Effect of chronic delivery of the toll-like receptor 4 antagonist (+)-naltrexone on incubation of heroin craving
Date
2013
Authors
Theberge, F.
Li, X.
Kambhampati, S.
Pickens, C.
St Laurent, R.
Bossert, J.
Baumann, M.
Hutchinson, M.
Rice, K.
Watkins, L.
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Journal article
Citation
Biological Psychiatry, 2013; 73(8):729-737
Statement of Responsibility
Florence 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
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Abstract
BACKGROUND 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.
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