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Werner J. Schmidt - One of the best experts on this subject based on the ideXlab platform.
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serotonergic influence on the potentiation of d amphetamine and apomorphine induced rotational behavior by the α2 adrenoceptor antagonist 2 methoxy Idazoxan in hemiparkinsonian rats
Journal of Neural Transmission, 2005Co-Authors: J. Srinivasan, Werner J. SchmidtAbstract:The α2-adrenoceptor antagonists potentiate both ipsilateral and contralateral rotations induced by amphetamine and apomorphine respectively in hemiparkinsonian rats. The present study investigated the role of serotonergic transmission in this potentiation in unilaterally 6-hydroxydopamine nigral lesioned rats. D-amphetamine (0.5 mg/kg, i.p.) produced ipsilateral rotations, which were decreased by the dopamine receptor antagonist haloperidol (0.2 mg/kg, i.p.) and the α1-receptor antagonist prazosin (1 mg/kg, i.p.). The selective α2-antagonist 2-methoxy Idazoxan (0.2 mg/kg, i.p.) potentiated the amphetamine-induced ipsilateral rotations, that were attenuated by haloperidol and prazosin. The selective serotonin re-uptake inhibitor citalopram (10 mg/kg, i.p.) and selective serotonin synthesis inhibitor p-chlorophenylalanine (150 mg/kg, i.p., 3 days) decreased and increased the observed potentiation respectively. Apomorphine (0.2 mg/kg, s.c.) produced contralateral rotations, which were decreased by haloperidol but not by prazosin. 2-methoxy Idazoxan potentiated these rotations which were attenuated by haloperidol but not by prazosin. Citalopram and p-chlorophenylalanine increased and decreased the observed potentiation respectively. Citalopram and p-chlorophenylalanine had no effect by per se on D-amphetamine and apomorphine-induced rotations. 2-methoxy Idazoxan alone increased both ipsilateral and contralateral spontaneous rotations. Taken together, these findings indicate that an increase in noradrenergic tone by 2-methoxy Idazoxan potentiates both D-amphetamine-induced ipsilateral and apomorphine induced contralateral rotations. α1-Antagonism attenuates D-amphetamine induced ipsilateral rotations and its potentiation by 2-methoxy Idazoxan but not apomorphine rotations or its potentiation. Increasing and decreasing the serotonergic transmission decreases and increases D-amphetamine potentiation, whereas increases and decreases apomorphine potentiation respectively. The possible mechanisms for these findings are discussed.
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treatment with α2 adrenoceptor antagonist 2 methoxy Idazoxan protects 6 hydroxydopamine induced parkinsonian symptoms in rats neurochemical and behavioral evidence
Behavioural Brain Research, 2004Co-Authors: J. Srinivasan, Werner J. SchmidtAbstract:Abstract Noradrenaline, not only functions as a synaptic transmitter, but also promotes neural differentiation and regenerative processes. In Parkinson’s disease, besides the dopaminergic degeneration, noradrenergic neurons of locus coeruleus origin degenerate as well. Drugs enhancing noradrenergic transmission in the locus coeruleus (e.g. α 2 -adrenoceptor antagonists) have been shown to be neuroprotective against Huntington’s and ischemic animal models. However, in Parkinsonian animal models, most of the studies evaluated the worsening of experimental nigral neurodegeneration after locus coeruleus lesions. Here, it has been tested, whether treatment with the selective α 2 -adrenoceptor antagonist, 2-methoxy Idazoxan (2.5 mg/kg i.p., twice daily for 5 days), before an experimental lesion to nigra, protects dopaminergic neurodegeneration. Dopaminergic degeneration was produced by 6-hydroxydopamine lesion in the median forebrain bundle. The concentrations of dopamine, 5-hydroxytryptamine and its metabolites were analysed in the various regions of the basal ganglia. The concentrations of noradrenaline and dopamine were measured in the regions innervated by locus coeruleus neurons and in the basal ganglia respectively, after 2-methoxy Idazoxan treatment. The Parkinsonian behavior was assessed by catalepsy and activity test. 2-Methoxy Idazoxan specifically increased the concentration of noradrenaline in the brain regions, innervated by locus coeruleus neurons. 6-OHDA lesion strongly depleted the concentration of dopamine and its metabolites in the striatum and SN, producing catalepsy and hypoactivity. Multiple treatments with 2-methoxy Idazoxan reduced some of the observed neurochemical and behavioral indices of 6-hydroxydopamine-induced Parkinsonism, indicating neuroprotection. Although the mechanism underlying the neuroprotective property remains elusive, the therapeutic usage of α 2 -antagonists might be helpful in slowing the neuronal death and progression of Parkinson’s disease.
