{"doi":"10.1101/2021.03.24.436801","title":"Role of ventral subiculum neuronal ensembles in incubation of oxycodone craving after electric barrier-induced voluntary abstinence","abstract":"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 statement High 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 drug’s 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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":216302,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9498,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":670623,"name":"Aniruddha Shekara","orcid":"0000-0003-2392-6079","position":1,"is_corresponding":false},{"id":670625,"name":"Sarah V. Applebey","orcid":"0000-0002-8162-8785","position":2,"is_corresponding":false},{"id":812745,"name":"Angelica Minier-Toribio","orcid":null,"position":3,"is_corresponding":false},{"id":694963,"name":"Lindsay Altidor","orcid":"0000-0003-4475-4077","position":4,"is_corresponding":false},{"id":515079,"name":"Carlo Cifani","orcid":"0000-0001-6180-828X","position":5,"is_corresponding":false},{"id":355729,"name":"Bruce T. Hope","orcid":"0000-0001-5804-7061","position":6,"is_corresponding":false},{"id":355727,"name":"Jennifer M. Bossert","orcid":"0000-0001-5636-4071","position":7,"is_corresponding":false},{"id":288988,"name":"Yavin Shaham","orcid":"0000-0002-8242-3319","position":8,"is_corresponding":false},{"id":356297,"name":"Ida Fredriksson","orcid":"0000-0002-3443-3870","position":0,"is_corresponding":true}],"reference_count":62,"raw_metadata":null,"created_at":"2026-07-18T23:53:11.245932Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}