Ketamine anesthesia during the first week of life can cause long-lasting cognitive deficits in rhesus monkeys.
Previously our laboratory has shown that ketamine exposure (24h of clinically relevant anesthesia) causes significant increases in neuronal cell death in perinatal rhesus monkeys. Sensitivity to this ketamine-induced neurotoxicity was observed on gestational days 120-123 (in utero exposure via maternal anesthesia) and on postnatal days (PNDs) 5-6, but not on PNDs 35-37. In the present study, six monkeys were exposed on PND 5 or 6 to intravenous ketamine anesthesia to maintain a light surgical plane for 24h and six control animals were unexposed. At 7 months of age all animals were weaned and began training to perform a series of cognitive function tasks as part of the National Center for Toxicological Research (NCTR) Operant Test Battery (OTB). The OTB tasks used here included those for assessing aspects of learning, motivation, color discrimination, and short-term memory. Subjects responded for banana-flavored food pellets by pressing response levers and press-plates during daily (M-F) test sessions (50 min) and were assigned training scores based upon their individual performance. As reported earlier (Paule et al., 2009) beginning around 10 months of age, control animals significantly outperformed (had higher training scores than) ketamine-exposed animals for approximately the next 10 months. For animals now over 3 and one-half years of age, the cognitive impairments continue to manifest in the ketamine-exposed group as poorer performance in the OTB learning and color and position discrimination tasks, as deficits in accuracy of task performance, but also in response speed. There are also apparent differences in the motivation of these animals which may be impacting OTB performance. These observations demonstrate that a single 24-h episode of ketamine anesthesia, occurring during a sensitive period of brain development, results in very long-lasting deficits in brain function in primates and provide proof-of-concept that general anesthesia during critical periods of brain development can result in subsequent functional deficits. Supported by NICHD, CDER/FDA and NCTR/FDA.
Division of Neurotoxicology, National Center for Toxicological Research/FDA, 3900 NCTR Road, Jefferson, AR 72079-9502, USA. merle.paule@fda.hhs.gov
M G
MG
Paule
M
M
Li
R R
RR
Allen
F
F
Liu
X
X
Zou
C
C
Hotchkiss
J P
JP
Hanig
T A
TA
Patterson
W
W
Slikker
C
C
Wang
D000778:Anesthetics, Dissociative / Q000008:administration & dosage / Q000009:adverse effects*; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000187:drug effects; D003072:Cognition Disorders / Q000139:chemically induced*; D003627:Data Interpretation, Statistical; D004193:Discrimination Learning / Q000187:drug effects; D004334:Drug Administration Schedule; D007262:Infusions, Intravenous; D007649:Ketamine / Q000008:administration & dosage / Q000009:adverse effects*; D008253:Macaca mulatta; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects; D009042:Motivation / Q000187:drug effects; D012054:Reinforcement, Psychology; D013997:Time Factors; D014886:Weaning
D000778:Anesthetics, Dissociative; D007649:Ketamine
Physiol Behav. 1999 Jun;66(4):627-37
10386907
Essays Biochem. 1998;33:165-78
10488449
Neuroscience. 2010 Mar 31;166(3):852-63
20080153
Ann Neurol. 1999 Jun;45(6):724-35
10360764
Brain Res. 1990 Dec 17;536(1-2):146-52
