The Effects of Chronic Administration of Inhibitors of Flavin and Quinone Amine Oxidases on Imidazoline I₁ Receptor Density in Rat Whole Brain

Abstract

Many imidazoline ligands have been shown to bind to the active sites of several amine oxidases, and endogenous ligands such as agmatine and tryptamine are amine oxidase substrates. In order to ascertain whether concentrations of endogenous imidazoline receptor agonists might be regulated by amine oxidase activities, rats were administered saline, clorgyline, deprenyl, MDL 72274A, aminoguanidine, or a combination of clorgyline, deprenyl, and aminoguanidine, for 14 days, and then binding parameters for [(3)H]clonidine at imidazoline I(1) receptors were determined in whole brain. Several EC 1.4.3.4, 1.4.3.6, and 1.5.3.11 amine oxidase activities were also measured ex vivo in tissues from treated animals. Results showed that drug treatments did not alter the affinity of clonidine for imidazoline I(1) receptors. There was a tendency toward a reduction in receptor density when monoamine oxidase (MAO)-A 1 MAO-B, MAO-B 1 semicarbazide-sensitive amine oxidase (SSAO), or SSAO 1 diamine oxidase (DAO) were inhibited, and a marked reduction in density when MAO-A 1 MAO-B 1 SSAO were inhibited. These data suggest that amines that are substrates both for MAO and for SSAO, such as tryptamine and other trace amines, may act as endogenous imidazoline I(1) receptor agonists, at which they may have neuromodulatory efficacy. A role for beta-carbolines, which can form endogenously from tryptamine, is also supported by the present findings.

Allosteric modulation of semicarbazide‐sensitive amine oxidase activities in vitro by imidazoline receptor ligands

“…Nevertheless, despite numerous physicochemical differences, these enzyme classes share many substrates and inhibitors, and perhaps some functions ( Lyles, 1984 ; 1996 ; Callingham et al ., 1991 ). For example, chronic inhibition of both activities in vivo results in a downregulation of rat brain I 1 R, presumably as a result of a prolonged increase in the levels of an endogenous I 1 R agonist that is also a substrate for both MAO and SSAO ( Holt et al ., 2003 ).…”

“…A few other enzymes also show affinity for I 2 BS ligands, including several amine oxidases of the EC 1.4.3.6 subclass ( Carpéné et al ., 1995 ; Holt & Baker, 1995 ; Holt et al ., 2003 ). This family of copper‐containing amine oxidases includes diamine oxidase, plasma amine oxidases and tissue‐bound semicarbazide‐sensitive amine oxidase (SSAO) ( Callingham et al ., 1991 ).…”

Mammalian central nervous system trace amines. Pharmacologic amphetamines, physiologic neuromodulators

“…Here, β‐carbolines selectively attenuated neuronal responses to GABA, while having no effect on responses to either glutamate or 5‐HT (Paterson 1985). The possibility that some of the trace amine receptors are synonymous with previously described imidazoline binding sites, for which tryptamine and β‐carbolines are ligands, was recently highlighted (Holt et al . 2003).…”

“…Here, b-carbolines selectively attenuated neuronal responses to GABA, while having no effect on responses to either glutamate or 5-HT (Paterson 1985). The possibility that some of the trace amine receptors are synonymous with previously described imidazoline binding sites, for which tryptamine and b-carbolines are ligands, was recently highlighted (Holt et al 2003). As research into the basic mechanisms involved in trace amine function progresses, the potential clinical utility of trace amine receptor agonists and antagonists will be considerably clarified.…”

The Potential of Trace Amines and Their Receptors for Treating Neurological and Psychiatric Diseases

“…Likewise, MAO-B is well documented to be present in a number of extraneuronal peripheral tissues including platelets (see [16] and references therein). In this respect, it is also worth noting that a number of other amine oxidases are present in the plasma and the trace amines are substrates for at least some of these [17]. The relevance of such extraneuronal synthesis and metabolism of trace amines to their neuronal functioning has not been specifically studied and will not be considered further here.…”