Relevance of Imidazoline Receptors and Agmatine to Psychiatry: A Decade of Progress

Abstract

The cardiovascular relevance of imidazoline receptors (IR) has received tremendous attention since their discovery in 1984. However, evidence also has accumulated for the relevance of IR and an endogenous ligand, agmatine, to psychiatric disease. Emphasis has been placed on altered levels of the I(1)-imidazoline site on human platelets and in human postmortem brain tissue from depressed patients. Attempts at exploring the molecular nature of the I(1) protein have led to the cloning of a protein, IRAS. Based on transfection studies, IRAS seems to be involved in neuronal plasticity events. The I(2) site also appears linked to psychiatric research since some of these sites are localized to a specific domain on monoamine oxidases. Different peptides have been identified by means of an imidazoline-receptor-binding-protein (IRBP) antiserum, and these peptides, some of which appear to be fragments derived from IRAS, undergo changes in platelets and brain commensurate with altered mood states of the subject, notably depressive symptomatology. The search for an endogenous ligand for imidazoline receptor(s) also has led to agmatine, a decarboxylated derivative of arginine. Research on agmatine has mushroomed over the past several years and its measurement in the blood and brain has opened new research opportunities. This novel neurotransmitter interacts with a variety of receptors and has been implicated in mediation of stress responses, analgesia, drug addiction and withdrawal, convulsions, and neuroprotection. Given that IR and agmatine appear involved in a multitude of neurophysiologic and pathologic functions, the potential for new drug development is intriguing.

Platelet imidazoline receptors as state marker of depressive symptomatology

“…IRAS interacts with a number of membranous receptors, such as the mu-opioid receptor, of relevance to mood disorders Piletz et al, 2000a;Wu et al, 2005). Exactly how IR-1 transduces signal is an area of active research, but one suggestion is that IR-1 modulates the shape of cells through interaction with integrins (Halaris et al, 2003). Furthermore, IR-1 inhibit neurotransmitter release in some neurons, similar to the manner of α 2 -adrenoceptors.…”

“…2000;Piletz, Halaris, & Ernsberger, 1994;Schittecatte et al, 2002). Other α 2 -adrenergic radioligands and molecular probes had been utilized (Garcia-Sevilla et al, 1999), but most findings for up-regulated α 2 -adrenoceptors have used clonidine (Halaris et al, 2003). Hence the question: What makes clonidine unique?…”

“…A number of early studies had shown increased platelet α 2 -adrenoceptors in depression (Garcia-Sevilla, 1989;Garcia-Sevilla et al 1986). Yet, an equal number of negative studies now exist of platelet α 2 -adrenoceptors in depression, and it has been documented that most of the earlier positive studies had utilized clonidine as radioligand (Fu et al, 2001;Garcia-Sevilla et al, 1999;Halaris et al, 2003;Mokrani et a. 2000;Piletz, Halaris, & Ernsberger, 1994;Schittecatte et al, 2002).…”

“…Although clonidine and structurally related compounds have high affinity for α 2 -adrenoceptors, these imidazoline compounds also have high affinity for the IR-1 subtype of IR (Piletz, Zhu, & Chikkala, 1996c). Several endogenous compounds have been proposed as putative neurotransmitters for IR: agmatine, harmane, and imidazole-ribotide (Halaris & Piletz, 2003;Musgrave & Badoer, 2000;Prell et al, 2004). None of the classical monoamines have substantial affinity for IR (Bousquet, 1997).…”

“…None of the classical monoamines have substantial affinity for IR (Bousquet, 1997). Imidazoline receptors have been linked to neuroplasticity (Piletz, Wang, & Zhu, 2003b), have been postulated to be a possible state marker for depression (Halaris et al, 2003), and may be a target for anxiolytic drug action (Zhu, Paul, Stec, Peeler, & Piletz, 2003b).…”