Xinran LI, Mo LIU, Yue LI, Cen GUO, Lina LI, Yanan LI, Yuxin WANG, Yiming ZHANG, Li GAO

Effects of ketamine on monoamine neurotransmitters and GABA in embryonic neurocytes from fetal rat

The effect of ketamine, a drug commonly used as an anesthetic, on monoaminergic neurotransmitters and GABA in neurocytes from fetal rats has not yet been elucidated. We thus decided to investigate these effects by first evaluating ketamine levels in the cerebrospinal fluid by high-performance liquid chromatography. We thus determined the concentrations of GABA, DA, NE, 5-HT, and 5-HIAA following the addition of four different concentrations of ketamine at day 7 of nerve cell culture. GABA, 5-HT, and 5-HIAA levels were increased after an initial decrease: they showed the lowest levels at 10-15 min and the highest peaks at 45-90 min, followed by a declining trend. On the other hand, the trends of DA and NE levels were opposite. These changes in neurotransmitter levels showed a significant impact on monoamine neurotransmitters and GABA, consistent with the clinical changes in anesthetized rats. The role of ketamine in anesthesia may be explained by the changing levels of these indicators. Ketamine may be involved in the inhibition of the production and storage of excitatory neurotransmitters and the promotion of the generation and storage of inhibitory neurotransmitters, exerting its anesthetic action by reducing messenger molecules and related enzyme activity.

Keywords:

Ketamine, neurocytes, rat, monoamine neurotransmitters, GABA,

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Mathew SJ, Shah A, Lapidus K, Clark C, Jarun N, Ostermeyer B, Murrough JW. Ketamine for treatment-resistant unipolar depression. CNS Drugs 2012; 26: 189-204.
Delgermurun D, Ito S, Ohta T, Yamaguchi S, Otsuguro K. Endogenous 5-HT outflow from chicken aorta by 5-HT uptake inhibitors and amphetamine derivatives. J Vet Med Sci 2016; 78: 71-76.
Batool F, Haleem DJ. Increased precursor availability did not increase food intake and 5-HT turnover rate in the hypothalamus of diazepam injected rats. Pak J Pharm Sci 1999; 12: 21-26.
Secher T, Novitskaia V, Berezin V, Bock E, Glenthøj B, Klementiev B. A neural cell adhesion molecule–derived fibroblast growth factor receptor agonist, the FGL-peptide, promotes early postnatal sensorimotor development and enhances social memory retention. Neuroscience 2006; 141: 1289-1299.
Beaudoin GM 3rd, Lee SH, Singh D, Yuan Y, Ng YG, Reichardt LF, Arikkath J. Culturing pyramidal neurons from the early postnatal mouse hippocampus and cortex. Nat Protoc 2012; 7: 1741-1754.
Casoni D, Spadavecchia C, Wampfler B, Thormann W, Levionnois OL. Clinical and pharmacokinetic evaluation of S-ketamine for intravenous general anaesthesia in horses undergoing field castration. Acta Vet Scand 2015; 57: 21.
Casoni D, Spadavecchia C, Adami C. S-ketamine versus racemic ketamine in dogs: their relative potency as induction agents. Vet Anaesth Analg 2015; 42: 250-259.
De Monte V, Staffieri F, Di Meo A, Vannucci J, Bufalari A. Comparison of ketamine-dexmedetomidine-methadone and tiletamine-zolazepam-methadone combinations for short- term anaesthesia in domestic pigs. Vet J 2015; 205: 364-368.
Graff CL, Pollack GM. Drug Transport at the Blood-Brain Barrier and the Choroid Plexus. Curr Drug Metab 2004; 5: 95- 108.
Ghersi-Egea JF, Strazielle N. Choroid plexus transporters for drugs and other xenobiotics. J Drug Target 2002; 10: 353-357.
Lukatch HS, Kiddoo CE, Maciver MB. Anesthetic-induced burst suppression EEG activity requires glutamate-mediated excitatory synaptic transmission. Cereb Cortex 2005; 15: 1322- 1331.
Irifune M, Sato T, Kamata Y, Nishikawa T, Dohi T, Kawahara M. Evidence for GABA A receptor agonistic properties of ketamine: convulsive and anesthetic behavioral models in mice. Anesth Analg 2000; 91: 230-236.
Maldifassi MC, Baur R, Sigel E. Functional sites involved in modulation of the GABA receptor channel by the intravenous anesthetics propofol, etomidate and pentobarbital. Neuropharmacology 2016; 105: 207-214.
Pejo E, Santer P, Wang L, Dershwitz P, Husain SS, Raines DE. γ-Aminobutyric acid type A receptor modulation by etomidate analogs. BMC Anesthesiol 2016; 124: 651-663.
Stern AT, Forman SA. A cysteine substitution probes β3H267 interactions with propofol and other potent anesthetics in α1β3γ2L γ-aminobutyric acid type A receptors. BMC Anesthesiol 2016; 124: 89-100.
Hevers W, Hadley SH, Lüddens H, Amin J. Ketamine, but not phencyclidine, selectively modulates cerebellar GABAA receptors containing α6 and δ subunits. J Neurosci 2008; 28: 5383-5393.
Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH. Antidepressant effects of ketamine in depressed patients. Biol Psychiat 2000; 47: 351-354.
Kapur S, Seeman P. NMDA receptor antagonists ketamine and PCP have direct effects on the dopamine D 2 and serotonin 5-HT 2 receptors—implications for models of schizophrenia. Mol Psychiatr 2002; 7: 837-844.
Moghaddam B, Adams B, Verma A, Daly D. Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci 1997; 17: 2921-2927.
Robinson BL, Dumas M, Cuevas E, Gu Q, Paule MG, Ali SF, Kanungo J. Distinct effects of ketamine and acetyl l-carnitine on the dopamine system in zebrafish. Neurotoxicol Teratol 2016; 54: 52-60.
Tan S, Lam WP, Wai MS, Yu WHA, Yew DT. Chronic ketamine administration modulates midbrain dopamine system in mice. PLoS One 2012; 7: e43947.
Vazey EM, Aston-Jones G. Designer receptor manipulations reveal a role of the locus coeruleus noradrenergic system in isoflurane general anesthesia. P Natl Acad Sci USA 2014; 111: 3859-3864.
Wu XW, Xin B, Zou JF, Yan ZW, Qiu Y, Liu SY. Effect of rotation stimulation on the anesthetic sensitivity of sevoflurane in rats. Zhongguo Ying Yong Sheng Li Xue Za Zhi 2012; 28: 114-117 (in Chinese with abstract in English).
Nikiforuk A, Holuj M, Kos T, Popik P. The effects of a 5-HT receptor antagonist in a ketamine-based rat model of cognitive dysfunction and the negative symptoms of schizophrenia. Neuropharmacology 2016; 105: 351-360.
Amat J, Dolzani SD, Tilden S, Christianson JP, Kubala KH, Bartholomay K, Sperr K, Ciancio N, Watkins LR, Maier SF. Previous ketamine produces an enduring blockade of neurochemical and behavioral effects of uncontrollable stress. J Neurosci 2016; 36: 153-161.
Robinson BL, Dumas M, Paule MG, Ali SF, Kanungo J. Opposing effects of ketamine and acetyl L-carnitine on the serotonergic system of zebrafish. Neurosci Lett 2015; 607: 17- 22.