Design of a desipramine dosing regimen for the rapid induction and maintenance of maximal cortical β-adrenoceptor downregulation

Argenti, Domenick; D’mello, Anil P.

doi:10.1016/0028-3908(94)90151-1

Cited by 8 publications

(7 citation statements)

References 9 publications

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“…Adults rats were given 10 mg/kg twice daily for 4 days, a treatment paradigm that has previously been shown to down-regulate the ␤-adrenergic receptor (Argenti and D'Mello, 1994a). To compare the effects of DMI administration on adrenergic receptor density in juvenile rats with that seen with adult rats, it was first necessary to ensure that the dose of DMI given to the juvenile rats would produce brain DMI concentrations that were comparable with those produced in adult rats.…”

Section: Resultsmentioning

confidence: 99%

“…The studies on adult animals confirm that our treatment paradigms are appropriate and that they produce a response similar to that reported by others. DMI has been shown in adult rats to produce down-regulation of the ␤-adrenergic receptor when it is given either by twice daily injections for 4 days ( Argenti and D'Mello, 1994a) or by continual infusion for 2 weeks (Beer et al, 1987).…”

Section: Discussionmentioning

confidence: 99%

“…Three factors have been reported to play a role in the extent of down-regulation of the ␤-adrenergic receptor: 1) dose (Scott and Crews, 1983;Sethy et al, 1988;Argenti and D'Mello, 1994a,b;Goodnough and Baker, 1994), 2) time ( Scott and Crews, 1983;Sethy et al, 1988;Argenti and D'Mello, 1994a;Argenti and D'Mello, 1994b;Newman-Tancredi et al, 1996), and 3) concentration of the active metabolite DDMI ( Argenti and D'Mello, 1994b). Argenti and D'Mello (1994b) have previously shown that the extent of down-regulation of the ␤-adrenergic receptor following 4 days of DMI injection is dependent on the dose of drug with 20 mg/kg/day producing maximal reduction.…”

Section: Discussionmentioning

confidence: 99%

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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: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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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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“…This suggests that noradrenergic drugs cause long-term adaptive changes that are therapeutic. Chronic treatment with desipramine produces a series of changes in presynaptic and postsynaptic α- and β-adrenoceptors and causes long-term downregulation of cortical β-adrenoceptors [111-113]. This suggests that behavioural improvement can perhaps be achieved by decreased noradrenergic activation of cortical β-adrenoceptors, thereby decreasing noradrenergic function, which is consistent with a hyperactive noradrenergic system and the dopamine/norepinephrine imbalance hypothesis of ADHD.…”

Section: Introductionmentioning

confidence: 84%

Animal models of attention-deficit hyperactivity disorder

2005

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Although animals cannot be used to study complex human behaviour such as language, they do have similar basic functions. In fact, human disorders that have animal models are better understood than disorders that do not. ADHD is a heterogeneous disorder. The relatively simple nervous systems of rodent models have enabled identification of neurobiological changes that underlie certain aspects of ADHD behaviour. Several animal models of ADHD suggest that the dopaminergic system is functionally impaired. Some animal models have decreased extracellular dopamine concentrations and upregulated postsynaptic dopamine D1 receptors (DRD1) while others have increased extracellular dopamine concentrations. In the latter case, dopamine pathways are suggested to be hyperactive. However, stimulus-evoked release of dopamine is often decreased in these models, which is consistent with impaired dopamine transmission. It is possible that the behavioural characteristics of ADHD result from impaired dopamine modulation of neurotransmission in cortico-striato-thalamo-cortical circuits. There is considerable evidence to suggest that the noradrenergic system is poorly controlled by hypofunctional α2-autoreceptors in some models, giving rise to inappropriately increased release of norepinephrine. Aspects of ADHD behaviour may result from an imbalance between increased noradrenergic and decreased dopaminergic regulation of neural circuits that involve the prefrontal cortex. Animal models of ADHD also suggest that neural circuits may be altered in the brains of children with ADHD. It is therefore of particular importance to study animal models of the disorder and not normal animals. Evidence obtained from animal models suggests that psychostimulants may not be acting on the dopamine transporter to produce the expected increase in extracellular dopamine concentration in ADHD. There is evidence to suggest that psychostimulants may decrease motor activity by increasing serotonin levels. In addition to providing unique insights into the neurobiology of ADHD, animal models are also being used to test new drugs that can be used to alleviate the symptoms of ADHD.

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“…From a pharmacokinetic standpoint, once or twice daily injections result in peaks and valleys in the brain drug concentrations, whereas with continuous infusion steady-state conditions are reached within about 2 days. Twice daily injections of DMI results in down-regulation of betaadrenergic receptors in four days (Argenti and D'Mello, 1994a) whereas studies with continuous infusion are usually done for two to four weeks, in order to more closely mimic the time course for clinical improvement frequently seen in humans. In comparing the two dosing regimens in juvenile rats we found that PND 9-12 rats needed far less drug (2 -3 mg/kg/ injection) to obtain the same brain concentrations at the adult rats (10 mg/kg/injection).…”

Section: Dmi and Ddmi Levels In Receptor Regulation Study Paradigmsmentioning

confidence: 99%

Appropriate dosing regimens for treating juvenile rats with desipramine for neuropharmacological and behavioral studies

Kozisek

Deupree

Burke

et al. 2007

Journal of Neuroscience Methods

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The tricyclic antidepressants, including desipramine (DMI), are no better than placebo in treating childhood and adolescent depression, but are effective in adult depression. Animal studies comparing the effects of DMI in juveniles and adults are complicated by age-related variations in elimination rates. Thus, different dosing regiments are needed to achieve similar brain drug levels in juvenile and adult rats. We compared the half-life of DMI as well as the brain and serum concentrations of DMI and its active metabolite desmethyldesipramine in juvenile and adult rats after various drug administration paradigms. After acute i.p. administration DMI is eliminated from the brain more slowly in postnatal day (PND) 21 and 28 rats as compared to adults. After chronic i.p. administration (for 4-5 days between PND 9 and 28), lower doses of DMI are needed with juvenile rats to obtain the same brain DMI concentrations as adults. By contrast, two weeks of continuous drug delivery (minipump) to PND 21-35 and adult rats result in similar brain DMI concentrations. Thus, the pharmacokinetic properties of DMI varies with the age of the animal and dosing of DMI and needs to be carefully adjusted in order to have appropriate brain levels of the drug.

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Design of a desipramine dosing regimen for the rapid induction and maintenance of maximal cortical β-adrenoceptor downregulation

Cited by 8 publications

References 9 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

Animal models of attention-deficit hyperactivity disorder

Appropriate dosing regimens for treating juvenile rats with desipramine for neuropharmacological and behavioral studies

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