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The effect of the α2-adrenoreceptor antagonist Idazoxan against 6-hydroxydopamine-induced Parkinsonism in rats: multiple facets of action?
Naunyn-Schmiedeberg's archives of pharmacology, 2004Co-Authors: J. Srinivasan, Werner J. SchmidtAbstract:The α2-adrenoreceptor antagonist Idazoxan counteracts catalepsy induced by neuroleptic agents and improves Parkinsonian signs in 1-methyl-4-phenyl 1,2,3,6,tetrahydropyridine-treated monkeys and in patients. The present study addressed the question of whether systemic administration of Idazoxan (1.5 mg/kg i.p.) improves Parkinsonian symptoms in a rat model of permanent dopaminergic neurodegeneration. Dopaminergic degeneration was induced by injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle (MFB). Parkinsonian behaviour was assessed by catalepsy and open-field exploratory behaviour tests. Since dopaminergic and serotonergic mechanisms are thought to account for the anti-cataleptic/anti-Parkinsonian property of Idazoxan, dopamine, 5-hydroxytryptamine (5-HT) and its metabolites in the regions of the basal ganglia and prefrontal cortex were analysed by HPLC. 6-OHDA lesions in the MFB produced catalepsy and hypoactivity in the open field and depleted dopamine and its metabolites in the basal ganglia and prefrontal cortex, but did not affect 5-HT. Treatment with Idazoxan counteracted the observed Parkinsonian behaviour in 6-OHDA-lesioned rats and increased the spontaneous open-field activity in control rats. In both 6-OHDA and control animals, Idazoxan increased DA level in the prefrontal cortex, but not in any other structures including the striatum. Idazoxan also increased the levels of 5-HT in the anterior striatum, prefrontal cortex and the ventral tegmental area of both 6-OHDA and control animals. These findings indicate that systemic administration of Idazoxan counteracts 6-OHDA-induced Parkinsonian symptoms in rats and that both dopaminergic and serotonergic mechanisms could contribute to its anti-Parkinsonian effect.
David J Nutt - One of the best experts on this subject based on the ideXlab platform.
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The effects of Idazoxan on reaction times, eye movements and the mood of healthy volunteers and patients with upper respiratory tract illnesses
Journal of psychopharmacology (Oxford England), 1999Co-Authors: Andrew Paul Smith, Sue Wilson, Wendy Sturgess, Neil Rich, Carolyn Frances Brice, Claire Collison, Jayne E Bailey, David J NuttAbstract:An experiment was carried out to determine whether Idazoxan, a drug which increases the turnover of central noradrenaline, removes the malaise (reduced alertness, slower psychomotor performance) associated with upper respiratory tract illness (URTI). Eighty-one volunteers were tested when healthy and 17 returned to the laboratory when they developed URTIs. Those who remained healthy were then recalled as a control group. Volunteers were tested before and after receiving either Idazoxan (40 mg) or a lactose placebo. Idazoxan removed the URTI-induced slowing in a simple reaction time task and this group performed at a comparable level to the healthy group. No significant stimulant effect of Idazoxan was found in the healthy subjects. The results suggest that at least part of the malaise induced by URTIs may reflect reductions in central noradrenaline and that this can be reversed by compounds such as Idazoxan.
