title: Chronic ketamine exposure induces permanent impairment of brain functions in adolescent cynomolgus monkeys.
abstract: Ketamine, a non-competitive N-methyl-D-aspartic acid receptor antagonist, has emerged as an increasingly popular drug among young drug abusers worldwide. Available evidence suggests that ketamine produces acute impairments of working, episodic and semantic memory along with psychotogenic and dissociative effects when a single dose is given to healthy volunteers. However, understanding of the possible chronic effects of ketamine on behavior, cognitive anomalies and neurochemical homeostasis is still incomplete. Although previous human studies demonstrate that ketamine could impair a range of cognitive skills, investigation using non-human models would permit more precise exploration of the neurochemical mechanisms which may underlie the detrimental effects. The current study examined the abnormalities in behavior (move, walk, jump and climb) and apoptosis of the prefrontal cortex using terminal deoxynucleotidyl transferase-mediated biotinylated dUTP nick end labeling (TUNEL) and apoptotic markers, including Bax, Bcl-2 and caspase-3 in adolescent male cynomolgus monkeys (Macaca fascicularis) after 1 or 6 months of sub-anesthetic ketamine administration (1 mg/kg, i.v.). Results showed that ketamine decreased locomotor activity and increased cell death in the prefrontal cortex of monkeys with 6 months of ketamine treatment when compared with the control monkeys. Such decreases were not found in the 1-month ketamine-treated group. Our study suggested that ketamine administration of recreational dose in monkeys might produce permanent and irreversible deficits in brain functions due to neurotoxic effects, involving the activation of apoptotic pathways in the prefrontal cortex.
authors.affiliation: Department of Medical Psychology, Shandong University School of Medicine, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Sun
authors.forename: Qi
authors.initials: Q
authors.lastname: Li
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.forename: Yuzhe
authors.initials: Y
authors.lastname: Zhang
authors.forename: Dexiang
authors.initials: D
authors.lastname: Liu
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
authors.forename: Fang
authors.initials: F
authors.lastname: Pan
authors.forename: David T
authors.initials: DT
authors.lastname: Yew
mesh_terms: D000293:Adolescent; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects*; D015153:Blotting, Western / Q000379:methods; D053148:Caspase 3 / Q000378:metabolism; D002908:Chronic Disease; D003072:Cognition Disorders / Q000139:chemically induced; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D006801:Humans; D020287:In Situ Nick-End Labeling / Q000379:methods; D007275:Injections, Intravenous; D007649:Ketamine / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D008252:Macaca fascicularis; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced; D009043:Motor Activity / Q000187:drug effects*; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011897:Random Allocation; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D019966:Substance-Related Disorders / Q000378:metabolism / Q000503:physiopathology; D015430:Weight Gain / Q000187:drug effects; D055815:Young Adult; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D018691:Excitatory Amino Acid Antagonists; D019253:Proto-Oncogene Proteins c-bcl-2; D016194:Receptors, N-Methyl-D-Aspartate; D051028:bcl-2-Associated X Protein; D007649:Ketamine; D053148:Caspase 3
keywords: apoptosis; behavioral depression; cynomolgus monkeys; ketamine; prefrontal cortex