Chronic ketamine exposure induces permanent impairment of brain functions in adolescent cynomolgus monkeys

被引:54
作者
Sun, Lin [1 ]
Li, Qi [2 ,3 ]
Li, Qing [1 ]
Zhang, Yuzhe [1 ]
Liu, Dexiang [1 ]
Jiang, Hong [1 ]
Pan, Fang [1 ]
Yew, David T. [4 ]
机构
[1] Shandong Univ, Sch Med, Dept Med Psychol, Jinan 250012, Peoples R China
[2] Univ Hong Kong, Dept Psychiat, Hong Kong, Hong Kong, Peoples R China
[3] Univ Hong Kong, Ctr Reprod Growth & Dev, Hong Kong, Hong Kong, Peoples R China
[4] Chinese Univ Hong Kong, Fac Med, Sch Biomed Sci, Hong Kong, Hong Kong, Peoples R China
关键词
apoptosis; behavioral depression; cynomolgus monkeys; ketamine; prefrontal cortex; PREFRONTAL CORTEX; RECEPTOR-BINDING; MEMORY; PATTERNS; BEHAVIOR; VULNERABILITY; ORGANIZATION; ASSOCIATION; ACTIVATION; DEPRESSION;
D O I
10.1111/adb.12004
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
070307 [化学生物学]; 071010 [生物化学与分子生物学];
摘要
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 (1mg/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.
引用
收藏
页码:185 / 194
页数:10
相关论文
共 57 条
[1]
Ketamine does not decrease striatal dopamine D2 receptor binding in man [J].
Aalto, S ;
Hirvonen, J ;
Kajander, J ;
Scheinin, H ;
Någren, K ;
Vilkman, H ;
Gustafsson, L ;
Syvälahti, E ;
Hietala, J .
PSYCHOPHARMACOLOGY, 2002, 164 (04) :401-406
[3]
Ketamine-induced changes in rat behaviour: A possible animal model of schizophrenia [J].
Becker, A ;
Peters, B ;
Schroeder, H ;
Mann, T ;
Huether, G ;
Grecksch, G .
PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY, 2003, 27 (04) :687-700
[4]
KINSHIP, ASSOCIATION, AND SOCIAL RELATIONSHIPS IN RHESUS-MONKEYS (MACACA-MULATTA) [J].
BERNSTEIN, IS ;
JUDGE, PG ;
RUEHLMANN, TE .
AMERICAN JOURNAL OF PRIMATOLOGY, 1993, 31 (01) :41-53
[5]
Breier A, 1997, AM J PSYCHIAT, V154, P805
[6]
Unraveling the mechanisms involved in motor neuron degeneration in ALS [J].
Bruijn, LI ;
Miller, TM ;
Cleveland, DW .
ANNUAL REVIEW OF NEUROSCIENCE, 2004, 27 :723-749
[7]
Downregulation in the human and mice cerebella after ketamine versus ketamine plus ethanol treatment [J].
Chan, W. M. ;
Xu, Jie ;
Fan, Ming ;
Jiang, Yanling ;
Tsui, Therese Y. M. ;
Wai, Maria S. M. ;
Lam, W. P. ;
Yew, D. T. .
MICROSCOPY RESEARCH AND TECHNIQUE, 2012, 75 (03) :258-264
[8]
PRIMATE SOCIAL-ORGANIZATION AND ECOLOGY [J].
CLUTTONB.TH .
NATURE, 1974, 250 (5467) :539-542
[9]
Ketamine-induced distractibility:: An oculomotor study in monkeys [J].
Condy, C ;
Wattiez, N ;
Rivaud-Péchoux, S ;
Gaymard, B .
BIOLOGICAL PSYCHIATRY, 2005, 57 (04) :366-372
[10]
Adolescent cortical development: A critical period of vulnerability for addiction [J].
Crews, Fulton ;
He, Jun ;
Hodge, Clyde .
PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR, 2007, 86 (02) :189-199