Age-specific treatment effects of orexin/hypocretin-receptor antagonism on methamphetamine-seeking behavior

Natalie E. Zlebnik, Nathan A. Holtz, Victoria C. Lepak, Amy T. Saykao, Yanan Zhang, Marilyn E. Carroll

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13 Scopus citations


Background: Worldwide methamphetamine (METH) use has increased significantly over the last 10 years, and in the US, METH dependence has sky-rocketed among individuals with opioid use disorder. Of significant concern, METH use is gaining popularity among groups with susceptibility to developing severe substance use disorders, such as women and adolescents. Nevertheless, there is no established pharmacotherapy for METH addiction. Emerging evidence has identified the orexin/hypocretin system as an important modulator of reward-driven behavior and a potential target for the treatment of drug addiction and relapse. However, to date, there have been no investigations into the therapeutic efficacy of orexin/hypocretin receptor antagonists for METH-motivated behavior in adolescents or adults. In the present study, we examined the effects of selective antagonists of the orexin-1 (SB-334867, 20 mg/kg) and orexin-2 (TCS-OX2-29, 20 mg/kg) receptors on the reinstatement of METH seeking in both adolescent and adult male and female rats. Methods: Rats were trained to self-administer METH (0.05 mg/kg/inf, iv) during two 2-h sessions/day for 5 days. Following 20 sessions of extinction over 10 days, a within-subjects design was used to test for METH seeking precipitated by METH (1 mg/kg, ip) or METH cues after systemic pretreatment with SB-334867 or TCS-OX2-29. Results: SB-334867 reduced cue-induced reinstatement in males and females, regardless of age. Additionally, METH-induced METH seeking was attenuated by SB-334867 in adolescents and by TCS-OX2-29 in adults. Conclusion: Selective orexin/hypocretin receptor antagonists have significant therapeutic potential for diminishing METH-seeking behavior, although their treatment efficacy may be influenced by age.

Original languageEnglish (US)
Article number108719
JournalDrug and alcohol dependence
StatePublished - Jul 1 2021

Bibliographical note

Funding Information:
This work was supported by the National Institute on Drug Abuse (NIDA) grants K99 DA047419 (NEZ), R01 DA019942 (MEC), R01 DA003240 (MEC), and K05 DA015267 (MEC). The authors would like to thank Vanessa Adamson, Yosef Amrami, Tom Baron, Cole Batty, Katie Bressler, Luke Bushman, Clare Chamberlain, Alex Claxton, Seth Johnson, Brandon Knight, Sarah Korthauer, Nathan Omdalen, Aneal Rege, Tyler Rehbein, Rachael Turner, Heather Veglahn, and Ashley Xiong for technical assistance and Krista Walkowiak, DVM, for veterinary care.

Publisher Copyright:
© 2021 Elsevier B.V.


  • Adolescent
  • Hypocretin
  • Methamphetamine
  • Orexin
  • Reinstatement
  • Sex differences


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