Imidazoline binding sites mediates anticompulsive-like effect of agmatine in marble-burying behavior in mice

Dixit, Madhura P.; Thakre, Prajwal P.; Pannase, Akshay S.; Aglawe, Manish M.; Taksande, Brijesh G.; Kotagale, Nandkishor R.

doi:10.1016/j.ejphar.2014.02.045

Cited by 26 publications

(16 citation statements)

References 61 publications

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“…While the ANS is known to involve cortical and subcortical circuits, our understanding of how these regions are integrated to affect behavior (Benarroch, 1993; Verberne and Owens, 1998; Saper, 2002; Beissner et al, 2013) are not fully understood. With the exception of thigmotaxis, in which there was no significant difference, CKO mice display reduced anxiety behaviors, including more time in the open arms of the EPM (Espejo, 1997; Sorregotti et al, 2013), more head dips over the apparatus edge during the cliff avoidance task (Soares et al, 2013) and apparent indifference to foreign objects in the marble burying paradigm (Dixit et al, 2014; Kedia and Chattarji, 2014). Consistent with the decreased anxiety exhibited by the CKO mice, our morphometric analysis also revealed that the lateral amygdaloid nucleus was reduced in the CKO brain.…”

Section: Discussionmentioning

confidence: 99%

The Familial Dysautonomia disease gene,Ikbkap/Elp1, is required in the developing and adult central nervous system

Chaverra

George

Mergy

et al. 2017

Disease Models &Amp; Mechanisms

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Hereditary sensory and autonomic neuropathies (HSANs) are a genetically and clinically diverse group of disorders defined by peripheral nervous system (PNS) dysfunction. HSAN type III, known as familial dysautonomia (FD), results from a single base mutation in the gene IKBKAP that encodes a scaffolding unit (ELP1) for a multi-subunit complex known as Elongator. Since mutations in other Elongator subunits (ELP2 to ELP4) are associated with central nervous system (CNS) disorders, the goal of this study was to investigate a potential requirement for Ikbkap in the CNS of mice. The sensory and autonomic pathophysiology of FD is fatal, with the majority of patients dying by age 40. While signs and pathology of FD have been noted in the CNS, the clinical and research focus has been on the sensory and autonomic dysfunction, and no genetic model studies have investigated the requirement for Ikbkap in the CNS. Here, we report, using a novel mouse line in which Ikbkap is deleted solely in the nervous system, that not only is Ikbkap widely expressed in the embryonic and adult CNS, but its deletion perturbs both the development of cortical neurons and their survival in adulthood. Primary cilia in embryonic cortical apical progenitors and motile cilia in adult ependymal cells are reduced in number and disorganized. Furthermore, we report that, in the adult CNS, both autonomic and non-autonomic neuronal populations require Ikbkap for survival, including spinal motor and cortical neurons. In addition, the mice developed kyphoscoliosis, an FD hallmark, indicating its neuropathic etiology. Ultimately, these perturbations manifest in a developmental and progressive neurodegenerative condition that includes impairments in learning and memory. Collectively, these data reveal an essential function for Ikbkap that extends beyond the peripheral nervous system to CNS development and function. With the identification of discrete CNS cell types and structures that depend on Ikbkap, novel strategies to thwart the progressive demise of CNS neurons in FD can be developed.

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Section: Discussionmentioning

confidence: 99%

The Familial Dysautonomia disease gene,Ikbkap/Elp1, is required in the developing and adult central nervous system

Chaverra

George

Mergy

et al. 2017

Disease Models &Amp; Mechanisms

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“…1a; Angoa-Pérez et al, 2013;Jimenez-Gomez et al, 2011;Thomas et al, 2009), sawdust (Supplementary Fig. 1b;Bruins Slot et al, 2008;Dixit et al, 2014;Harasawa et al, 2006;Krass, Rünkorg, Wegener, & Volke, 2010), wood chips (Supplementary Fig. 1c; Llaneza & Frye, 2009;Londei et al, 1998;Saadat, Elliott, Colado, & Gree, 2006;Thomas et al, 2009), wood shavings (Supplementary Fig.…”

Section: Burying Substrate and Its Relation To Marble Sizementioning

confidence: 99%

“…Arena size is important because the Bdensity^of marbles spread across the bedding material surface, depending on the number of marbles used, would differ between smaller and larger arenas. Betweenlaboratory differences in this regard may significantly influence behavioral performance and the subsequent interpretation of data, especially in experimental paradigms employing a 1Z setup (Badgujar & Surana, 2010;Bruins Slot et al, 2008;Dixit et al, 2014). In experiments in which the possibility to avoid exposure to marbles is undesirable (1Z condition), large between-marble spaces may undermine the purpose of the investigation, as is evident when comparing the ratios of floor space to marbles reported in the literature.…”

Section: Arena Sizementioning

confidence: 99%

A critical inquiry into marble-burying as a preclinical screening paradigm of relevance for anxiety and obsessive–compulsive disorder: Mapping the way forward

Brouwer

Fick

Harvey

et al. 2018

Cogn Affect Behav Neurosci

126

111

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Rodent marble-burying behavior in the marble-burying test (MBT) is employed as a model or measure to study anxiety-and compulsive-like behaviors or anxiolytic and anticompulsive drug action. However, the test responds variably to a range of pharmacological interventions, and little consensus exists regarding specific methodologies for its execution. Regardless, the test is widely applied to investigate the effects of pharmacological, genetic, and behavioral manipulations on purported behaviors related to the said neuropsychiatric constructs. Therefore, in the present review we attempt to expound the collective translational significance of the MBT. We do this by (1) reviewing burying behavior as a natural behavioral phenotype, (2) highlighting key aspects of anxiety and obsessive-compulsive disorder from a translational perspective, (3) reviewing the history and proof of concept of the MBT, (4) critically appraising potential methodological confounds in execution of the MBT, and (5) dissecting responses of the MBT to various pharmacological interventions. We conclude by underlining that the collective translational value of the MBT will be strengthened by contextually valid experimental designs and objective reporting of data.

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“…In contrast, cardiovascular studies demonstrated that central administration of agmatine into the RVLM did not reproduce the central actions of clonidine on arterial blood pressure [54]. In behavioural studies, agmatine was shown to promote anticompulsive-like effects similarly to I 1 -BS and I 2 -BS selective ligands and was blocked by their respective I-BS antagonists [55]. Moreover, intracerebroventricular administration of agmatine in mice and rats produced an elevation in morphine, ethanol and nicotine induced antinociception; which was also observed with agmatine and the selective I 2 -BS agonists 2-BFI [15, 56,57] and more notably CR4056, which is currently underway for Phase II clinical trials [15].…”

Section: Imidazoleacetic Acid Ribotide Agmatinementioning

confidence: 96%

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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Imidazoline binding sites mediates anticompulsive-like effect of agmatine in marble-burying behavior in mice

Cited by 26 publications

References 61 publications

The Familial Dysautonomia disease gene,Ikbkap/Elp1, is required in the developing and adult central nervous system

The Familial Dysautonomia disease gene,Ikbkap/Elp1, is required in the developing and adult central nervous system

A critical inquiry into marble-burying as a preclinical screening paradigm of relevance for anxiety and obsessive–compulsive disorder: Mapping the way forward

Borne Identity: Leading Endogenous Suspects at Imidazoline Binding Sites

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