Thesis (M.S.)--Miami University, Dept. of Chemistry and Biochemistry, 2003. / Title from first page of PDF document. Document formatted into pages; contains xii, 83 p. : ill. Includes bibliographical references.

published_or_final_version / Physiology / Doctoral / Doctor of Philosophy

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Thesis (Ph. D.)--University of Hong Kong, 1993.

Thesis (Ph. D.)--Oregon State University, 2011. / Printout. Includes bibliographical references (leaves 136-149). Also available on the World Wide Web.

Thesis (Ph. D.)--Ohio State University, 2005. / Title from first page of PDF file. Document formatted into pages; contains xiv, 110 p.; also includes graphics. Includes bibliographical references (p. 100-110). Available online via OhioLINK's ETD Center

Typescript (photocopy). / Digitized by Kansas Correctional Industries

The binding of [³H]flunitrazepam (FLU) to membranes prepared from mammalian brain, retina and kidney was investigated by means of conventional filtration assay techniques. In the mouse brain a study of the ontogeny of [³H]FLU binding was conducted. Specific [³H]FLU binding was present early in development and there was a rapid increase in receptor density (Bmax) during the first 2 weeks of neonatal life. This increase could be described by the function, a·eᵏˣ, where a = 1.8 pmol/brain, k = 0.23 weeks⁻¹ and x = time in weeks (r = 0.98). By 3-4 weeks of age, adult levels of [³H]FLU binding were reached (∼115 fmol/mg tissue). Notable changes in the equilibrium dissociation constant (K(d)) during development were not observed. γ-Aminobutyric acid (GABA) has previously been shown to increase the affinity of [³H]FLU binding in the adult rat brain; in the present studies this effect was shown to be present throughout the development of the mouse brain. Kinetic analyses of the GABA enhancement of [³H]FLU binding indicated that the change in K(d) was due to a decrease in the rate constant of dissociation (k₋₁). [³H]FLU binding has been shown to occur in the mammalian retina and it has all the characteristics of cerebral [³H]FLU binding. Monosodium glutamate (MSG) is toxic to retinal neurons and it was used to ascertain the putative cellular localization of retinal BZD binding sites. Nine weeks following neonatal MSG administration, histologic evidence showed the virtual absence of ganglion cells and a marked reduction in the number of inner nuclear neurons in MSG retinae. A corresponding 73 percent decrease in GABA content and a 77 percent decrease in the Bmax of [³H]FLU were found in the retinae from MSG treated rats as compared to controls. There were no significant changes in [³H]FLU binding in the cerebella, cerebral cortices and hypothalami from MSG treated rats. The binding of [³H]FLU was characterized for the rat kidney. Binding was specific, saturable and of moderately high affinity (Bmax, ∼320 fmol/mg tissue; K(d), ∼11 nM). Drug specificity studies with renal membranes showed that inhibition of [³H]FLU binding by various BZD's did not correlate either with their pharmacologic potency as anxiolytic agents or with their potency as inhibitors of [³H]FLU binding in the brain. An intrarenal distribution of specific [³H]FLU binding was found in the bovine kidney; specific binding was greatest in the outer cortex and virtually absent in the medulla, the minor calyx and the renal artery. In rats made hypertensive by simultaneous deoxycorticosterone acetate and NaCl administration, there was a significant 35-43 percent increase in the Bmax of renal [³H]FLU binding. Binding in the cerebral cortex of these animals was unchanged. The inhibition of [³H]FLU binding by a triazolopyridazine (CL 218,872) was studied in membranes prepared from bovine retina, rat cerebral cortex, cerebellum and kidney. The affinity of CL 218,872 for the inhibition of [³H]FLU binding was greatest in the cerebellum, followed by the retina, cerebral cortex and kidney (60, 150, 200, and 1,800 nM, respectively). The slope factors (Hill coefficients) were ∼1 for the kidney, ∼0.9 for the cerebellum and ∼0.7 for the cerebral cortex and retina. A nonlinear least squares regression analysis of the data from the cerebral cortex, retina and cerebellum gave an excellent fit for a model containing 2 binding sites. In washed membrane preparations from the cerebral cortex, cerebellum and retina, Kᵢ values for CL 218,872 were significantly decreased an average of 60 percent in the presence of 100 μM GABA. (+)Bicuculline could antagonize this effect of GABA. GABA had no effect upon the Kᵢ of CL 218,872 in renal membranes.

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