Advances in biochemical psychopharmacology最新文献

The involvement of GABAergic systems in the pathogenesis of HE was supported by electrophysiologic studies of single Purkinje neurons from rabbits with HE which demonstrated the hypersensitivity of these neurons to depression by GABA and BZ receptor agonists. In contrast, these neurons were excited by BZ receptor antagonists. At concentrations which had no effect on neuronal activity, BZ receptor antagonists also reversed the hypersensitivity of HE neurons to depression by muscimol. This combination of neuronal responses is consistent with an increase in the concentration or availability of a ligand for the BZ receptor with agonist properties in the brains of rabbits with HE. Subsequent neurochemical studies support these electrophysiologic observations. Autoradiographic techniques indicated the presence of a reversible inhibitor of [3H]Ro 15-1788 and [3H]flunitrazepam binding to the cerebral and cerebellar cortices of rabbits with HE. The ability of this substance to inhibit [3H]flunitrazepam binding to HE rabbit brain sections was further enhanced in the presence of NaCl and GABA. The autoradiographic studies suggested that the density and affinity of the components of the GABA-BZ receptor complex are unaltered in this animal model of HE. This inference is fully supported by the subsequent studies of radioligand binding to well-washed membrane preparations. Finally, extracts of HE rabbit brains yielded a family of substances with the properties of BZ receptor agonists. These substances may include, but are not limited to, diazepam, oxazepam and desmethyldiazepam, but do not include substances commonly elevated in the plasma and CSF of patients with HE4. The positive identification of these substances awaits confirmation by mass-spectroscopic analysis. However, the precedent for the presence of a family of benzodiazepines in animals that were not administered these drugs has been set. The origin of these substances is a matter of ongoing research. Several studies have shown the presence of benzodiazepines in plant and animal materials. It is possible that these "endogenous" benzodiazepines are the result of contamination of the food chain. A normally functioning liver would capture and metabolize these compounds after their absorption from the gut. This function of the liver would be impaired in liver failure, thus allowing sufficient levels of BZ receptor agonists to accumulate in the CNS, contributing to the pathogenesis of HE. However, studies by DeBlas and coworkers have reported that 1,4 benzodiazepines are present in human brains preserved prior to the commercial use of these compounds. Further, they have found benzodiazepines in cell lines cultured without potential exogenous sources of benzodiazepines.(ABSTRACT TRUNCATED AT 400 WORDS)

Chronic benzodiazepine administration is associated with neurochemical alterations in the GABAergic system, as determined in a variety of animal models and tissue culture systems. In animals, effects of chronic benzodiazepine agonists on receptor binding are uncertain, but several studies indicate a decrease in GABA-dependent chloride uptake. In contrast, limited data indicate that chloride uptake is increased after chronic antagonist administration, and results of inverse agonist administration are uncertain. Most animal studies are limited by lack of attention to drug choice and to pharmacokinetic variables, and by failure to determined delivered drug concentrations. More limited data in tissue culture systems are conflicting with regard to effects on benzodiazepine binding, but recent studies indicate that GABA-dependent chloride uptake may be decreased after chronic agonist exposure, and increased after chronic antagonist and inverse agonist administration. Data from these systems may complement results obtained in intact animals, and cultures may allow more detailed examination of the kinetics and specificity of drug effects.