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Stress-Induced Changes in t-[³⁵S]Butylbicyclophosphorothionate Binding to γ-Aminobutyric Acid-Gated Chloride Channels Are Mimicked by In Vitro Occupation of Benzodiazepine Receptors

Corresponding Author

R. Trullas

Laboratory of Bioorganic Chemistry, NIDDK

Address correspondence and reprint requests to Dr. R. Trullas at Section on Neurobiology, Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, Building 8, Room 103, Bethesda, MD 20892, U.S.A.Search for more papers by this author

H. Havoundjian,

H. Havoundjian

Laboratory of Bioorganic Chemistry, NIDDK

Howard Hughes Medical Institute, National Institutes of Health, Bethesda, Maryland, U.S.A.

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P. Skolnick,

P. Skolnick

Laboratory of Bioorganic Chemistry, NIDDK

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R. Trullas,

Corresponding Author

R. Trullas

Laboratory of Bioorganic Chemistry, NIDDK

H. Havoundjian,

H. Havoundjian

Laboratory of Bioorganic Chemistry, NIDDK

Howard Hughes Medical Institute, National Institutes of Health, Bethesda, Maryland, U.S.A.

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P. Skolnick,

P. Skolnick

Laboratory of Bioorganic Chemistry, NIDDK

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First published: September 1987

https://doi.org/10.1111/j.1471-4159.1987.tb00988.x

Citations: 35

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Abstract

Abstract: The allosteric modulation of t-[³⁵S]butylbicyclo-phosphorothionate binding by flunitrazepam was studied in well-washed brain membranes prepared from control and swim-stressed rats. Swim stress has been reported to decrease the K_D, and increase the B_max of this radioligand. Flunitrazepam increased radioligand binding with equal potency (EC₅₀∼ 11 nM) in both groups, but the maximal enhancement (efficacy) produced by this drug was significantly greater in control than in swim-stressed rats. Ro 15–1788 (a benzodiazepine receptor antagonist) blocked the effect of flunitrazepam on t-[³⁵S]butylbicyclophosphorothionate binding in both groups. This increase in t-[³⁵S]butylbicyclophosphorothionate binding resulted from a significant reduction in K_D with no alteration in B_max. The K_D values obtained in cortical membranes of control rats after addition of flunitrazepam were not significantly different from those in the swim-stressed group. Preincubation of cortical homogenates from control animals with flunitrazepam prior to extensive tissue washing resulted in B_max and K_D values of t-[³⁵S]butylbicyclophosphorothionate similar to those obtained in stressed animals. These findings suggest that stress and flunitrazepam may share a common mechanism in regulating t-[³⁵S]butylbicyclophosphorothionate binding and support the concept that stress-induced modification of γ-aminobutyric acid (GABA)-gated chloride channels in the CNS results from the release of an endogenous modulator (with benzodiazepine-like properties) of the benzodiazepine-GABA receptor chloride ionophore receptor complex.

Abbreviations used:

ANOVA: analysis of variance
E _max: maximal effect
GABA: γ-aminobutyric acid
TBPS: t-butylbicyclophos- phorothionate

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Volume49, Issue3

September 1987

Pages 968-974

Stress-Induced Changes in t-[³⁵S]Butylbicyclophosphorothionate Binding to γ-Aminobutyric Acid-Gated Chloride Channels Are Mimicked by In Vitro Occupation of Benzodiazepine Receptors

Abstract

Abbreviations used:

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Stress-Induced Changes in t-[³⁵S]Butylbicyclophosphorothionate Binding to γ-Aminobutyric Acid-Gated Chloride Channels Are Mimicked by In Vitro Occupation of Benzodiazepine Receptors