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Selective effects of MAO inhibition on peripheral benzodiazepine receptor binding in the mouse
C H Park1, L G Lukacs, J Mastropaolo
1Psychiatry Service, Department of Veterans Affairs Medical Center, Washington DC 20422, USA.
Abstract:
Monoamine Oxidase (MAO) and the peripheral benzodiazepine binding site (PBR) share a close physical proximity to each other in the outer mitochondrial membrane. Furthermore, MAO activity and the density of PBR sites are affected by stress; benzodiazepines may influence stress-induced changes in MAO activity. In view of the close physical association between MAO and the PBR, we examined the effects of chronic administration of selective and nonselective MAO inhibitors to mice on the specific binding of 3H-Ro5-4864 and 3H-PK-11195 to crude membranes prepared from kidney, heart and liver. Chronic MAO inhibition was associated with alterations in PBR binding in all three tissues; however, in heart and liver changes were not detectable with 3H-PK-11195. Perhaps, the ability to discern changes with 3H-Ro5-4864 that are not detectable with 3H-PK-11195 reflects a functional change in the "activity" of the PBR site in heart and liver that is elicited by chronic MAO inhibition and mediated by a change in the "conformation" of the protein that is detected with 3H-Ro5-4864. Importantly, iproniazid, the nonselective MAO inhibitor, caused changes in PBR binding in all three of the tissues.
Insights
Chronic Monoamine Oxidase (MAO) inhibition alters peripheral benzodiazepine binding sites (PBR) in mouse tissues. These changes suggest a functional modification of PBR activity, particularly in the heart and liver, following MAO inhibition.
Area of Science:
- Biochemistry
- Neuropharmacology
- Mitochondrial Biology
Background:
- Monoamine Oxidase (MAO) and peripheral benzodiazepine binding sites (PBR) are located in close proximity within the outer mitochondrial membrane.
- MAO activity and PBR density are influenced by stress, with benzodiazepines potentially modulating stress-induced MAO changes.
Purpose of the Study:
- To investigate the impact of chronic MAO inhibition on PBR binding characteristics.
- To explore potential functional alterations in PBR activity mediated by MAO inhibition.
Main Methods:
- Chronic administration of selective and nonselective MAO inhibitors to mice.
- Assessment of specific binding of radioligands (3H-Ro5-4864 and 3H-PK-11195) to crude membranes from kidney, heart, and liver.
Main Results:
- Chronic MAO inhibition led to alterations in PBR binding across all examined tissues (kidney, heart, liver).
- Changes in PBR binding were detectable with 3H-Ro5-4864 in heart and liver, but not with 3H-PK-11195, suggesting a conformational or functional PBR modification.
- The nonselective MAO inhibitor, iproniazid, induced PBR binding changes in all three tissues.
Conclusions:
- Chronic MAO inhibition induces significant alterations in peripheral benzodiazepine binding site characteristics.
- The differential binding observed with 3H-Ro5-4864 and 3H-PK-11195 suggests a functional modulation of PBR activity, possibly via conformational changes, following MAO inhibition.
- These findings highlight the intricate relationship between MAO activity and PBR function in various tissues.