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Idazoxan induced reductions in cortical glucose use are accompanied by an increase in noradrenaline release complementary 14c 2 deoxyglucose and microdialysis studies
Neuropharmacology, 1995Co-Authors: N French, David J Nutt, M D Lalies, Judith A PrattAbstract:Abstract The autoradiographic [14C]2-deoxyglucose procedure was used to map function-related alterations in local cerebral glucose use following acute administration of the α2-adrenoceptor antagonist, Idazoxan (0.3–3 mg kg−1 s.c.). The most prominent feature of the results obtained was the significant reduction in glucose use in certain locus coeruleus projection areas. Thus, in various cortical, hippocampal and thalamic regions, as well as structures involved in auditory and visual function, Idazoxan administration was associated with a 13–20% decrease in glucose use. In a complementary microdialysis study, the effect of Idazoxan on extracellular noradrenaline levels in the frontal cortex of rats, manipulated in the same fashion as during the [14C]2-deoxyglucose procedure (i.e. following the application of surgery and partial restraint), was examined. Both surgery and restraint were associated with a modest but significant increase in basal noradrenaline release ( + 31% and + 26%, respectively). Subsequent administration of Idazoxan (3 mg kg−1 s.c.) evoked a further increase in noradrenaline release, the magnitude of which was the same as that observed following its administration to freely-moving rats (+ 113%). These combined data suggest that Idazoxan-induced reductions in cerebral glucose use, at least in the frontal cortex, may occur as a consequence of the increase in noradrenaline release. In addition, it appears that surgery and partial restraint do not alter α2-adrenoceptor tone in the frontal cortex.
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Characterization and autoradiographical localization of non-adrenoceptor Idazoxan binding sites in the rat brain.
British journal of pharmacology, 1992Co-Authors: N.j. Mallard, Alan L. Hudson, David J NuttAbstract:1. In rat whole brain homogenates, saturation analysis revealed that both [3H]-Idazoxan and [3H]-RX821002, a selective alpha 2-adrenoceptor ligand, bound with high affinity to an apparent single population of sites. However, the Bmax for [3H]-Idazoxan was significantly (P less than 0.01) greater than that for [3H]-RX821002. 2. In competition studies, (-)-adrenaline displaced 3 nM [3H]-Idazoxan binding with an affinity consistent with [3H]-Idazoxan labelling alpha 2-adrenoceptors. However, this displacement was incomplete since 23.68 +/- 1.11% of specific [3H]-Idazoxan binding remained in the presence of an excess concentration (100 microM) of (-)-adrenaline. In contrast, unlabelled Idazoxan promoted a complete displacement of [3H]-Idazoxan binding with a Hill slope close to unity and an affinity comparable with its KD determined in saturation studies. 3. Displacement of [3H]-Idazoxan binding by the alpha 2-adrenoceptor antagonists yohimbine, RX821002 (2-(2-methoxy-1,4-benzodioxan-2-yl)-2-imidazoline) and RX811059 (2-(2-ethoxy-1,4-benzodioxan-2-yl)-2-imidazoline) was more complex, with Hill slopes considerably less than unity, and best described by a two-site model of interaction comprising a high and low affinity component. The proportion of sites with high affinity for each antagonist was similar (60-80%). 4. The rank order of antagonist potency for the high affinity component in each displacement curve (RX821002 greater than RX811059 greater than yohimbine) is similar to that determined against the binding of [3H]-RX821002 to rat brain, suggesting that these components reflect the inhibition of [3H]-Idazoxan binding to alpha 2-adrenoceptors.The remaining component in each displacement curve exhibiting low affinity towards these antagonists is attributable to the displacement of [3H]-idazoxin from a non-adrenoceptor Idazoxan binding site (NAIBS) since a comparable amount of [3H]-Idazoxan binding was not displaced by an excess concentration of (-)-adrenaline.5. The displacement of [3H]-Idazoxan binding by RX801023 (6-fluoro-(2-(1,4-benzodioxan-2-yl)-2-imidazoline) was also best described by a model assuming a two site interaction with 20.07 +/- 3.11% of the sites labelled displaying high affinity for RX801023. The Ki of RX801023 for the remainder of the sites labelled was similar to its Ki versus [3H]-RX821002, indicating that this drug displays improved affinity and NAIBS/z2-adrenoceptor selectivity compared with Idazoxan.6. In autoradiographical studies, the distribution of 5 nM [3H]-Idazoxan binding to sections of rat whole brain was consistent with that reported from previous studies and resembled the distribution ofM2-adrenoceptors. However, when sections of brain were coincubated with concentrations of alpha2-adrenoceptor agonists or antagonists predicted to saturate alpha2-adrenoceptors, there remained distinct areas of binding corresponding to discrete brain nuclei. This remaining binding was however displaced by unlabelled Idazoxan (3 microM) or RX801023 (3 microM) indicative of the labelling of NAIBS.7. Quantitative autoradiography of NAIBS revealed several brain nuclei which contained higher densities of these sites than alpha2-adrenoceptors, notably the area postrema, interpeduncular nucleus,arcuate nucleus, ependyma and pineal gland.
