title: Ethanol inhibition of NMDA-induced responses and acute tolerance to the inhibition in rat rostral ventrolateral medulla in vivo: Involvement of cAMP-dependent protein kinases.
abstract: Our recent study showed that intravenous ethanol selectively inhibited the pressor effects elicited by the microinjection of N-methyl-D-aspartate (NMDA) into rostral ventrolateral medulla (RVLM) and acute tolerance to the inhibition was observed during prolonged application of ethanol in anesthetized Sprague-Dawley rats. In this study, we examined the role of the cAMP-dependent protein kinase (PKA) signaling pathway in acute tolerance to ethanol inhibition of NMDA-induced responses in rat RVLM. A significant increase in the level of PKA-regulated phosphoserine 897 on the NMDA NR1 subunit was found in the rostroventral medulla during acute ethanol tolerance. Reduction of NMDA-induced pressor effects was observed at 10 min but disappeared at 40 min after continuous ethanol infusion. This effect was dose-dependently blocked by microinjection of KT5720 (0.04-4 pmol, a selective PKA inhibitor) or cAMPS-Rp (0.02, 0.2 pmol, a cAMP antagonist) into the RVLM 10 min post-injection of ethanol; KT 5720 or cAMPS-Rp alone at doses tested had no significant effects on NMDA-induced responses. Post-treatment with cAMPS-Sp (10 pmol, a cAMP activator) did not affect acute ethanol tolerance. Interestingly, administration of KT 5720 (0.4, 4 pmol) or cAMPS-Rp (2,10 pmol) into the RVLM 20 min before the injection of ethanol also reduced the inhibitory effects of ethanol on NMDA-induced pressor effects in a dose-dependent manner. Our results provide the first in vivo evidence that PKA signaling pathways participate in acute tolerance to ethanol inhibition of NMDA receptor function. Furthermore, PKA-mediated signaling pathways may also be involved in the interaction between ethanol and NMDA receptors.
authors.affiliation: Department of Physiology, Tzu Chi University, Hualien 970, Taiwan.
authors.forename: Hsun Hsun
authors.initials: HH
authors.lastname: Lin
authors.forename: Shih-Jung
authors.initials: SJ
authors.lastname: Chang
authors.forename: Hui-Jhan
authors.initials: HJ
authors.lastname: Shie
authors.forename: Chih-Chia
authors.initials: CC
authors.lastname: Lai
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D001794:Blood Pressure / Q000187:drug effects*; D015153:Blotting, Western / Q000379:methods; D002492:Central Nervous System Depressants / Q000097:blood / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000431:Ethanol / Q000097:blood / Q000494:pharmacology*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects*; D008845:Microinjections / Q000379:methods; D016202:N-Methylaspartate / Q000494:pharmacology; D010768:Phosphoserine / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D002492:Central Nervous System Depressants; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D010768:Phosphoserine; D000431:Ethanol; D016202:N-Methylaspartate; D017868:Cyclic AMP-Dependent Protein Kinases