Behavioral, neuroendocrine and neurochemical effects of the imidazoline I2 receptor selective ligand BU224 in naive rats and rats exposed to the stress of the forced swim test

Finn, David P.; Martı́, Octavi; Harbuz, Michael S.; Vallès, Astrid; Belda, Xavier; Márquez, Cristina; Jessop, David S.; Lalies, Margaret D.; Armario, Antonio; Nutt, David; Hudson, Alan L.

doi:10.1007/s00213-003-1392-3

Cited by 49 publications

(31 citation statements)

References 62 publications

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“…Water depth was 40 cm, and temperature was maintained at 23 Ϯ 1°C. Stress exposure was always commenced at 9:00 A.M., when the plasma corticosterone levels are low (Finn et al, 2003, Krugers et al, 2005.…”

Section: Methodsmentioning

confidence: 99%

Differential Modulation of Long-Term Depression by Acute Stress in the Rat Dorsal and Ventral Hippocampus

Maggio

Segal²

2009

Journal of Neuroscience

112

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The ventral hippocampus (VH) was recently shown to express lower-magnitude long-term potentiation (LTP) than the dorsal hippocampus (DH). An exposure to acute stress reversed this difference, and VH slices from stressed rats expressed larger LTP than controls, whereas LTP in the DH was suppressed by stress. We have now used long-term depression (LTD)-generating trains of stimulation to examine whether this differential LTP reflects a genuine difference in synaptic modifiability between the two sectors of the hippocampus. Surprisingly, slices of DH and VH express similar magnitudes of LTD. However, while prior stress enhanced LTD in the DH, it actually converted LTD to slow-onset, robust LTP in the VH. These two effects of stress on LTD were blocked by glucocorticosterone receptor (GR) and mineralocorticosterone receptor (MR) antagonists, respectively. Acute exposure of slices to a GR agonist dexamethasone facilitated LTD in slices of both DH and VH, while activation of MRs by aldosterone converted LTD to LTP in both regions. Thus, differential activation of the two species of corticosterone receptors determines the ability of the two sectors of the hippocampus to undergo plastic changes in response to LTD-inducing stimulation.

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Section: Methodsmentioning

confidence: 99%

Differential Modulation of Long-Term Depression by Acute Stress in the Rat Dorsal and Ventral Hippocampus

Maggio

Segal²

2009

Journal of Neuroscience

112

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“…Additionally, I 2 sites have been linked to several central nervous system disorders for which changes in the binding density have been observed in postmortem brain tissue. These include depression (5,6), addiction (7), glial tumor (8)(9)(10), and neurodegenerative disorders such as Alzheimer's disease (11) and Huntington's chorea (12). An in vivo imaging probe to study I 2 sites in living tissue would therefore prove invaluable in further delineating the precise physiologic role of these binding sites in healthy and disease states.…”

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confidence: 99%

Imaging Imidazoline-I₂ Binding Sites in Porcine Brain Using ¹¹C-BU99008

et al. 2012

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Changes in the density of imidazoline-I 2 binding sites have been observed in a range of neurologic disorders including Alzheimer's disease, Huntington's chorea, and glial tumor; however, the precise function of these sites remains unclear. A PET probe for I 2 binding sites would further our understanding of the target and may find application as a biomarker for early disease diagnosis. Compound BU99008 has previously been identified as a promising I 2 ligand from autoradiography studies, displaying high affinity and good selectivity toward the target. In this study, BU99008 was radiolabeled with 11 C in order to image the I 2 binding sites in vivo using PET. Methods: 11 C-BU99008 was radiolabeled by N-alkylation of the desmethyl precursor using 11 C-methyl iodide. A series of PET experiments was performed to investigate the binding of 11 C-BU99008 in porcine brains, in the presence or absence of a nonradiolabeled, competing I 2 ligand, BU224. Results: 11 C-BU99008 was obtained in good yield and specific activity. In vivo, 11 C-BU99008 displayed good brain penetration and gave a heterogeneous distribution with high uptake in the thalamus and low uptake in the cortex and cerebellum. 11 C-BU99008 brain kinetics were well described by the 1-tissue-compartment model, which was used to provide estimates for the total volume of distribution (V T ) across brain regions of interest. Baseline V T values were ranked in the following order: thalamus . striatum . hippocampus . frontal cortex $ cerebellum, consistent with the known distribution and concentration of I 2 binding sites. Administration of a selective I 2 binding site ligand, BU224, reduced the V T to near-homogeneous levels in all brain regions. Conclusion: 11 C-BU99008 appears to be a suitable PET radioligand for imaging the I 2 binding sites in vivo.

