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| Paper IPM / Cognitive / 15927 |
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The orexin (hypocretin) system is multifaceted, and regulates sleep-wake cycles, nociception, endocrine function and reward-seeking behavior. We have established an important role for this system in motivation for drugs of abuse. The orexin-1 receptor (Ox1R) antagonist SB334867 (SB) reduces seeking of drug reward under conditions of high motivation. There is some evidence that the effects of systemic SB on reward seeking persist beyond the pharmacological availability of the drug, however the time course of these effects is not well characterized, nor is it known whether similar persistent effects are observed following intraparenchymal injections. Here, we used a behavioral economics paradigm, which allows for repeated testing of drug motivation across consecutive days, to examine the persistent effects of acute systemic and local treatment with SB on motivation for the short-acting μâopioid receptor agonist remifentanil. Systemic injections of SB immediately prior to behavioral testing reduced motivation for remifentanil; this effect was sustained on a subsequent test at 24â¯h, but not on a third test at 48â¯h. When injected into ventral pallidum (VP) the effects of SB were more persistent, with reduced motivation observed for up to 48â¯h. We next made SB injections into VP 24â¯h prior to behavioral testing; this produced effects that persisted for at least 72â¯h post-treatment. Cued reinstatement of extinguished remifentanil seeking was also attenuated by pretreatment with SB 24â¯h earlier. These data indicate that the effects of SB on opioid seeking behavior persist beyond the bioavailability of the compound. These observations have important ramifications for the future clinical use of orexin receptor antagonists for the treatment of addiction.
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