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the effects of Idazoxan and other α2 adrenoceptor antagonists on food and water intake in the rat
British Journal of Pharmacology, 1991Co-Authors: Helen C Jackson, Ian J Griffin, David J NuttAbstract:1. Idazoxan (1, 3, 10 mg kg-1, 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 alpha 2-adrenoceptor antagonists, RX811059 (0.3, 1, 3 mg kg-1, i.p.) and RX821002 (0.3, 1, 3 mg 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 alpha 2-adrenoceptor antagonist, L-659,066 (1, 3, 10 mg kg-1, i.p.), did not affect food intake in the 4 h following injection, but the highest dose (10 mg kg-1), produced a large increase in water intake. 4. These results indicate that alpha 2-adrenoceptor antagonists may increase water intake by a peripherally mediated mechanism. 5. The lack of effect 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 alpha 2-adrenoceptor blockade but may instead reflect its affinity for a non-adrenoceptor site, a property not shared by the other alpha 2-antagonists.
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the effects of Idazoxan and other alpha 2 adrenoceptor antagonists on food and water intake in the rat
British Journal of Pharmacology, 1991Co-Authors: Helen C Jackson, Ian J Griffin, David J NuttAbstract:1. Idazoxan (1, 3, 10 mg kg-1, 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 alpha 2-adrenoceptor antagonists, RX811059 (0.3, 1, 3 mg kg-1, i.p.) and RX821002 (0.3, 1, 3 mg 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 alpha 2-adrenoceptor antagonist, L-659,066 (1, 3, 10 mg kg-1, i.p.), did not affect food intake in the 4 h following injection, but the highest dose (10 mg kg-1), produced a large increase in water intake. 4. These results indicate that alpha 2-adrenoceptor antagonists may increase water intake by a peripherally mediated mechanism. 5. The lack of effect 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 alpha 2-adrenoceptor blockade but may instead reflect its affinity for a non-adrenoceptor site, a property not shared by the other alpha 2-antagonists.
J. Srinivasan - One of the best experts on this subject based on the ideXlab platform.
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serotonergic influence on the potentiation of d amphetamine and apomorphine induced rotational behavior by the α2 adrenoceptor antagonist 2 methoxy Idazoxan in hemiparkinsonian rats
Journal of Neural Transmission, 2005Co-Authors: J. Srinivasan, Werner J. SchmidtAbstract:The α2-adrenoceptor antagonists potentiate both ipsilateral and contralateral rotations induced by amphetamine and apomorphine respectively in hemiparkinsonian rats. The present study investigated the role of serotonergic transmission in this potentiation in unilaterally 6-hydroxydopamine nigral lesioned rats. D-amphetamine (0.5 mg/kg, i.p.) produced ipsilateral rotations, which were decreased by the dopamine receptor antagonist haloperidol (0.2 mg/kg, i.p.) and the α1-receptor antagonist prazosin (1 mg/kg, i.p.). The selective α2-antagonist 2-methoxy Idazoxan (0.2 mg/kg, i.p.) potentiated the amphetamine-induced ipsilateral rotations, that were attenuated by haloperidol and prazosin. The selective serotonin re-uptake inhibitor citalopram (10 mg/kg, i.p.) and selective serotonin synthesis inhibitor p-chlorophenylalanine (150 mg/kg, i.p., 3 days) decreased and increased the observed potentiation respectively. Apomorphine (0.2 mg/kg, s.c.) produced contralateral rotations, which were decreased by haloperidol but not by prazosin. 2-methoxy Idazoxan potentiated these rotations which were attenuated by haloperidol but not by prazosin. Citalopram and p-chlorophenylalanine increased and decreased the observed potentiation respectively. Citalopram and p-chlorophenylalanine had no effect by per se on D-amphetamine and apomorphine-induced rotations. 2-methoxy Idazoxan alone increased both ipsilateral and contralateral spontaneous rotations. Taken together, these findings indicate that an increase in noradrenergic tone by 2-methoxy Idazoxan potentiates both D-amphetamine-induced ipsilateral and apomorphine induced contralateral rotations. α1-Antagonism attenuates D-amphetamine induced ipsilateral rotations and its potentiation by 2-methoxy Idazoxan but not apomorphine rotations or its potentiation. Increasing and decreasing the serotonergic transmission decreases and increases D-amphetamine potentiation, whereas increases and decreases apomorphine potentiation respectively. The possible mechanisms for these findings are discussed.
