Modulation of stress by imidazoline binding sites: Implications for psychiatric disorders

Figures & data

Figure 1 (A) Schematic depicting expression of imidazoline binding sites in the rat brain as determined by receptor autoradiography using [³H]BU224 (I₂ selective ligand), [³H]2BFI (I₂ selective ligand) and [³H] rilmenidine (I₁ selective ligand). The regions highlighted have been shown to express a moderate to high density of imidazoline binding sites (King et al. 1995; Lione et al. 1998; Robinson et al. 2002; Tyacke et al. 2002). The figure also summarises the effects of imidazoline binding site activation on neuronal firing and terminal release of monoamines in these regions. I₁ (red) and I₂ (blue) binding sites are colocalised (purple) in some brain regions. (B) Schematic depicting [³H]harmane binding (green) in discrete rat brain regions and the effects of harmane administration on neuronal firing and terminal release of monoamines in these regions. Harmane is a putative endogenous IBS ligand. Abbreviations used: 5-HT, serotonin; AP, area postrema; Arc, arcuate nucleus; CG, central grey; Cx, Cortex; DR, dorsal raphe; DM, dorsomedial hypothalamic nucleus; Fr, frontal cortex; ICV, intracerebroventricular; IP, interpeduncular nucleus; LC, locus coeruleus; LM, lateral mammillary nucleus; LS, lateral septal nucleus; MHb, medial habenular nucleus; NA, noradrenaline; Occ, occipital cortex; Pi, pineal gland; PVN, paraventricular nucleus (hypothalamus); Sol, nucleus of the solitary tract; SuG, superficial gray layer of the superior colliculus; VMH, ventromedial hypothalamic nucleus and 12, hypoglossal nucleus.

Table I.  Modulation of brain monoamine activity by IBS ligandsa in rodents in vivo.

Ligand	Pharmacology	Action	Brain region	References
Harmane	Endogenous	↑ noradrenergic firing	Locus coeruleus	Ruiz-Durantez et al. (2001)
		↓ serotoninergic firing	Dorsal raphe	Touiki et al. (2005); Ugedo et al. (1998)
		↑ serotonin	Hippocampus	Adell et al. (1996)
		↑ serotonin and dopamine	Nucleus accumbens	Baum et al. (1996)
		spontaneous neuronal activity		Ergene and Schoener (1993)
BU224	I2 ligand	↑ noradrenaline	PVN	Finn et al. (2002)
		↑ noradrenaline	Frontal Cortex and hippocampus	Hudson et al. (1999); Nutt et al. (1997)
		↓ noradrenaline turnover	Frontal Cortex	Finn et al. (2003)
		↓ serotonin turnover	Hippocampus and hypothalamus	Finn et al. (2003)
2-BFI	I2 ligand	↑ noradrenaline	Frontal cortex and hippocampus	Nutt et al. (1995)
		↑ noradrenergic firing	Locus coeruleus	Ugedo et al. (1998)
		↑ noradrenaline	Striatum	Sastre-Coll et al. (2001)
BU98008	I2 ligand	↑ noradrenaline and ↑ dopamine overflow	Frontal cortex	Abu Ghazaleh et al. (2007)
Clonidine with EEDQ pre-treatment	I1/I2 ligand	↑ noradrenergic firing	Locus coeruleus	Pineda et al. (1993)
		↓ DOPA, 5-HTP synthesis	Cerebral cortex, hippocampus	Sastre-Coll et al. (1999)
			Striatum
Moxonidine	I1 agonist	↓ DOPA, 5-HTP synthesis	Cerebral cortex	Sastre-Coll et al. (1999)
			Hippocampus
Rilmenidine	I1 agonist	↑ neuronal activation	Brain	Pineda et al. (1993)
		↓ DOPA synthesis	Striatum	Sastre-Coll et al. (1999)
		↓ 5-HTP synthesis	Cerebral cortex
Cirazoline	I1 agonist	↑ neuronal activation	Brain	Pineda et al. (1993)
Efaroxan	I1 antagonist	↓ 5-HT synthesis	Hippocampus & Cerebral cortex	Sastre-Coll et al. (1999)

Increased understanding of the pharmacology and signal transduction mechanisms associated with I₁ IBS permits the designation of pharmacological activity (agonist/antagonist) to the majority of I₁ IBS selective compounds. In contrast, I₂ IBS pharmacology and signalling mechanisms are less well understood and it is therefore more difficult to assign pharmacological properties to I₂ compounds. However, similarities between the effects of I₂ ligands BU224, 2BFI and BU99066 with those of the endogenous ligand harmane, together with supporting evidence (Diaz et al. 1997; Sanchez-Blazquez et al. 2000), suggest that these ligands may be agonistic in nature.

Figure 2 Effect of systemic (i.p., imraperitoneal) administration of the selective I₂ IBS ligand, BU224, on (A) extracellular levels of NA in the hypothalamic PVN region and (B) plasma corticosterone concentrations in control rats and rats with adjuvant-induced arthritis (AA; a chronic stressor). Values are expressed as means ± s.e.m. **p < 0.01, *p < 0.05 comparing post-injection levels with basal levels in the Con + BU224 group; ⁺p < 0.05, ⁺⁺p < 0.01 comparing post-injection levels with basal levels in the AA + BU224 group; ^$p < 0.05 comparing AA + BU224 with Con + BU224 group at 60 min. Con, Control; Sal, Saline vehicle. Reproduced with permission from Finn et al. (2002).

Figure 3 Effects of the selective I₂ binding site ligand BU224 (10 mg/kg, i.p.) on plasma corticosterone concentrations in control and restraint-stressed rats. Results are expressed as means ± s.e.m. (n = 5–7). **p < 0.01 and ⁺⁺p < 0.01 compared with saline-treated controls at 30 and 60 min, respectively. ^‡p < 0.05 and ^†p < 0.01 compared with BU224-treated controls (not restrained) at 30 and 60 min, respectively. ^$$p < 0.05 compared with saline-treated restrained rats at 60 min. Sal + Con, Saline + Control (no restraint); BU + Con: BU224 + Control; Sal + Res, Saline + Restraint; and BU + Res, BU224 + Restraint. Reproduced with permission from Finn et al. (2004).

Table II.  Modulation of stress hormones by IBS ligands.

Ligand	Pharmacology	Species	Action on HPA axis	References
BU224	Ligand	Rat	↑ plasma ACTH	Finn et al. (2003)
		Rat	↑ plasma corticosterone	Finn et al. (2002, 2004)
		Human	↑ plasma ACTH and cortisol	Munoz-Hoyos et al. (2000)
Harmaline	Endogenous	Cat	↑ CRF expression	Cummings et al. (1994)
Idazoxan	I2 ligand	Rat	↑ plasma corticosterone	Finn et al. (2004)
		Human	↓ diurnal cortisol tone	Glue et al. (1992)
Clonidine	I1 ligand	Horse	↓ ACTH secretion	Alexander and Irvine (2000)
			↓ plasma ACTH and cortisol	Munoz-Hoyos et al. (2000)

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