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“…Preclinical studies have shown that harmane exhibits anxiolytic and anti-depressant properties [120], which was also projected by I 2 -BS ligands [11,70,121]. In restraint-stressed rats, harmane and BU224 treatment elevated Fos expression in distinct brain regions in a comparable manner; emphasizing the overlap of these molecules for the same target site [12].…”

Section: Harmane -The Endogenous Ligand At Imidazoline Binding Sites?mentioning

confidence: 99%

“…In addition, the immunoreactivity of the I 1 -BS protein candidate IRAS, as well as the proposed 29/30 kD I 2 -BS protein, were also notably changed in platelets and brains of depressed suicide victims in comparison to healthy subjects [66,67]. In preclinical studies, selective I 2 -BS compounds such as 2-BFI and BU224 exhibited antidepressant activity by regulating central monoamine levels [68,69] and increasing mobility time in the Porsolt forced swim paradigm [11,70,71]. Behaviour analyses showed that agmatine along with I-BS ligands (2-BFI, moxonidine and clonidine) mediated the antidepressant like effects of selective serotonin reuptake inhibitors (SSRIs).…”

Section: Imidazoleacetic Acid Ribotide Agmatinementioning

confidence: 99%

“…These findings along with the structure-affinity relationship of harmane binding to I 1 -BS propose that harmane is a ligand at I 1 -BS. In the rat central nervous system (CNS), harmane has been shown to modulate monoamine turnover [103] in a comparable manner to selective I 2 -BS ligands such as 2-BFI and BU224 [68,70]. The regulation of central monoamine levels by harmane and I 2 -BS compounds was proposed to occur partially through MAO inhibition [104].…”

Section: Harmane -The Endogenous Ligand At Imidazoline Binding Sites?mentioning

confidence: 99%

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Borne Identity: Leading Endogenous Suspects at Imidazoline Binding Sites

Ghazaleh¹,

Tyacke²,

Hudson³

2015

J Neurol Neurosci

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The imidazoline binding sites (I-BS) represent a heterogenous family of receptors/sites that stemmed from studies investigating the hypotensive effect of the imidazoline compound clonidine [1]. Structure-affinity relationship studies complemented by functional analyses characterised three types of I-BS, denoted I 1 -BS, I 2 -BS (I 2A and I 2B ) and I 3 -BS [2]. Extensive research has established the involvement of central I 1 -BS in cardiovascular function [3]. Other reported functions include alleviating symptoms associated with metabolic syndrome X [4] and Huntington's Disease [5], promoting natriuresis [6], regulating intraocular pressure [7], and modulating mRNA expression for phenylethanolamine N-methyl transferase (PNMT) [8]. Furthermore, the expression of these sites was shown to be altered in conditions such as depression [9] and dysphoric premenstrual syndrome [10] AbstractOver the past few years, a vast amount of research has shed light on the pharmacology of imidazoline binding sites (I-BS). To date, at least three classes of imidazoline binding sites have been characterised in accordance to their localisation, drug selectivity, proposed signalling pathways and functional roles. The existence of these sites raises the question as to whether an endogenous modulator exists. The identification of an endogenous extract denoted as clonidine displacing substance prompted the search for the active ingredient capable of mimicking the action of selective ligands at these sites. A number of candidates have been isolated and their functional activities have been assessed at these sites. Such endogenous ligands include agmatine, imidazoleacetic acid ribotide and the β-carboline harmane. As of yet, no consensus has been made to confirm the identity of the endogenous ligand at I-BS. The current review collates and reports what is known about these substances and their functional significance at I-BS.

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Behavioral, neuroendocrine and neurochemical effects of the imidazoline I2 receptor selective ligand BU224 in naive rats and rats exposed to the stress of the forced swim test

Abstract: The selective I(2) receptor ligand BU224 reduces immobility of rats in the FST, indicative of antidepressant-like activity. This effect is accompanied by alterations in HPA axis and central monoaminergic activity.

Cited by 49 publications

References 62 publications

Differential Modulation of Long-Term Depression by Acute Stress in the Rat Dorsal and Ventral Hippocampus

Differential Modulation of Long-Term Depression by Acute Stress in the Rat Dorsal and Ventral Hippocampus

Imaging Imidazoline-I₂ Binding Sites in Porcine Brain Using ¹¹C-BU99008

Borne Identity: Leading Endogenous Suspects at Imidazoline Binding Sites

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Behavioral, neuroendocrine and neurochemical effects of the imidazoline I2 receptor selective ligand BU224 in naive rats and rats exposed to the stress of the forced swim test

Abstract: The selective I(2) receptor ligand BU224 reduces immobility of rats in the FST, indicative of antidepressant-like activity. This effect is accompanied by alterations in HPA axis and central monoaminergic activity.

Cited by 49 publications

References 62 publications

Differential Modulation of Long-Term Depression by Acute Stress in the Rat Dorsal and Ventral Hippocampus

Differential Modulation of Long-Term Depression by Acute Stress in the Rat Dorsal and Ventral Hippocampus

Imaging Imidazoline-I2 Binding Sites in Porcine Brain Using 11C-BU99008

Borne Identity: Leading Endogenous Suspects at Imidazoline Binding Sites

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Imaging Imidazoline-I₂ Binding Sites in Porcine Brain Using ¹¹C-BU99008