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treatment with α2 adrenoceptor antagonist 2 methoxy Idazoxan protects 6 hydroxydopamine induced parkinsonian symptoms in rats neurochemical and behavioral evidence
Behavioural Brain Research, 2004Co-Authors: J. Srinivasan, Werner J. SchmidtAbstract:Abstract Noradrenaline, not only functions as a synaptic transmitter, but also promotes neural differentiation and regenerative processes. In Parkinson’s disease, besides the dopaminergic degeneration, noradrenergic neurons of locus coeruleus origin degenerate as well. Drugs enhancing noradrenergic transmission in the locus coeruleus (e.g. α 2 -adrenoceptor antagonists) have been shown to be neuroprotective against Huntington’s and ischemic animal models. However, in Parkinsonian animal models, most of the studies evaluated the worsening of experimental nigral neurodegeneration after locus coeruleus lesions. Here, it has been tested, whether treatment with the selective α 2 -adrenoceptor antagonist, 2-methoxy Idazoxan (2.5 mg/kg i.p., twice daily for 5 days), before an experimental lesion to nigra, protects dopaminergic neurodegeneration. Dopaminergic degeneration was produced by 6-hydroxydopamine lesion in the median forebrain bundle. The concentrations of dopamine, 5-hydroxytryptamine and its metabolites were analysed in the various regions of the basal ganglia. The concentrations of noradrenaline and dopamine were measured in the regions innervated by locus coeruleus neurons and in the basal ganglia respectively, after 2-methoxy Idazoxan treatment. The Parkinsonian behavior was assessed by catalepsy and activity test. 2-Methoxy Idazoxan specifically increased the concentration of noradrenaline in the brain regions, innervated by locus coeruleus neurons. 6-OHDA lesion strongly depleted the concentration of dopamine and its metabolites in the striatum and SN, producing catalepsy and hypoactivity. Multiple treatments with 2-methoxy Idazoxan reduced some of the observed neurochemical and behavioral indices of 6-hydroxydopamine-induced Parkinsonism, indicating neuroprotection. Although the mechanism underlying the neuroprotective property remains elusive, the therapeutic usage of α 2 -antagonists might be helpful in slowing the neuronal death and progression of Parkinson’s disease.
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The effect of the α2-adrenoreceptor antagonist Idazoxan against 6-hydroxydopamine-induced Parkinsonism in rats: multiple facets of action?
