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  • 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.
    Author: Lin HH, Chang SJ, Shie HJ, Lai CC.
    Journal: Neuropharmacology; 2006 Sep; 51(4):747-55. PubMed ID: 16806304.
    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.
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