A lipophilic substance with high affinity for central benzodiazepine receptors has been extracted from rat brain tissue. The lipophilic substance reduces gamma-aminobutyric acid-stimulated uptake of chloride in synaptoneurosomes. The Lipophilic Substance does not appear to be a benzodiazepine, a beta-carboline or a polypeptide. Housing rats in single cages for a week may increase the presence of the Lipophilic Substance in brain tissue. The objectives of this grant should help explain why humans vary in response to the """"""""mood-altering"""""""" or sedating effects of the benzodiazepines. The first specific aim is to obtain the lipophilic substance in 95 to 100 percent purity. State of the art spectroscopic equipment is being used to determine the structure of the lipophilic substance. The affinity of the lipophilic substance for central and peripheral benzodiazepine receptors is being assessed by its ability to displace 3H-flumazenil and 3H-PK11195 specific binding, respectively. The selectivity of the lipophilic substance for benzodiazepine receptors is being determined by its ability to displace the specific binding of radioligands with selectivity for other receptors. The potency of the lipophilic compound in decreasing muscimol-stimulated chloride uptake in synaptoneurosomes is being measured. The mechanism by which the lipophilic substance initiates the decrease in muscimol-stimulated chloride uptake will be clarified. Flumazenil, PK11195 and Ro15-4513 will be examined for an ability to antagonize the reduction in muscimol- stimulated chloride uptake elicited by the lipophilic substance.
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