Naunyn-Schmiedeberg's archives of pharmacology, 2004Co-Authors: J. Srinivasan, Werner J. SchmidtAbstract:The α2-adrenoreceptor antagonist Idazoxan counteracts catalepsy induced by neuroleptic agents and improves Parkinsonian signs in 1-methyl-4-phenyl 1,2,3,6,tetrahydropyridine-treated monkeys and in patients. The present study addressed the question of whether systemic administration of Idazoxan (1.5 mg/kg i.p.) improves Parkinsonian symptoms in a rat model of permanent dopaminergic neurodegeneration. Dopaminergic degeneration was induced by injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle (MFB). Parkinsonian behaviour was assessed by catalepsy and open-field exploratory behaviour tests. Since dopaminergic and serotonergic mechanisms are thought to account for the anti-cataleptic/anti-Parkinsonian property of Idazoxan, dopamine, 5-hydroxytryptamine (5-HT) and its metabolites in the regions of the basal ganglia and prefrontal cortex were analysed by HPLC. 6-OHDA lesions in the MFB produced catalepsy and hypoactivity in the open field and depleted dopamine and its metabolites in the basal ganglia and prefrontal cortex, but did not affect 5-HT. Treatment with Idazoxan counteracted the observed Parkinsonian behaviour in 6-OHDA-lesioned rats and increased the spontaneous open-field activity in control rats. In both 6-OHDA and control animals, Idazoxan increased DA level in the prefrontal cortex, but not in any other structures including the striatum. Idazoxan also increased the levels of 5-HT in the anterior striatum, prefrontal cortex and the ventral tegmental area of both 6-OHDA and control animals. These findings indicate that systemic administration of Idazoxan counteracts 6-OHDA-induced Parkinsonian symptoms in rats and that both dopaminergic and serotonergic mechanisms could contribute to its anti-Parkinsonian effect.
William Z. Potter - One of the best experts on this subject based on the ideXlab platform.
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chronic lithium administration enhances noradrenergic responses to intravenous administration of the alpha2 antagonist Idazoxan in healthy volunteers
Journal of Clinical Psychopharmacology, 2004Co-Authors: Aysegul Ozerdem, Mark E. Schmidt, Husseini K. Manji, Robert C. Risinger, William Z. PotterAbstract:The acute and chronic effects of lithium carbonate administration at therapeutic blood levels on peripheral noradrenergic activity and sympathetic responses to alpha2 adrenoceptor blockade were examined in 10 medically and psychiatrically healthy volunteers. Supine resting levels of plasma norepinephrine and the increases in norepinephrine following intravenous infusion of 200 microg/kg of Idazoxan, a selective alpha2 adrenoceptor antagonist, were determined before lithium (Li+) administration and after 5 days and after 4 weeks of daily Li+ treatment. Chronic Li+ treatment significantly increased mean resting plasma norepinephrine levels by 53.6%. The noradrenergic responses to infusions of Idazoxan were slightly enhanced after 5 days of Li+ administration and significantly increased following 4 weeks of Li+ treatment. The possibility that Li+ produces functional alpha2 subsensitivity causing enhanced peripheral noradrenergic activity in humans is supported by the findings of increased mean resting plasma norepinephrine and increased response to Idazoxan following chronic Li+ administration. Alteration of regulatory mechanisms in the noradrenergic system may be relevant to understanding the clinical effects of Li+ in manic-depressive illness.
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A double-blind study comparing Idazoxan and bupropion in bipolar depressed patients.
Journal of Affective Disorders, 1999Co-Authors: F Grossman, William Z. Potter, E A Brown, G MaislinAbstract:Background: There is a small body of evidence indicating that Idazoxan, a potent and selective alpha-2 antagonist, may be effective in treating bipolar depressive disorder. The purpose of this prospective controlled study is to compare Idazoxan to bupropion, an antidepressant which has been suggested to have some advantages over other antidepressants in treating bipolar depressed patients. Methods: Bipolar I depressed patients were randomly assigned in this 6-week double-blind out-patient study to receive either Idazoxan, titrated to 240 mg/day and placebo bupropion, or bupropion, titrated to 450 mg/day and placebo Idazoxan. These doses were achieved after 2 weeks. Depression severity was assessed with the Hamilton Depression Rating Scale and possible psychosis with the Brief Psychiatric Rating Scale. Side effects, heart rate, weight, and orthostatic blood pressure were also monitored. Results: Fourteen patients completed this study (seven in each group). Both Idazoxan and bupropion demonstrated significant improvement over time with reductions in Hamilton scores of 50%. Limitations: Limitations of this study include lack of a placebo group and small sample size. Conclusion: In light of our preliminary findings suggesting the usefulness of Idazoxan in bipolar depression, larger more rigorous studies are indicated.
