kg/infusion, 6-h/d) for 14 days. The rats were then exposed for 14 days to an electric barrier of increasing intensity (0.1 to 0.4 mA) near the drug-paired lever that caused voluntary abstinence or were exposed to 14 days of forced abstinence. We tested Sprague-Dawley rats for relapse to oxycodone seeking without shock and drug on abstinence day 15 and extracted their brains for Fos-immunohistochemistry, or tested them after vSub vehicle or muscimol-baclofen injections on abstinence days 1 and 15. We performed Daun02 inactivation of relapse-activated vSub Fos neurons in Fos-lacZ transgenic rats on abstinence day 15 and then tested them for relapse on abstinence day 18. Relapse after electric barrier-induced abstinence increased Fos expression in vSub. Muscimol-baclofen inactivation or Daun02 selective inactivation of vSub Fos-expressing neuronal ensembles decreased "incubated" oxycodone seeking after voluntary abstinence. Muscimol-baclofen vSub inactivation had no effect on non-incubated opioid seeking on abstinence day 1 or incubation after forced abstinence. Our results demonstrate a selective role of vSub neuronal ensembles in incubation of opioid craving after cessation of drug self-administration by adverse consequences of drug seeking. Significance statementHigh relapse rate is a cardinal feature of opioid addiction and a major impediment for successful treatment. In humans, abstinence is often self-imposed, and relapse typically involves a conflict situation between the desire to experience the drugs rewarding effects and negative consequences of drug seeking. To mimic this human condition, we recently introduced a rat model of incubation of oxycodone craving after electric barrier-induced voluntary abstinence. Here, we used the activity marker Fos, muscimol-baclofen (GABAergic agonists) inactivation, and Daun02 chemogenetic inactivation to demonstrate a selective role of vSub neuronal ensembles in incubation of oxycodone craving after electric barrier-induced voluntary abstinence, but not in incubation of opioid craving after forced abstinence or non-incubated opioid seeking during early abstinence.

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Fredriksson, I., Shekara, A., Applebey, S. V., Minier-Toribio, A., Altidor, L., Cifani, C., Hope, B. T., Bossert, J. M., Shaham, Y.. 2021-03-25. Role of ventral subiculum neuronal ensembles in incubation of oxycodone craving after electric barrier-induced voluntary abstinence. https://doi.org/10.1101/2021.03.24.436801

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