Differential in vivo effects of H3 receptor ligands in a new mouse dipsogenia model

Fox, Gerard B.; Pan, Jia Bao; Esbenshade, Timothy A.; Bitner, Robert S.; Nikkel, Arthur L.; Miller, Tom; Kang, Chae Hee; Bennani, Youssef L.; Black, Lawrence A.; Faghih, Ramin; Hancock, Arthur A.; Decker, Michael

doi:10.1016/s0091-3057(02)00745-1

Cited by 44 publications

(29 citation statements)

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“…Accordingly, rats that received systemic administrations of proxyfan showed a stronger response to the footshock-context association, as they spent more time freezing in the retention test. Full agonism of proxyfan was observed also in the cat, where it significantly increased deep slow-wave sleep, without affecting wakefulness, whereas in the mouse proxyfan behaved as a full inverse agonist (Gbahou et al, 2003), mimicking the arousal effect of the antagonist/inverse agonist ciproxifan (Parmentier et al, 2002), and as a partial agonist in the dipsogenia model (Fox et al, 2002b). Presumably, the agonist effect of proxyfan in our model implies that in the rat amygdala H 3 receptors are predominantly in a quiescent state and constitutive activity has a low efficacy.…”

Section: Discussionmentioning

confidence: 90%

“…Little is known of the behavioural effects of proxyfan. In a dipsogenia test in mice proxyfan behaves as an antagonist/partial agonist (Fox et al, 2002b). Furthermore, proxyfan modulates the sleep-wake cycle in a different manner depending on the animal species (Gbahou et al, 2003), hence depending on the conformation of the receptors and their constitutive activity.…”

Section: Introductionmentioning

confidence: 99%

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The H3 receptor protean agonist proxyfan enhances the expression of fear memory in the rat

et al. 2005

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Consolidation of fear memory requires neural changes to occur in the basolateral amygdala (BLA), including modulation of histaminergic neurotransmission. We previously demonstrated that local blockade or activation of histamine H 3 receptors in the BLA impaired or ameliorated, respectively, retention of fear memory. The histamine H 3 receptor is a G-protein-coupled receptor (GPCR) displaying high constitutive activity that regulates histamine neurons in the brain. Proxyfan is a high-affinity histamine H 3 receptor protean agonist exhibiting the full spectrum of pharmacological activities, from full agonist to full inverse agonist depending on the competition between constitutively active and quiescent H 3 receptors in a given tissue or brain region. Therefore, protean agonists are powerful tools to investigate receptor conformation and may be useful in designing specific compounds selective for the various receptor conformations. In the present study we examined the effect of post-training, systemic or intra-BLA injections of proxyfan on contextual fear memory. Rats receiving intra-BLA, bilateral injections of 1.66 ng proxyfan immediately after fear conditioning showed stronger memory for the context-footshock association, as demonstrated by longer freezing assessed at retention performed 72 hr later compared to controls. Comparable results were obtained when doses as low as 0.04 mg/kg of proxyfan were injected systemically. Hence, our results suggest that proxyfan behaves as an H 3 receptor agonist with a low level of constitutive activity of the H 3 receptor in the rat BLA.

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Section: Discussionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

The H3 receptor protean agonist proxyfan enhances the expression of fear memory in the rat

et al. 2005

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“…(R)-a-Methylhistamine does have significant H 4 receptor activity (binding pK i of 6.85, human H 4 receptor in transfected cells) (Liu et al, 2001a,b;Morse et al, 2001) and pK i = 6.1 at rat H 4 receptor. This agonist also induces water drinking in rodents, a finding used as the basis of an in vivo pharmacological model (Clapham and Kilpatrick, 1993;Ligneau et al, 1998;Fox et al, 2002). Prodrugs of (R)-a-methylhistamine have been described with an improved pharmacokinetic profile (Krause et al, 2001;Stark et al, 2001).…”

Section: E H 3 -Selective Ligandsmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

et al. 2015

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“…Functional Activity: Dipsogenia Mice were tested for blockade of H 3 R agonist-induced water intake in a dipsogenia model as previously described (Fox et al, 2002b). Briefly, each mouse was injected i.p.…”