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Responses to α2-adrenoceptor blockade by Idazoxan in healthy male and female volunteers
Psychoneuroendocrinology, 1997Co-Authors: Mark E. Schmidt, Robert C. Risinger, Richard L. Hauger, Jennifer L. Schouten, Michael E. Henry, William Z. PotterAbstract:Abstract Seven male and five female volunteers underwent double-blind infusions of the α2-adrenoceptor antagonist Idazoxan (100 and 200 μg/kg) and placebo in random order. Blood pressure, plasma norepinephrine, growth hormone and subjective responses were measured. The higher dose of Idazoxan produced increases in blood pressure, norepinephrine and growth hormone and slight increases in anxiety. Both subject age and sex appeared to influence the magnitude of responses.
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acute alpha 2 blockade by Idazoxan increases insulin and lowers plasma glucose during positron emission tomography
Psychopharmacology Bulletin, 1997Co-Authors: Mark E. Schmidt, David S Goldstein, J L Schouten, J A Matochik, H G Kim, William Z. PotterAbstract:The sympathetic nervous system can modulate glucose levels through a variety of mechanisms, including inhibition of insulin release by alpha2-adrenergic receptors. Such effects could potentially confound measurements of brain glucose metabolism during studies of the central actions of sympathomimetic drugs. Plasma glucose, insulin, and sympathetic responses to alpha2 blockade were measured following infusion of Idazoxan, a selective alpha2 antagonist, or placebo, in 33 healthy volunteers (Idazoxan: n = 23, placebo: n = 10). These measures were compared with estimates of global brain metabolism obtained from positron emission tomography (PET) scans before and after the infusion. Glucose levels fell and fractional levels of insulin rose after Idazoxan, compared with placebo. Relative increases in insulin correlated with increases in epinephrine after active drug. The increases in insulin are consistent with the hypothesized role of alpha2-adrenoceptors in regulating insulin release. Estimates of global brain glucose metabolism did not appear to be influenced by the modest changes in plasma glucose.
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Idazoxan and response to typical neuroleptics in treatment-resistant schizophrenia. Comparison with the atypical neuroleptic, clozapine.
The British journal of psychiatry : the journal of mental science, 1996Co-Authors: William Z. Potter, Walter W. HongAbstract:BACKGROUND We investigated whether antagonism of alpha 2 adrenergic receptors would augment treatment response in schizophrenia, by administering Idazoxan, an alpha 2 antagonist drug, to treatment-resistant patients on typical neuroleptics. METHOD Seventeen hospitalised treatment-resistant patients with DSM-III-R schizophrenia or schizoaffective disorder were studied on typical neuroleptic treatment, on treatment with Idazoxan plus typical neuroleptic, and after discontinuation of Idazoxan, in fixed, non-random order, and under double-blind, placebo-controlled conditions. RESULTS The addition of Idazoxan to fluphenazine treatment resulted in significant reductions of global psychosis and total, positive and negative symptoms on the Brief Psychiatric Rating Scale, compared to neuroleptic treatment alone. Symptom improvement significantly correlated with Idazoxan-induced changes in indices of noradrenergic function. In a subgroup of patients, Idazoxan plus typical neuroleptic treatment compared favourably with clozapine treatment, when both were compared to typical neuroleptic treatment alone. CONCLUSIONS The antagonism of alpha 2 receptors augmented therapeutic response to typical neuroleptic treatment in treatment-resistant patients with schizophrenia. This antagonism may contribute to clozapine's superior antipsychotic effects.
Jesús A. García-sevilla - One of the best experts on this subject based on the ideXlab platform.
