Dual regulation by ethanol of the inhibitory effects of ketamine on spinal NMDA-induced pressor responses in rats

Journal of Biomedical Science

Chih-Chia Lai¹  Wei-Kung Hsieh²  Huei-Ru Lin³  Hsun-Hsun Lin⁵  Nien-Tzu Keng⁴ 

[1] Department of Pharmacology, Tzu Chi University, Hualien, Taiwan;General Education Center, National Taitung Junior College, Taitung, Taiwan;Department of Laboratory Medicine and Biotechnology, Tzu Chi University, Hualien, Taiwan;Department of Radiological Technology, Tzu Chi College of Technology, Hualien, Taiwan;Department of Physiology, Tzu Chi University, Hualien, Taiwan

关键词: sympathetic neuron;    phosphorylation;    PKA;    NMDA receptor;    ketamine;    alcohol;   

Others  :  825812
DOI  :  10.1186/1423-0127-19-11

 received in 2011-10-13, accepted in 2012-02-02,  发布年份 2012

【 摘 要 】

Background

Acute exposure of ethanol (alcohol) inhibits NMDA receptor function. Our previous study showed that acute ethanol inhibited the pressor responses induced by NMDA applied intrathecally; however, prolonged ethanol exposure may increase the levels of phosphorylated NMDA receptor subunits leading to changes in ethanol inhibitory potency on NMDA-induced responses. The present study was carried out to examine whether acute ethanol exposure influences the effects of ketamine, a noncompetitive NMDA receptor antagonist, on spinal NMDA-induced pressor responses.

Methods

The blood pressure responses induced by intrathecal injection of NMDA were recorded in urethane-anesthetized rats weighing 250-275 g. The levels of several phosphorylated residues on NMDA receptor GluN1 subunits were determined by western blot analysis.

Results

Intravenous injection of ethanol or ketamine inhibited spinal NMDA-induced pressor responses in a dose-dependent and reversible manner. Ketamine inhibition of NMDA-induced responses was synergistically potentiated by ethanol when ethanol was applied just before ketamine. However, ketamine inhibition was significantly reduced when applied at 10 min after ethanol administration. Western blot analysis showed that intravenous ethanol increased the levels of phosphoserine 897 on GluN1 subunits (pGluN1-serine 897), selectively phosphorylated by protein kinase A (PKA), in the lateral horn regions of spinal cord at 10 min after administration. Intrathecal administration of cAMPS-Sp, a PKA activator, at doses elevating the levels of pGluN1-serine 897, significantly blocked ketamine inhibition of spinal NMDA-induced responses.

Conclusions

The results suggest that ethanol may differentially regulate ketamine inhibition of spinal NMDA receptor function depending on ethanol exposure time and the resulting changes in the levels of pGluN1-serine 897.