Section: Downloaded Frommentioning

confidence: 99%

“…on the opposite side of the abdomen, and the mice were returned to their respective home cages. After 30 min, mice were individually placed into shoe box cages with access to water at the back of the cage via a modified sipper (Fox et al, 2002b). The mice remained in these cages in a quiet room for a further 30 min, after which they were removed to their home cages once again; the amount of water consumed was then measured from the modified sippers to the nearest 0.01 ml.…”

Section: Downloaded Frommentioning

confidence: 99%

Pharmacological Properties of ABT-239 [4-(2-{2-[(2R)-2-Methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile]: II. Neurophysiological Characterization and Broad Preclinical Efficacy in Cognition and Schizophrenia of a Potent and Selective Histamine H₃ Receptor Antagonist

Fox

Esbenshade²,

Pan³

et al. 2004

J Pharmacol Exp Ther

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Acute pharmacological blockade of central histamine H 3 receptors (H 3 Rs) enhances arousal/attention in rodents. However, there is little information available for other behavioral domains or for repeated administration using selective compounds. ABT-239 [4-(2-{2-[(2R)-2-methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile] exemplifies such a selective, nonimidazole H 3 R antagonist with high affinity for rat (pK i ϭ 8.9) and human (pK i ϭ 9.5) H 3 Rs. Acute functional blockade of central H 3 Rs was demonstrated by blocking the dipsogenia response to the selective H 3 R agonist (R)-␣-methylhistamine in mice. In cognition studies, acquisition of a five-trial, inhibitory avoidance test in rat pups was improved with ABT-239 (0.1-1.0 mg/kg), a 10-to 150-fold gain in potency, with similar efficacy, over previous antagonists such as thioperamide, ciproxifan, A-304121 [(4-(3-(4 -furamide], and A-349821 [(4Ј-(3-((R,R)2,5-dimethyl-pyrrolidin-1-yl)-propoxy)-biphenyl-4-yl)-morpholin-4-yl-methanone]. Efficacy in this modelwas maintained for 3 to 6 h and following repeated dosing with ABT-239. Social memory was also improved in adult (0.01-0.3 mg/kg) and aged (0.3-1.0 mg/kg) rats. In schizophrenia models, ABT-239 improved gating deficits in DBA/2 mice using prepulse inhibition of startle (1.0 -3.0 mg/kg) and N40 (1.0 -10.0 mg/kg). Furthermore, ABT-239 (1.0 mg/kg) attenuated methamphetamineinduced hyperactivity in mice. In freely moving rat microdialysis studies, ABT-239 enhanced acetylcholine release (0.1-3.0 mg/kg) in adult rat frontal cortex and hippocampus and enhanced dopamine release in frontal cortex (3.0 mg/kg), but not striatum. In summary, broad efficacy was observed with ABT-239 across animal models such that potential clinical efficacy may extend beyond disorders such as ADHD to include Alzheimer's disease and schizophrenia.

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Differential in vivo effects of H3 receptor ligands in a new mouse dipsogenia model

Cited by 44 publications

References 16 publications

The H3 receptor protean agonist proxyfan enhances the expression of fear memory in the rat

The H3 receptor protean agonist proxyfan enhances the expression of fear memory in the rat

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

Pharmacological Properties of ABT-239 [4-(2-{2-[(2R)-2-Methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile]: II. Neurophysiological Characterization and Broad Preclinical Efficacy in Cognition and Schizophrenia of a Potent and Selective Histamine H₃ Receptor Antagonist

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Differential in vivo effects of H3 receptor ligands in a new mouse dipsogenia model

Cited by 44 publications

References 16 publications

The H3 receptor protean agonist proxyfan enhances the expression of fear memory in the rat

The H3 receptor protean agonist proxyfan enhances the expression of fear memory in the rat

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

Pharmacological Properties of ABT-239 [4-(2-{2-[(2R)-2-Methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile]: II. Neurophysiological Characterization and Broad Preclinical Efficacy in Cognition and Schizophrenia of a Potent and Selective Histamine H3 Receptor Antagonist

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Pharmacological Properties of ABT-239 [4-(2-{2-[(2R)-2-Methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile]: II. Neurophysiological Characterization and Broad Preclinical Efficacy in Cognition and Schizophrenia of a Potent and Selective Histamine H₃ Receptor Antagonist