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The α2-adrenoceptor antagonist Idazoxan is an agonist at 5-HT1A autoreceptors modulating serotonin synthesis in the rat brain in vivo☆
Neuroscience letters, 1996Co-Authors: Jerònia Lladó, Susana Esteban, Jesús A. García-sevillaAbstract:The in vivo effects of the alpha 2-adrenoceptor Idazoxan, rauwolscine and phentolamine on alpha 2-auto/heteroreceptors and 5-HT1A autoreceptors modulating the synthesis of dopa/noradrenaline and 5-HTP/serotonin were assessed in rats, using the accumulation of dopa and 5-HTP after decarboxylase inhibition as a measure of the rate of tyrosine and tryptophan hydroxylation. The acute administration of Idazoxan (0.1-40 mg/kg) induced a pronounced dose-dependent increase in the synthesis of dopa in the cerebral cortex (22-86%) and hippocampus (8-80%), as a consequence of the powerful blockade of alpha 2-autoreceptors. However, Idazoxan did not increase the synthesis of 5-HTP in these brain regions, as it would have been expected by the concurrent blockade of alpha 2-heteroreceptors on serotonergic terminals. Instead, Idazoxan decreased the synthesis of 5-HTP in the cerebral cortex (13-33%) and hippocampus (25-48%), suggesting that these inhibitory effects were mediated through activation of 5-HT1A autoreceptors. Similar results were obtained for rauwolscine. Pre-treatment of rats with the selective 5-HT1A receptor antagonist WAY100135 (10 mg/kg) fully antagonized the inhibitory effects of Idazoxan (10 mg/kg) on 5-HTP synthesis, but it did not prevent the stimulatory effects of Idazoxan on dopa synthesis. The results indicate that Idazoxan is a potent and specific agonist at 5-HT1A autoreceptors modulating brain serotonin synthesis in vivo.
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Discrimination and pharmacological characterization of I2-imidazoline sites with [3H]Idazoxan and alpha-2 adrenoceptors with [3H]RX821002 (2-methoxy Idazoxan) in the human and rat brains.
The Journal of pharmacology and experimental therapeutics, 1993Co-Authors: Antonio Miralles, Gabriel Olmos, M. Sastre, F Barturen, I. Martín, Jesús A. García-sevillaAbstract:The alpha-2 adrenoceptor antagonist Idazoxan has been shown to also recognize with high affinity nonadrenoceptor sites (I2-imidazoline sites). In contrast, the 2-methoxy derivative of Idazoxan, 2-methoxy Idazoxan (RX821002), binds almost exclusively to alpha-2 adrenoceptors. The purpose of this study was to assess and extend the pharmacological characterization of I2-imidazoline sites and alpha-2 adrenoceptors in the human and rat brains. Competition studies with several imidazoli(di)ne/guanidine drugs and other nonrelated structures were performed in cortical membranes against [3H]Idazoxan (4 nM in the presence of 10(-6) M I-epinephrine to prevent binding to alpha-2 adrenoceptors) or [3H]RX821002 (1 nM). Drugs such as cirazoline, guanoxan, naphazoline, tolazoline, clonidine, bromoxidine (UK 14,304) and phenylbiguanide displaced [3H]Idazoxan from two distinct binding sites, which suggested the existence of two affinity states for I2-imidazoline sites that were not modulated by MgCl2 or the nucleotide analog guanylyl-5'-imido-diphosphate. Binding affinities at the low-affinity site (KiL) were consistently more than 2 orders of magnitude lower than binding affinities at the high-affinity site (KiH), and there was a good correlation between KiH and KiL values for a given drug in the human (r = 0.89) and rat (r = 0.92) brains. For 18 to 22 drugs, the Ki values in the human brain correlated well with the corresponding Ki values in the rat brain both for I2-imidazoline sites (r = 0.94) and alpha-2 adrenoceptors (r = 0.97). However, the Ki values for I2-imidazoline sites did not correlate with the Ki values for alpha-2 adrenoceptors in human and rat brains. The order of drug potency for the I2-imidazoline sites was: guanoxan (1.3 nM) approximately cirazoline > Idazoxan approximately naphazoline > clonidine > phentolamine > RX821002 > (8aR, 12aS, 13aS)-3-methoxy-12-methanesulfonyl-5,6,8a,9,10,11,12,12a,13,13a- decahydro-8H-isoquino[2,1-g]-naphthyridine (RS 15385-197) (> 10 microM). In contrast, the potencies at the alpha-2 adrenoceptor were: RS 1538-197 (0.3 nM) > RX821002 > clonidine > phentolamine > Idazoxan approximately naphazoline > guanoxan approximately cirazoline (307 nM). The results demonstrate that I2-imidazoline sites (labeled by [3H]Idazoxan) and alpha-2 adrenoceptors are different pharmacological entities with similar characteristics in the human and rat brains. In both species, I2-imidazoline sites are markedly heterogeneous in nature.
