Cortical alpha-adrenoceptor downregulation by tricyclic antidepressants in the rat brain

Subhash, M. N.; Nagaraja, M R; Sharada, S.; Vinod, K. Yaragudri

doi:10.1016/s0197-0186(03)00097-4

Cited by 50 publications

(31 citation statements)

References 55 publications

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“…injection of 10 mg/kg DMI (Tang et al, 1981), or in the locus coeruleus following 14 days of once daily injections of 10 mg/kg DMI (Sacchetti et al, 2001). A major difference between our studies and those reported by others (Smith et al, 1981a;Tang et al, 1981;Subhash et al, 2003) is that we used the radiolabeled antagonist [ 3 H]RX821002, which measures changes in total receptor population (high-and low-affinity states), and the other investigators used the radiolabeled agonist [ 3 H]clonidine, which is more likely to measure changes in high-affinity state of the receptor. Our studies indicate that the total receptor population of ␣-2-adrenergic receptors does not change in the prefrontal or cortex in the adult rat following either four twice daily injections of a high dose of DMI or 2 weeks of continual drug delivery at a lower dose, which agrees with other studies using the antagonist radioligand (Sacchetti et al, 2001).…”

Section: Discussioncontrasting

confidence: 79%

“…Treatment with monoamine oxidase inhibitors (clorgyline and tranylcypromine) for 2 h to 14 days resulted in a time-dependent decrease in ␣-2-adrenergic receptors in the cerebral cortex (Giralt and Garcia-Sevilla, 1989). Forty days of chronic treatment of rats with tricyclic antidepressants, including DMI, produced a down-regulation of both ␣-1 and ␣-2-adrenergic receptors in the cortex, but not in the hippocampus (Subhash et al, 2003). However, down-regulation of the ␣-2 receptor in the cortex was not detected following 3 weeks of once daily i.p.…”

Section: Discussionmentioning

confidence: 90%

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Differential Effects of the Tricyclic Antidepressant Desipramine on the Density of Adrenergic Receptors in Juvenile and Adult Rats

Deupree

Reed²,

Bylund

2007

J Pharmacol Exp Ther

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Although the tricyclic antidepressants, such as desipramine (DMI), are among the most efficacious treatments for adult depression, they are not effective in treating childhood and adolescent depression. Because the adrenergic nervous system is not fully developed until late adolescence, we hypothesized that the mechanisms regulating receptor density may not yet be mature in young mammals. To test this hypothesis, the effects of DMI treatment on cortical ␣-1-, ␣-2-, and ␤-adrenergic receptors were compared in juvenile and adult rats. DMI was delivered either by 4 days of twice daily injections to postnatal day 9 to 13 (4 and 7 mg/kg/day) and adult (20 mg/ kg/day) rats, or by 2 weeks of continual drug infusion (osmotic minipumps) to postnatal day 21-35 (15 mg/kg/day) and adult (10 mg/kg/day) rats. These delivery paradigms gave juvenile brain concentrations of DMI similar to those in adult rats. The ␤-adrenergic receptor was down-regulated with both treatment paradigms in both juvenile and adult rats. By contrast, in the postnatal day 9 to 13 rats, there was a dose-dependent upregulation of the ␣-1 in the cortex and ␣-2-adrenergic receptor in the prefrontal cortex, whereas there was no change in density in adult rats. These differences in the ␣-adrenergic receptor regulation after DMI treatment suggest that the lack of efficacy of tricyclic antidepressants in treating childhood depression may be related to immature regulatory mechanisms for these receptors.

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Section: Discussioncontrasting

confidence: 79%

Section: Discussionmentioning

confidence: 90%

Differential Effects of the Tricyclic Antidepressant Desipramine on the Density of Adrenergic Receptors in Juvenile and Adult Rats

Deupree

Reed²,

Bylund

2007

J Pharmacol Exp Ther

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“…These data suggest that a sustained release of noradrenaline over the course of ECS in the frontal cortex may have induced a compensatory down-regulation of the presynaptic α 2 -adrenoceptors in the frontal cortex but not in hippocampus, explaining why idazoxan did not have any effect on the α 2 -adrenoceptors in frontal cortex of the ECS treated rats (Thomas et al, 1992). Our data are consistent with the observations of Subhash et al (2003) and Thomas et al (1992), finding no significant differences in the hippocampal region of the ECS treated FSL and FRL rats compared to the sham treated rats, but demonstrating down-regulation in cortical regions in the FSL rats and in cortical and amygdaloid regions in the FRL rats. Moreover, the lack of alteration in receptor binding in the hippocampal region is in line with the unresponsiveness of hippocampal pydamidal neurons to norepinephrine found following ECS (de Montigny, 1984).…”

