The long term objectives of the proposed work are to increase knowledge regarding the neurochemical events leading to the acute and chronic behavioral effects of ethanol. Past results indicate that low level hyperbaric exposure represents a direct antagonist of ethanol's initial molecular action(s) that can be used, in place of a more traditional, stereospecific, receptor antagonist, to investigate the cascade of events leading to acute intoxication, tolerance and physical dependence.
The Specific Aims are: 1) To further characterize the mechanism(s) by which hyperbaric exposure antagonizes acute and chronic behavioral effects of ethanol. This work will determine the specificity of the antagonism with respect to the acute behavioral effects of other alcohols, general anesthetics and non-anesthetic drugs; will determine whether hyperbaric exposure represents a competitive antagonist of ethanol's acute activating and depressant effects on locomotor activity; will determine whether increased general excitability contributes to the antagonism; and will investigate the mechanism by which hyperbaric exposure antagonizes the development of chronic functional tolerance and dependence; 2) To use hyperbaric exposure as a tool for investigating the neurochemical changes which mediate the stimulant and depressant effects of ethanol. These studies will test hypotheses regarding the importance of dopaminergic and prostanoid systems in meidating intoxication; and 3) To use hyperbaric exposure as a tool for investigating whether ethanol-induced membrane changes underlie the development of chronic functional tolterance and physical dependence. These studies will test hypotheses suggesting that adaptive membrane changes mediate chronic behavioral effects of ethanol. To achieve these goals, the effects of exposure to 12 atmospheres absolute helium-oxygen on sensitivity to the behavioral and neurochemical effects of ethanol and other drugs will be determined. Behavioral studies will use locomotor activity, duration of righting reflex loss, wake-up ethanol concentrations, seizure threshold, intoxication and withdrawal ratings to assess sensitivity and response to acute and chronic ethanol administration. Brain synaptosomal plasma membrane composition and fluidity, catecholamine turnover and prostanoid levels will be used as neurochemical indices of the effects of ethanol and pressure. We hope that this work will help in the identification of specific targets at which therapeutically relevant antagonists can be directed to reduce alcohol-related problems.
| Wyatt, Letisha R; Finn, Deborah A; Khoja, Sheraz et al. (2014) Contribution of P2X4 receptors to ethanol intake in male C57BL/6 mice. Neurochem Res 39:1127-39 |
| Popova, Maya; Trudell, James; Li, Kaixun et al. (2013) Tryptophan 46 is a site for ethanol and ivermectin action in P2X4 receptors. Purinergic Signal 9:621-32 |
| Perkins, Daya I; Trudell, James R; Asatryan, Liana et al. (2012) Charge and geometry of residues in the loop 2 ? hairpin differentially affect agonist and ethanol sensitivity in glycine receptors. J Pharmacol Exp Ther 341:543-51 |
| Ostrovskaya, Olga; Asatryan, Liana; Wyatt, Letisha et al. (2011) Ethanol is a fast channel inhibitor of P2X4 receptors. J Pharmacol Exp Ther 337:171-9 |
| Popova, Maya; Asatryan, Liana; Ostrovskaya, Olga et al. (2010) A point mutation in the ectodomain-transmembrane 2 interface eliminates the inhibitory effects of ethanol in P2X4 receptors. J Neurochem 112:307-17 |
| Perkins, Daya I; Trudell, James R; Crawford, Daniel K et al. (2010) Molecular targets and mechanisms for ethanol action in glycine receptors. Pharmacol Ther 127:53-65 |
| Asatryan, Liana; Popova, Maya; Perkins, Daya et al. (2010) Ivermectin antagonizes ethanol inhibition in purinergic P2X4 receptors. J Pharmacol Exp Ther 334:720-8 |
| Perkins, Daya I; Trudell, James R; Crawford, Daniel K et al. (2009) Loop 2 structure in glycine and GABA(A) receptors plays a key role in determining ethanol sensitivity. J Biol Chem 284:27304-14 |
| Perkins, Daya I; Trudell, James R; Crawford, Daniel K et al. (2008) Targets for ethanol action and antagonism in loop 2 of the extracellular domain of glycine receptors. J Neurochem 106:1337-49 |
| Crawford, Daniel K; Perkins, Daya I; Trudell, James R et al. (2008) Roles for loop 2 residues of alpha1 glycine receptors in agonist activation. J Biol Chem 283:27698-706 |
Showing the most recent 10 out of 51 publications
