Gene Expression Changes in GABA(A) Receptors and Cognition Following Chronic Ketamine Administration in Mice

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2011 Jun 30

PMID 21712993

Citations 27

Authors

Sijie Tan

John A Rudd

David T Yew

Affiliations

Soon will be listed here.

Abstract

Ketamine is a well-known anesthetic agent and a drug of abuse. Despite its widespread use and abuse, little is known about its long-term effects on the central nervous system. The present study was designed to evaluate the effect of long-term (1- and 3-month) ketamine administration on learning and memory and associated gene expression levels in the brain. The Morris water maze was used to assess spatial memory and gene expression changes were assayed using Affymetrix Genechips; a focus on the expression of GABA(A) receptors that mediate a tonic inhibition in the brain, was confirmed by quantitative real-time PCR and western blot. Compared with saline controls, there was a decline in learning and memory performance in the ketamine-treated mice. Genechip results showed that 110 genes were up-regulated and 136 genes were down-regulated. An ontology analysis revealed the most significant effects of ketamine were on GABA(A) receptors. In particular, there was a significant up-regulation of both mRNA and protein levels of the alpha 5 subunit (Gabra5) of the GABA(A) receptors in the prefrontal cortex. In conclusion, chronic exposure to ketamine impairs working memory in mice, which may be explained at least partly by up-regulation of Gabra5 subunits in the prefrontal cortex.

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References

Ricci V, Martinotti G, Gelfo F, Tonioni F, Caltagirone C, Bria P . Chronic ketamine use increases serum levels of brain-derived neurotrophic factor. Psychopharmacology (Berl). 2010; 215(1):143-8. DOI: 10.1007/s00213-010-2121-3. View

Jones E . GABAergic neurons and their role in cortical plasticity in primates. Cereb Cortex. 1993; 3(5):361-72. DOI: 10.1093/cercor/3.5.361-a. View

Baddeley A . Working memory: looking back and looking forward. Nat Rev Neurosci. 2003; 4(10):829-39. DOI: 10.1038/nrn1201. View

Mhatre M, Ticku M . Aging related alterations in GABAA receptor subunit mRNA levels in Fischer rats. Brain Res Mol Brain Res. 1992; 14(1-2):71-8. DOI: 10.1016/0169-328x(92)90012-z. View

Rissman R, Mishizen-Eberz A, Carter T, Wolfe B, De Blas A, Miralles C . Biochemical analysis of GABA(A) receptor subunits alpha 1, alpha 5, beta 1, beta 2 in the hippocampus of patients with Alzheimer's disease neuropathology. Neuroscience. 2003; 120(3):695-704. DOI: 10.1016/s0306-4522(03)00030-7. View

Mizukami K, Ikonomovic M, Grayson D, Rubin R, Warde D, Sheffield R . Immunohistochemical study of GABA(A) receptor beta2/3 subunits in the hippocampal formation of aged brains with Alzheimer-related neuropathologic changes. Exp Neurol. 1997; 147(2):333-45. DOI: 10.1006/exnr.1997.6591. View

Watanabe M, Maemura K, Kanbara K, Tamayama T, Hayasaki H . GABA and GABA receptors in the central nervous system and other organs. Int Rev Cytol. 2002; 213:1-47. DOI: 10.1016/s0074-7696(02)13011-7. View

Mak Y, Lam W, Lu L, Wong Y, Yew D . The toxic effect of ketamine on SH-SY5Y neuroblastoma cell line and human neuron. Microsc Res Tech. 2009; 73(3):195-201. DOI: 10.1002/jemt.20774. View

Miller E, Cohen J . An integrative theory of prefrontal cortex function. Annu Rev Neurosci. 2001; 24:167-202. DOI: 10.1146/annurev.neuro.24.1.167. View

10.

Ricaurte G, McCann U . Recognition and management of complications of new recreational drug use. Lancet. 2005; 365(9477):2137-45. DOI: 10.1016/S0140-6736(05)66737-2. View

11.

Hijazi Y, Boulieu R . Contribution of CYP3A4, CYP2B6, and CYP2C9 isoforms to N-demethylation of ketamine in human liver microsomes. Drug Metab Dispos. 2002; 30(7):853-8. DOI: 10.1124/dmd.30.7.853. View

12.

Chambers M, Atack J, Broughton H, Collinson N, Cook S, Dawson G . Identification of a novel, selective GABA(A) alpha5 receptor inverse agonist which enhances cognition. J Med Chem. 2003; 46(11):2227-40. DOI: 10.1021/jm020582q. View

13.

Lin L, Chen L, Zirrolli J, Harris R . General anesthetics potentiate gamma-aminobutyric acid actions on gamma-aminobutyric acidA receptors expressed by Xenopus oocytes: lack of involvement of intracellular calcium. J Pharmacol Exp Ther. 1992; 263(2):569-78. View

14.

Curran H, Morgan C . Cognitive, dissociative and psychotogenic effects of ketamine in recreational users on the night of drug use and 3 days later. Addiction. 2000; 95(4):575-90. DOI: 10.1046/j.1360-0443.2000.9545759.x. View

15.

Yoshiike Y, Kimura T, Yamashita S, Furudate H, Mizoroki T, Murayama M . GABA(A) receptor-mediated acceleration of aging-associated memory decline in APP/PS1 mice and its pharmacological treatment by picrotoxin. PLoS One. 2008; 3(8):e3029. PMC: 2515633. DOI: 10.1371/journal.pone.0003029. View

16.

Hirota K, Sikand K, Lambert D . Interaction of ketamine with mu2 opioid receptors in SH-SY5Y human neuroblastoma cells. J Anesth. 2003; 13(2):107-9. DOI: 10.1007/s005400050035. View

17.

Li F, Tsien J . Memory and the NMDA receptors. N Engl J Med. 2009; 361(3):302-3. PMC: 3703758. DOI: 10.1056/NEJMcibr0902052. View

18.

Kleinschmidt A, Bear M, Singer W . Blockade of "NMDA" receptors disrupts experience-dependent plasticity of kitten striate cortex. Science. 1987; 238(4825):355-8. DOI: 10.1126/science.2443978. View

19.

Shi Q, Guo L, Patterson T, Dial S, Li Q, Sadovova N . Gene expression profiling in the developing rat brain exposed to ketamine. Neuroscience. 2010; 166(3):852-63. PMC: 5739315. DOI: 10.1016/j.neuroscience.2010.01.007. View

20.

Honey G, Honey R, OLoughlin C, Sharar S, Kumaran D, Suckling J . Ketamine disrupts frontal and hippocampal contribution to encoding and retrieval of episodic memory: an fMRI study. Cereb Cortex. 2004; 15(6):749-59. PMC: 3838947. DOI: 10.1093/cercor/bhh176. View