Section: Discussionsupporting

confidence: 91%

“…However, it must be noted that post-mortem changes in binding do not always correlate with the in vivo functional response of receptors and increased sensitivity of amygdaloid neurons to monoaminergic transmitters has been found following antidepressant treatment (Wang and Aghajanian, 1980). A decreased density in α 2 -adrenoceptors was found by Subhash et al (2003) in cortical areas, but not in hippocampal areas, in the rat brain after chronic treatment with tricyclic antidepressants suggesting region-specific down-regulation and Thomas et al (1992) found a release of noradrenaline 24 h after the last chronic ECS treatment session in rat frontal cortex, but not in hippocampus, compared to sham treated controls. Furthermore, when Thomas et al (1992) challenged these rats with the α 2 -adrenoceptor antagonist idazoxan, increased release of noradrenaline was found in the sham treated rats in both brain regions, but in the chronically ECS treated rats, the release was only observed in the hippocampus.…”

Section: Discussionmentioning

confidence: 90%

Electroconvulsive shocks decrease α2-adrenoceptor binding in the Flinders rat model of depression

Lillethorup

Iversen

Fontain

et al. 2015

European Neuropsychopharmacology

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Despite years of drug development, electroconvulsive therapy (ECT) remains the most effective treatment for severe depression. The exact therapeutic mechanism of action of ECT is still unresolved and therefore we tested the hypothesis that the beneficial effect of ECT could in part be the result of increased noradrenergic neurotransmission leading to a decrease in α 2 -adrenoceptor binding. We have previously shown that both the Flinders sensitive line (FSL) and Flinders resistant line (FRL) rats had altered α 2 -adrenoceptor binding compared to control Sprague-Dawley (SD) rats. In this study, we treated female FSL, FRL and SD rats with electroconvulsive shock (ECS), an animal model of ECT, or sham stimulation for 10 days before brains were removed and cut into 20 mm thick sections. Densities of α 2 -adrenoceptors were measured by quantitative autoradiography in the hippocampus, thalamic nucleus, hypothalamus, amygdala, frontal cortex, insular cortex, and perirhinal cortex using the α 2 -adrenoceptor antagonist, [ 3 H]RX 821002. ECS decreased the binding of α 2 -adrenoceptors in cortical regions in the FSL and cortical and amygdaloid regions in the control FRL rats compared to their respective sham treated group. The normal SD controls showed no significant response to ECS treatment. Our data suggest that the therapeutic effect of ECS may be mediated through a decrease of α 2 -adrenoceptors, probably due to a sustained increase in noradrenaline release. These data confirm the importance of the noradrenergic system and the α 2 -adrenoceptor in depression and in the mechanism of antidepressant treatments.

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“…Treatment with monoamine oxidase inhibitors for two weeks resulted in a time-dependent decrease in alpha-2 adrenergic receptors in the cerebral cortex (Giralt and Garcia-Sevilla, 1989). Forty days of chronic treatment of rats with tricyclic antidepressants produced a down-regulation of both alpha-1 and alpha-2 adrenergic receptors in the cortex, but not in the hippocampus (Subhash et al, 2003)). On the other hand, down-regulation of the alpha-2 receptor in the cortex was not detected following 3 weeks of daily desipramine administration (Tang, et al, 1981), or in the locus coeruleus following 14 days of daily desipramine administration (Sacchetti et al, 2001).…”

Section: Effects Of Antidepressants On G Protein-coupled Receptors Inmentioning

confidence: 96%

Childhood and adolescent depression: Why do children and adults respond differently to antidepressant drugs?

Bylund

Reed

2007

Neurochemistry International

104

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Childhood and adolescent depression is an increasingly problematic diagnosis for young people due to a lack of effective treatments for this age group. The symptoms of adult depression can be treated effectively with multiple classes of antidepressant drugs which have been developed over the years using animal and human studies. But many of the antidepressants used to treat adult depression cannot be used for pediatric depression because of a lack of efficacy and/or side effects. The reason that children and adolescents respond differently to antidepressant treatment than adults is poorly understood. In order to better understand the etiology of pediatric depression and treatments that are effective for this age group the differences between and adults and children and adolescents needed to be elucidated. Much of the understanding of adult depression has come from studies using adult animals therefore studies using juvenile animals would likely help us to better understand childhood and adolescent depression. Recent studies have shown both neurochemical and behavioral differences between adult and juvenile animals after antidepressant treatment. Juvenile animals have differences compared to adult animals in the maturation of the serotonergic and noradrenergic systems, and in dose of antidepressant drug needed to achieve similar brain levels. Differences after administration of antidepressant drug have also been reported for adrenergic receptor regulation, a physiologic hypothermic response, as well as behavioral differences in two animal models of depression. The differences between adults and juveniles not only in the human response to antidepressants but also with animals studies warrant a specific distinction between the study of pediatric and adult depression and the manner in which new treatments are pursued.

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Cortical alpha-adrenoceptor downregulation by tricyclic antidepressants in the rat brain

Cited by 50 publications

References 55 publications

Differential Effects of the Tricyclic Antidepressant Desipramine on the Density of Adrenergic Receptors in Juvenile and Adult Rats

Differential Effects of the Tricyclic Antidepressant Desipramine on the Density of Adrenergic Receptors in Juvenile and Adult Rats

Electroconvulsive shocks decrease α2-adrenoceptor binding in the Flinders rat model of depression

Childhood and adolescent depression: Why do children and adults respond differently to antidepressant drugs?

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