【 授权许可】

   
2012 Keng et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

【 参考文献 】

• [1]Nagy J: Alcohol Related Changes in Regulation of NMDA Receptor Functions. Curr Neuropharmacol 2008, 6:39-54.
• [2]Krystal JH, Petrakis IL, Mason G, Trevisan L, D'Souza DC: N-methyl-D-aspartate glutamate receptors and alcoholism: reward, dependence, treatment, and vulnerability. Pharmacol Ther 2003, 99:79-94.
• [3]Davis KM, Wu JY: Role of glutamatergic and GABAergic systems in alcoholism. J Biomed Sci 2001, 8:7-19.
• [4]Lovinger DM, White G, Weight FF: Ethanol inhibits NMDA-activated ion current in hippocampal neurons. Science 1989, 243:1721-1724.
• [5]Woodward JJ, Ron D, Winder D, Roberto M: From blue states to up states: a regional view of NMDA-ethanol interactions. Alcohol Clin Exp Res 2006, 30:359-367.
• [6]Spanagel R: Alcoholism: a systems approach from molecular physiology to addictive behavior. Physiol Rev 2009, 89:649-705.
• [7]Cull-Candy S, Brickley S, Farrant M: NMDA receptor subunits: diversity, development and disease. Curr Opin Neurobiol 2001, 11:327-335.
• [8]Ron D: Signaling cascades regulating NMDA receptor sensitivity to ethanol. Neuroscientist 2004, 10:325-336.
• [9]Dampney RA: Functional organization of central pathways regulating the cardiovascular system. Physiol Rev 1994, 74:323-364.
• [10]Lin HH, Hsieh WK, Shiu JY, Chiu TH, Lai CC: Inhibition by ethanol of NMDA-induced responses and acute tolerance to the inhibition in rat sympathetic preganglionic neurons in vitro and in vivo. Br J Pharmacol 2003, 140:955-963.
• [11]Hsieh WK, Lin HH, Lai CC: Involvement of protein kinase C and Src tyrosine kinase in acute tolerance to ethanol inhibition of spinal NMDA-induced pressor responses in rats. Br J Pharmacol 2009, 158:806-818.
• [12]Lin HR, Lin HL, Lee SF, Liu C, Lua AC: A fast screening procedure for ketamine and metabolites in urine samples with tandem mass spectrometry. J Anal Toxicol 2010, 34:149-154.
• [13]Lin HH, Chen CH, Hsieh WK, Chiu TH, Lai CC: Hydrogen peroxide increases the activity of rat sympathetic preganglionic neurons in vivo and in vitro. Neuroscience 2003, 121:641-647.
• [14]Chiu HY, Lin HH, Lai CC: Cocaine- and amphetamine-regulated transcript (CART) peptide activates ERK pathways via NMDA receptors in rat spinal cord dorsal horn in an age-dependent manner. Regul Pept 2010, 164:90-96.
• [15]Farber NB, Olney JW: Drugs of abuse that cause developing neurons to commit suicide. Brain Res Dev Brain Res 2003, 147:37-45.
• [16]Ikonomidou C, Bosch F, Miksa M, Bittigau P, Vockler J, Dikranian K, Tenkova TI, Stefovska V, Turski L, Olney JW: Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 1999, 283:70-74.
• [17]Lua AC, Lin HR, Tseng YT, Hu AR, Yeh PC: Profiles of urine samples from participants at rave party in Taiwan: prevalence of ketamine and MDMA abuse. Forensic Sci Int 2003, 136:47-51.
• [18]Moore KA, Kilbane EM, Jones R, Kunsman GW, Levine B, Smith M: Tissue distribution of ketamine in a mixed drug fatality. J Forensic Sci 1997, 42:1183-1185.
• [19]Licata M, Pierini G, Popoli G: A fatal ketamine poisoning. J Forensic Sci 1994, 39:1314-1320.
• [20]Orser BA, Pennefather PS, MacDonald JF: Multiple mechanisms of ketamine blockade of N-methyl-D-aspartate receptors. Anesthesiology 1997, 86:903-917.
• [21]Allgaier C: Ethanol sensitivity of NMDA receptors. Neurochem Int 2002, 41:377-382.
• [22]Ren H, Honse Y, Peoples RW: A site of alcohol action in the fourth membrane-associated domain of the N-methyl-D-aspartate receptor. J Biol Chem 2003, 278:48815-48820.
• [23]Ronald KM, Mirshahi T, Woodward JJ: Ethanol inhibition of N-methyl-D-aspartate receptors is reduced by site-directed mutagenesis of a transmembrane domain phenylalanine residue. J Biol Chem 2001, 276:44729-44735.
