Effects of idazoxan on catecholamine systems in rat brain

Walter, D.S.; Flockhart, Ian; Haynes, Margaret J.; Howlett, David; Lane, Anthony C.; Burton, Richard D. E.; Johnson, John D.; Dettmar, Peter W.

doi:10.1016/0006-2952(84)90623-3

Cited by 55 publications

(17 citation statements)

References 21 publications

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“…The mechanisms underlying the stimulatory effects of idazoxan on food intake presumably do not involve noradrenaline released following blockage of presynaptic a2-adrenoceptors (Walter et al, 1984;Dennis et al, 1987), since RX811059 and RX821002, which would also increase synaptic availability of noradrenaline, did not alter food intake. In accordance with these findings, the a2-adrenoceptor antagonist, yohimbine, does not increase food consumption in freely-feeding rats (Sanger, 1983).…”

Section: Discussionmentioning

confidence: 99%

The effects of idazoxan and other α₂‐adrenoceptor antagonists on food and water intake in the rat

Jackson

Griffin

Nutt

1991

British J Pharmacology

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1 Idazoxan (1, 3, l0mgkg-', i.p.) produced a significant increase in food and water intake in freely feeding rats during the daylight phase. 2 The more selective and specific a2-adrenoceptor antagonists, RX811059 (0.3, 1, 3 mgkg 1, i.p.) and RX821002 (0.3, 1, 3mg kg 1, i.p.), did not produce hyperphagia in rats, however, the highest dose produced a significant increase in water intake. 3 The peripherally acting a2-adrenoceptor antagonist, L-659,066 (1, 3, 10mgkg-1, i.p.), did not affect food intake in the 4h following injection, but the highest dose (l0mgkg '), produced a large increase in water intake. 4 These results indicate that a2-adrenoceptor antagonists may increase water intake by a peripherally mediated mechanism. 5 The lack of effect of RX811059 and RX821002 on food intake contrasts with the large dose-related increases induced by idazoxan and suggests that the hyperphagic effects of idazoxan are not due to a2-adrenoceptor blockade but may instead reflect its affinity for a non-adrenoceptor site, a property not shared by the other a2-antagonists.

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Section: Discussionmentioning

confidence: 99%

The effects of idazoxan and other α₂‐adrenoceptor antagonists on food and water intake in the rat

Jackson

Griffin

Nutt

1991

British J Pharmacology

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“…Idazoxan is a highly selective alpha-2-adrenoceptor antago nist that has no significant activity at opioid, histamine, acetyl choline, serotonin or dopamine receptors [ 15,48], It is far more selective in its action than the previously used antagonist, yo himbine, which also acts on alpha-1-adrenergic, dopaminergic and serotonergic receptors [16,22,48]. In the dose used in this study, idazoxan abolishes the sedative action of the alpha-2-adrenoceptor agonist clonidine in man, indicating that it exerts significant aIpha-2-adrenoceptor antagonist activity in the central nervous system [13], Idazoxan caused a small in crease in blood pressure and an accompanying bradycardia, which is compatible with its alpha-2-adrenoceptor antagonist activity.…”

Section: Discussionmentioning

confidence: 99%

The Role of Alpha-2-Adrenoceptors in the Control of ACTH Secretion; Interaction with the Opioid System

Al-Damluji

Bouloux²,

White³

et al. 1990

Neuroendocrinology

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This study examined the effects of an alpha-2-adrenoceptor antagonist on the secretion of ACTH basally and in response to the opioid antagonist naloxone, which is known to stimulate ACTH secretion by an adrenergic mechanism. Eight normal men were given, in double-blind, random order, intravenous infusions of normal saline (placebo), idazoxan (alpha-2-adrenoceptor antagonist), naloxone and the combination of idazoxan and naloxone. Naloxone increased plasma ACTH and cortisol concentrations in comparison to placebo. Idazoxan significantly enhanced the ACTH and cortisol responses to naloxone but had no effect on plasma ACTH or cortisol concentrations when given alone. These findings suggest that during some conditions of increased ACTH secretion, inhibitory alpha-2-adrenoceptors are activated and that these receptors limit the ACTH response. This provides an explanation for some of the apparent contradictions in interpreting the data from previous studies on the effects of catecholamines on the secretion of ACTH.

