Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0278080 (physical dependence)
 1,658 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An acute ethanol load administered to rats results in an enhancement in lipid peroxidation in the cerebellum, a brain area which is particularly sensitive to free radical attack. The ethanol load induces also a decrease in the cerebellar concentration of the three main endogenous anti-oxidant small molecules, i.e. alpha-tocopherol, ascorbate and glutathione. These findings are highly suggestive of a cerebellar oxidative stress due to acute ethanol administration. However this administration does not enhance brain mitochondrial superoxide production as well as cerebellar mitochondrial hydrogen peroxide production. An oxidative stress could also play a role in some effects of chronic alcohol intoxication on the brain. This is particularly suggested by the beneficial effects of the administration of desferrioxamine, an iron-chelator and free radical scavenger, on physical dependence on alcohol in rodents. A speculative synthesis of the mechanisms that might be involved in such an oxidative stress on the central nervous system is presented.
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PMID:Oxidative stress from alcohol in the brain. 342 57

1. Imidazoquinoxaline PNU-97775 and imidazoquinoline PNU-101017 are benzodiazepine site ligands with a second low affinity binding site on GABA(A) receptors, the occupancy of which at high drug concentrations reverses their positive allosteric activity via the benzodiazepine site, and may potentially minimize abuse liability and physical dependence. 2. In this study we discovered, with two imidazoquinoxaline analogues, that the functionality of the second site was altered by the nitrogen substituent on the piperazine ring moiety: PNU-100076 with a hydrogen substituent on the position produced a negative allosteric effect via the second low affinity site, like the parent compounds, while PNU-100079 with a trifluoroethyl substituent produced a positive allosteric response. 3. These functional characteristics were monitored with Cl- currents measurements in cloned rat alphaxbeta2gamma2 subtypes of GABA(A) receptors expressed in human embryonic kidney 293 cells, and further confirmed in rat cerebrocortical membranes containing complex subtypes of GABA(A) receptors with binding of [35S]-TBPS, which is a high affinity ligand specific for GABA(A) receptors with exquisite sensitivity to allosteric modulations. 4. This structure-functional relationship could be exploited to further our understanding of the second allosteric site of imidazoquinoxaline analogues, and to develop more effective benzodiazepine site ligands without typical side effects associated with those currently available on the market.
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PMID:Two imidazoquinoxaline ligands for the benzodiazepine site sharing a second low affinity site on rat GABA(A) receptors but with the opposite functionality. 960 52