TY - JOUR

T1 - Psychopharmacological characterization of an emerging drug of abuse, a synthetic opioid U-47700, in adult zebrafish

AU - Kolesnikova, Tatiana O

AU - Shevyrin, Vadim A

AU - Eltsov, Oleg S

AU - Khatsko, Sergey L

AU - Demin, Konstantin A

AU - Galstyan, David S

AU - de Abreu, Murilo S

AU - Kalueff, Allan V

N1 - Publisher Copyright: © 2020 Elsevier Inc.

PY - 2021/2

Y1 - 2021/2

N2 - 3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide (U-47700) is a selective μ-opioid receptor agonist originally synthesized as a prospective analgesic drug. Several times more potent than morphine, U-47700 has high abuse potential and may cause clinical neurotoxicity, euphoria, respiratory depression and occasional mortality. U-47700 also evokes analgesia, sedation and euphoria-like states in both humans and rodents. Despite the growing use and abuse of U-47700, its psychopharmacological and toxicological profiles remain poorly understood. The zebrafish (Danio rerio) is rapidly becoming a popular aquatic model organism for CNS disease modeling and drug discovery. Here, we examine acute (1, 5, 10, 25 and 50 mg/L for 20-min) and chronic (0.1, 0.5 and 1 mg/L for 14 days) effects of U-47700 in adult zebrafish. Overall, we found overt sedation by acute, and hyperlocomotion with an anxiolytic-like action by chronic, drug treatments. Acute treatment with 1 and 10 mg/L U-47700 also resulted in detectable amounts of this drug in the brain samples. Collectively, these findings emphasize a complex dose- and treatment-dependent CNS profile of U-47700 following its acute and chronic administration. Our study also supports high sensitivity of zebrafish to U-47700, and suggests these aquatic models as promising in-vivo screens for probing CNS effects evoked by novel synthetic opioid drugs.

AB - 3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide (U-47700) is a selective μ-opioid receptor agonist originally synthesized as a prospective analgesic drug. Several times more potent than morphine, U-47700 has high abuse potential and may cause clinical neurotoxicity, euphoria, respiratory depression and occasional mortality. U-47700 also evokes analgesia, sedation and euphoria-like states in both humans and rodents. Despite the growing use and abuse of U-47700, its psychopharmacological and toxicological profiles remain poorly understood. The zebrafish (Danio rerio) is rapidly becoming a popular aquatic model organism for CNS disease modeling and drug discovery. Here, we examine acute (1, 5, 10, 25 and 50 mg/L for 20-min) and chronic (0.1, 0.5 and 1 mg/L for 14 days) effects of U-47700 in adult zebrafish. Overall, we found overt sedation by acute, and hyperlocomotion with an anxiolytic-like action by chronic, drug treatments. Acute treatment with 1 and 10 mg/L U-47700 also resulted in detectable amounts of this drug in the brain samples. Collectively, these findings emphasize a complex dose- and treatment-dependent CNS profile of U-47700 following its acute and chronic administration. Our study also supports high sensitivity of zebrafish to U-47700, and suggests these aquatic models as promising in-vivo screens for probing CNS effects evoked by novel synthetic opioid drugs.

KW - Anxiety behavior

KW - Drug of abuse

KW - Synthetic opioids

KW - U-47700

KW - Zebrafish

UR - http://www.scopus.com/inward/record.url?scp=85097886986&partnerID=8YFLogxK

UR - https://www.mendeley.com/catalogue/52af5532-11ea-3b19-bbe7-f738c6927da2/

U2 - 10.1016/j.brainresbull.2020.11.017

DO - 10.1016/j.brainresbull.2020.11.017

M3 - Article

C2 - 33249261

VL - 167

SP - 48

EP - 55

JO - Brain Research Bulletin

JF - Brain Research Bulletin

SN - 0361-9230

ER -