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“…However, other than its noradrenergic properties, yohimbine acts at other receptors including DA receptors (Scatton et al 1980) so that the role of α 2 -adrenoceptors in mediating the antidyskinetic effects of yohimbine is unclear. Conversely, idazoxan (K i = 3 nM) is over ten times more potent than yohimbine (K i = 40 nM) at inhibiting [ 3 H]clonidine binding at the α 2 sites in brain tissue (P. Ladure, personal communication; Walter et al 1984). The affinity of idazoxan for the α 2 binding site is approximately 50 times higher than its affinity for the α 1 sites (K i = 142 nM), with negligible affinity for DA receptors (K i >100 µM; P. Ladure, personal communication; Walter et al 1984).…”

Section: Introductionmentioning

confidence: 97%

“…Conversely, idazoxan (K i = 3 nM) is over ten times more potent than yohimbine (K i = 40 nM) at inhibiting [ 3 H]clonidine binding at the α 2 sites in brain tissue (P. Ladure, personal communication; Walter et al 1984). The affinity of idazoxan for the α 2 binding site is approximately 50 times higher than its affinity for the α 1 sites (K i = 142 nM), with negligible affinity for DA receptors (K i >100 µM; P. Ladure, personal communication; Walter et al 1984). Thus, in order to extend our previous findings on the potential antidyskinetic effect of α 2 -adrenoceptor antagonists, we tested if idazoxan would have a similar profile of action in reducing dyskinesias to yohimbine, and if so, whether this antidyskinetic effect would be maintained over time with repeated administrations in MPTPtreated cynomolgus monkeys presenting L-dopa-induced dyskinesias.…”

Section: Introductionmentioning

confidence: 97%

Noradrenoceptor antagonism with idazoxan improves l-dopa-induced dyskinesias in MPTP monkeys

Grondin

Tahar

Doan

et al. 2000

Naunyn-Schmiedeberg's Arch Pharmacol

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Treatment of Parkinson's disease with L-dopa is plagued in a majority of patients by dyskinesias. Noradrenaline/dopamine interactions are proposed on behavioral, biochemical, physiological and anatomical grounds. The aim of the study was to test the potential antidyskinetic effect of the alpha2-adrenoceptor antagonist, idazoxan, in a primate model of Parkinson's disease. Six female cynomolgus monkeys previously rendered parkinsonian by the toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and presenting an unchanged syndrome for several months were used. All responded readily to L-dopa but had developed dyskinesias which were manifested with each dose. In the first part of the study, seven doses of idazoxan (ranging from 0.25 mg/kg to 10 mg/kg, p.o.) were administered together with the vehicle or in combination with a fixed dose of L-dopa/benserazide (100/25 mg, p.o.). In the second part of the study, a fixed dose of idazoxan (7.5 mg/kg) was administered daily for 10 days and L-dopa was added to idazoxan on days 1, 4, 7 and 10. Vehicle (empty capsule) was used as control. Idazoxan, by itself (ranging from 5 mg/kg to 10 mg/kg), increased locomotor activity and improved the disability score with virtually no dyskinesias in three animals. In combination with L-dopa, idazoxan did not impair the antiparkinsonian response but significantly reduced dyskinesias in all six animals up to 65% at doses of 7.5 mg/kg and 10 mg/kg and delayed their onset, so that the "ON" state without dyskinesias was prolonged. The antidyskinetic effect of idazoxan was maintained when repeatedly administered for 10 days. On day 10, the locomotor response to L-dopa was significantly potentiated by chronic administration of idazoxan. Our results indicate that idazoxan has some antiparkinsonian effect of its own and may constitute a useful adjunct to L-dopa as it can reduce dyskinesias without impairing the relief of symptoms, this effect being maintained over time in this model.

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Effects of idazoxan on catecholamine systems in rat brain

Cited by 55 publications

References 21 publications

The effects of idazoxan and other α₂‐adrenoceptor antagonists on food and water intake in the rat

The effects of idazoxan and other α₂‐adrenoceptor antagonists on food and water intake in the rat

The Role of Alpha-2-Adrenoceptors in the Control of ACTH Secretion; Interaction with the Opioid System

Noradrenoceptor antagonism with idazoxan improves l-dopa-induced dyskinesias in MPTP monkeys

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Effects of idazoxan on catecholamine systems in rat brain

Cited by 55 publications

References 21 publications

The effects of idazoxan and other α2‐adrenoceptor antagonists on food and water intake in the rat

The effects of idazoxan and other α2‐adrenoceptor antagonists on food and water intake in the rat

The Role of Alpha-2-Adrenoceptors in the Control of ACTH Secretion; Interaction with the Opioid System

Noradrenoceptor antagonism with idazoxan improves l-dopa-induced dyskinesias in MPTP monkeys

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The effects of idazoxan and other α₂‐adrenoceptor antagonists on food and water intake in the rat

The effects of idazoxan and other α₂‐adrenoceptor antagonists on food and water intake in the rat