Effect of chronic delivery of the toll-like receptor 4 antagonist (+)-naltrexone on incubation of heroin craving

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dc.contributor.authorTheberge, F.
dc.contributor.authorLi, X.
dc.contributor.authorKambhampati, S.
dc.contributor.authorPickens, C.
dc.contributor.authorSt Laurent, R.
dc.contributor.authorBossert, J.
dc.contributor.authorBaumann, M.
dc.contributor.authorHutchinson, M.
dc.contributor.authorRice, K.
dc.contributor.authorWatkins, L.
dc.contributor.authorShaham, Y.
dc.date.issued2013
dc.description.abstractBACKGROUND Recent evidence implicates toll-like receptor 4 (TLR4) in opioid analgesia, tolerance, conditioned place preference, and self-administration. Here, we determined the effect of the TLR4 antagonist (+)-naltrexone (a μ-opioid receptor inactive isomer) on the time-dependent increases in cue-induced heroin seeking after withdrawal (incubation of heroin craving). METHODS In an initial experiment, we trained rats for 9 hours per day to self-administer heroin (.1 mg/kg/infusion) for 9 days; lever presses were paired with a 5-second tone-light cue. We then assessed cue-induced heroin seeking in 30-minute extinction sessions on withdrawal day 1; immediately after testing, we surgically implanted rats with Alzet minipumps delivering (+)-naltrexone (0, 7.5, 15, 30 mg/kg/day, subcutaneous) for 14 days. We then tested the rats for incubated cue-induced heroin seeking in 3-hour extinction tests on withdrawal day 13. RESULTS We found that chronic delivery of (+)-naltrexone via minipumps during the withdrawal phase decreased incubated cue-induced heroin seeking. In follow-up experiments, we found that acute injections of (+)-naltrexone immediately before withdrawal day 13 extinction tests had no effect on incubated cue-induced heroin seeking. Furthermore, chronic delivery of (+)-naltrexone (15 or 30 mg/kg/day) or acute systemic injections (15 or 30 mg/kg) had no effect on ongoing extended access heroin self-administration. Finally, in rats trained to self-administer methamphetamine (.1 mg/kg/infusion, 9 hours/day, 9 days), chronic delivery of (+)-naltrexone (30 mg/kg/day) during the withdrawal phase had no effect on incubated cue-induced methamphetamine seeking. CONCLUSIONS The present results suggest a critical role of TLR4 in the development of incubation of heroin, but not methamphetamine, craving.
dc.description.statementofresponsibilityFlorence R. Theberge, Xuan Li, Sarita Kambhampati, Charles L. Pickens, Robyn St. Laurent, Jennifer M. Bossert, Michael H. Baumann, Mark R. Hutchinson, Kenner C. Rice, Linda R. Watkins, and Yavin Shaham
dc.identifier.citationBiological Psychiatry, 2013; 73(8):729-737
dc.identifier.doi10.1016/j.biopsych.2012.12.019
dc.identifier.issn0006-3223
dc.identifier.issn1873-2402
dc.identifier.orcidHutchinson, M. [0000-0003-2154-5950]
dc.identifier.urihttp://hdl.handle.net/2440/80705
dc.language.isoen
dc.publisherElsevier Science Inc
dc.relation.granthttp://purl.org/au-research/grants/arc/DP110100297
dc.rightsCopyright status unknown
dc.source.urihttps://doi.org/10.1016/j.biopsych.2012.12.019
dc.subjectCraving
dc.subjectextinction
dc.subjectglia
dc.subjectheroin self-administration
dc.subjectopioid drugs
dc.subjectreinstatement
dc.subjectrelapse
dc.subjectTLR4
dc.titleEffect of chronic delivery of the toll-like receptor 4 antagonist (+)-naltrexone on incubation of heroin craving
dc.typeJournal article
pubs.publication-statusPublished

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