1982236
Anesthesiology. 2009 Apr;110(4):849-61
19293696
J Physiol. 1983 Jan;334:33-46
6306230
FASEB J. 1994 Jul;8(10):745-52
8050674
Anesth Analg. 2008 Jun;106(6):1664-9
18499595
Behav Brain Res. 2004 Aug 31;153(2):367-76
15265631
Anesth Analg. 2010 Feb;110(2):431-7
19917621
Toxicol Sci. 2007 Jul;98(1):145-58
17426105
Anesthesiology. 2009 Apr;110(4):834-48
19293705
Neurotoxicol Teratol. 1999 May-Jun;21(3):223-30
10386825
Neurotoxicology. 2008 Jul;29(4):613-20
18456338
Neuroscience. 2008 Feb 19;151(4):1053-65
18201836
Ann Med. 2002;34(2):109-19
12108574
Anesthesiology. 2009 May;110(5):1077-85
19352168
Behav Brain Funct. 2008 Aug 07;4:35
18687139
Science. 1993 Apr 2;260(5104):95-7
8096653
Int J Dev Neurosci. 2000 Feb;18(1):121-31
10708913
Environ Health Perspect. 2000 Jun;108 Suppl 3:383-8
10852832
Neurotoxicology. 1988 Fall;9(3):367-78
3143955
Anesthesiology. 2010 Jun;112(6):1325-34
20460994
Anesthesiology. 2010 Apr;112(4):834-41
20234312
Cereb Cortex. 2005 Mar;15(3):349-58
15269112
Anesthesiology. 2009 Apr;110(4):703-8
19276968
J Pharmacol Exp Ther. 1988 Apr;245(1):178-86
2834536
Lancet. 1992 May 16;339(8803):1240
1349980
Clin Perinatol. 2009 Jun;36(2):215-26, vii
19559316
Anesth Analg. 2010 Feb 1;110(2):442-8
19955510
Biochem Pharmacol. 2001 Aug 15;62(4):401-5
11448448
Int J Dev Neurosci. 2009 Nov;27(7):727-31
19580862
Neurosci Lett. 2009 Sep 22;462(2):152-6
19596402
Anesth Analg. 2008 Jun;106(6):1659-63
18499594
Anesth Analg. 1998 Nov;87(5):1186-93
9806706
Neurotoxicol Teratol. 2010 Mar-Apr;32(2):142-51
19737611
Anesth Analg. 2007 Mar;104(3):509-20
17312200
Anesthesiology. 2009 Mar;110(3):628-37
19212262
Anesth Analg. 2008 Jun;106(6):1681-707
18499597
Anesthesiology. 2009 Apr;110(4):813-25
19293698
Brain Res. 2010 Jul 9;1343:14-9
20452333
Anesthesiology. 2007 Apr;106(4):746-53
17413912
J Am Assoc Lab Anim Sci. 2007 Nov;46(6):21-8
17994669
Toxicol Sci. 2002 Jul;68(1):9-17
12075105
Toxicol Sci. 2004 Oct;81(2):364-70
15254342
Brain Pathol. 2002 Oct;12(4):488-98
12408236
Brain Res Brain Res Rev. 1990 Jan-Apr;15(1):41-70
2163714
J Neurocytol. 1996 Dec;25(12):857-67
9023730
Pediatr Res. 2010 Feb;67(2):117-27
20091937
Anesthesiology. 2004 Aug;101(2):273-5
15277906
J Neurosci. 2003 Feb 1;23(3):876-82
12574416
Br J Pharmacol. 2005 Sep;146(2):189-97
15997239
Clin Neuropharmacol. 1998 Nov-Dec;21(6):320-32
9844787
Neurotoxicol Teratol. 1990 Sep-Oct;12(5):503-7
2247039
J Neural Transm (Vienna). 2011 Feb;118(2):203-11
20963452
Pharmacol Rev. 1989 Jun;41(2):143-210
2558391
Trends Pharmacol Sci. 2004 Mar;25(3):135-9
15019268
Toxicol Sci. 2009 Mar;108(1):149-58
19126600
Pediatr Res. 2007 Sep;62(3):283-90
17551412
Neuroscience. 2005;132(4):967-77
15857702
Ann Emerg Med. 2009 Aug;54(2):181-90
18990467
Anesthesiology. 2010 Aug;113(2):360-8
20613483
Neurotoxicol Teratol. 2001 Jul-Aug;23(4):319-32
11485835
Neuroscience. 2005;135(3):815-27
16154281
Ment Retard Dev Disabil Res Rev. 2001;7(4):267-75
11754521
Anesthesiology. 2004 Aug;101(2):527-30
15277935
Neurotoxicol Teratol. 2001 Jul-Aug;23(4):333-47
11485836
Ann Neurol. 2005 Aug;58(2):182-93
16049939
Front Biosci. 2005 Sep 01;10:2240-9
15970490
Anesthesiology. 2009 Apr;110(4):862-8
19293695
Neurotoxicology. 2002 Dec;23(6):659-68
12520755
Toxicol Sci. 2009 Oct;111(2):355-61
19638431
Toxicol Sci. 2006 May;91(1):192-201
16500925
Science. 1999 Jan 1;283(5398):70-4
9872743
Paediatr Anaesth. 2002 Nov;12(9):770-4
12519135