• [24]Peoples RW, Stewart RR: Alcohols inhibit N-methyl-D-aspartate receptors via a site exposed to the extracellular environment. Neuropharmacology 2000, 39:1681-1691.
• [25]Smothers CT, Woodward JJ: Effects of amino acid substitutions in transmembrane domains of the NR1 subunit on the ethanol inhibition of recombinant N-methyl-D-aspartate receptors. Alcohol Clin Exp Res 2006, 30:523-530.
• [26]Rondon ES, Vieira AS, Valadao CA, Parada CA: The improvement of the anti-hyperalgesic effect of ketamine and of its isomers by the administration of ifenprodil. Eur J Pharmacol 2010, 647:84-89.
• [27]Chen BS, Roche KW: Regulation of NMDA receptors by phosphorylation. Neuropharmacology 2007, 53:362-368.
• [28]Newton PM, Messing RO: Intracellular signaling pathways that regulate behavioral responses to ethanol. Pharmacol Ther 2006, 109:227-237.
• [29]Pandey SC: Neuronal signaling systems and ethanol dependence. Mol Neurobiol 1998, 17:1-15.
• [30]Anders DL, Blevins T, Sutton G, Swope S, Chandler LJ, Woodward JJ: Fyn tyrosine kinase reduces the ethanol inhibition of recombinant NR1/NR2A but not NR1/NR2B NMDA receptors expressed in HEK 293 cells. J Neurochem 1999, 72:1389-1393.
• [31]Maldve RE, Zhang TA, Ferrani-Kile K, Schreiber SS, Lippmann MJ, Snyder GL, Fienberg AA, Leslie SW, Gonzales RA, Morrisett RA: DARPP-32 and regulation of the ethanol sensitivity of NMDA receptors in the nucleus accumbens. Nat Neurosci 2002, 5:641-648.
• [32]Snell LD, Tabakoff B, Hoffman PL: Involvement of protein kinase C in ethanol-induced inhibition of NMDA receptor function in cerebellar granule cells. Alcohol Clin Exp Res 1994, 18:81-85.
• [33]Yu MC, Chen JH, Lai CY, Han CY, Ko WC: Luteolin, a non-selective competitive inhibitor of phosphodiesterases 1-5, displaced [3H]-rolipram from high-affinity rolipram binding sites and reversed xylazine/ketamine-induced anesthesia. Eur J Pharmacol 2010, 627:269-275.
• [34]Stubbs CD, Slater SJ: Ethanol and protein kinase C. Alcohol Clin Exp Res 1999, 23:1552-1560.
• [35]Das J, Pany S, Rahman GM, Slater SJ: PKC epsilon has an alcohol-binding site in its second cysteine-rich regulatory domain. Biochem J 2009, 421:405-413.
• [36]Grosshans DR, Clayton DA, Coultrap SJ, Browning MD: LTP leads to rapid surface expression of NMDA but not AMPA receptors in adult rat CA1. Nat Neurosci 2002, 5:27-33.
• [37]Alvestad RM, Grosshans DR, Coultrap SJ, Nakazawa T, Yamamoto T, Browning MD: Tyrosine dephosphorylation and ethanol inhibition of N-methyl-D-aspartate receptor function. J Biol Chem 2003, 278:11020-11025.
• [38]Kumar S, Porcu P, Werner DF, Matthews DB, Diaz-Granados JL, Helfand RS, Morrow AL: The role of GABA(A) receptors in the acute and chronic effects of ethanol: a decade of progress. Psychopharmacology (Berl) 2009, 205:529-564.
• [39]Schummers J, Browning MD: Evidence for a role for GABA(A) and NMDA receptors in ethanol inhibition of long-term potentiation. Brain Res Mol Brain Res 2001, 94:9-14.
• [40]Parry CD, Patra J, Rehm J: Alcohol consumption and non-communicable diseases: epidemiology and policy implications. Addiction 2011, 106:1718-1724.
• [41]Klatsky AL: Alcohol, coronary disease, and hypertension. Annu Rev Med 1996, 47:149-160.
• [42]Puddey IB, Beilin LJ: Alcohol is bad for blood pressure. Clin Exp Pharmacol Physiol 2006, 33:847-852.
• [43]Zilkens RR, Burke V, Hodgson JM, Barden A, Beilin LJ, Puddey IB: Red wine and beer elevate blood pressure in normotensive men. Hypertension 2005, 45:874-879.
• [44]Abdel-Rahman AA, Wooles WR: Ethanol-induced hypertension involves impairment of baroreceptors. Hypertension 1987, 10:67-73.
• [45]Hering D, Kucharska W, Kara T, Somers VK, Narkiewicz K: Potentiated sympathetic and hemodynamic responses to alcohol in hypertensive vs. normotensive individuals. J Hypertens 2011, 29:537-541.