Ethanol tachyphylaxis in spinal cord motorneurons: role of metabotropic glutamate receptors.

Abstract

1. Ethanol (EtOH) tachyphylaxis (acute tolerance), a time-dependent decrease in apparent potency, is known in vivo and in some neuronal preparations. The present studies characterize EtOH tachyphylaxis in spinal motorneurons and test the hypothesis that metabotropic glutamate receptors (mGluRs) play a role. 2. Patch clamp studies were carried out in motorneurons in rat spinal cord slices. Currents were evoked by pulses of glutamate, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) or N-methyl-D-aspartic acid (NMDA). 3. In nine of 15 cells, ethanol depression of glutamate-evoked currents was time-dependent. EtOH depressed current area 36.9+/-3% at 8-10 min, but only 16.8+/-3% at 20 min. Mean reduction in depression was 20.1+/-1%, N=9. Tachyphylaxis was less prominent in currents evoked by AMPA or NMDA, appearing in two of 10 AMPA and three of 11 NMDA currents. 4. The mGluR agonist trans-(1S,3R)-1-amino-1,3-cyclopentanedicarboxylic acid (ACPD) increased, the antagonist (+/-)-alpha-methyl-4-carboxyphenylglycine (MCPG) decreased the area of glutamate-evoked currents. ACPD also increased the area of NMDA- and AMPA-evoked currents. 5. ACPD increased the incidence of tachyphylaxis in glutamate-evoked currents to 100% (N=9); MCPG markedly reduced tachyphylaxis. ACPD also increased the incidence of tachyphylaxis in currents evoked by NMDA and AMPA to five of eight and four of seven neurons, respectively. 6. Block of G-protein pathways by intracellular GDP-beta-s abolished tachyphylaxis in glutamate-evoked currents (N=8); however, currents recovered only partially following EtOH washout. 7. Activation of mGluRs contributes to neuronal tachyphylaxis to EtOH in spinal cord motorneurons, probably via G-protein pathways.