Small molecule NOP agonists reverse locomotor sensitization induced by cocaine in male C57BL/6 mice.

Autor: Lutfy K; College of Pharmacy, Western University of Health Sciences, Pomona, CA 91766, United States of America. Electronic address: klutfy@westernu.edu., Hamid A; College of Pharmacy, Western University of Health Sciences, Pomona, CA 91766, United States of America., Zaveri NT; Astraea Therapeutics, 320 Logue Avenue, Mountain View, CA, United States of America. Electronic address: nurulain@astraeatherapeutics.com.
Jazyk: angličtina
Zdroj: Progress in neuro-psychopharmacology & biological psychiatry [Prog Neuropsychopharmacol Biol Psychiatry] 2024 Apr 20; Vol. 131, pp. 110941. Date of Electronic Publication: 2024 Jan 09.
DOI: 10.1016/j.pnpbp.2024.110941
Abstrakt: Orphanin FQ/nociceptin (OFQ/N), the endogenous ligand of the nociceptin opioid receptor (NOP) has been shown to block cocaine-induced locomotor sensitization in mice and rats, and also reverses this phenomenon when injected intracerebroventricularly in animals with an established sensitized response. In the present study, we determined whether small-molecule NOP agonists would recapitulate this effect after systemic administration. Male C57BL/6 mice treated with cocaine (15 mg/kg) on days 1-3 and showed locomotor sensitization to the same dose of cocaine on day 8 were injected with vehicle or one of the two NOP agonists (AT-202 and AT-524) (but not cocaine) on days 9-11. On day 15, locomotor sensitization was assessed after a cocaine challenge (15 mg/kg). Subchronic administration of the two NOP agonists to sensitized mice significantly decreased the sensitized response on day 15. In a separate experiment conducted in male and female mice lacking NOP and their wildtype littermates, AT-524 reversed sensitization in male wildtype but not in mice lacking NOP. Further, co-administration of the NOP agonist with cocaine for three days on days 16-18 prevented the development of locomotor sensitization from this cocaine treatment in wild-type but not in NOP knockout mice. However, none of these effects of the NOP agonist was observed in female mice. Together, these results suggest that subchronic repeated administration of small-molecule NOP agonists may reverse adaptive behavioral changes associated with repeated intermittent cocaine treatment in male but not female mice.
Competing Interests: Declaration of competing interest The authors declare no competing interests. Dr. Zaveri is the President of Astraea Therapeutics, which received funding through the NIH/NIDA for this project and had a subcontract with Western University of Health Sciences, where the behavioral studies were conducted by Abdul Hamid under the direct supervision of Kabirullah Lutfy.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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