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

Abstract

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.

Elements toward novel therapeutic targeting of the adrenergic system

“…These new elements are consistent with the previous related data which show that tricyclic antidepressants, monoamine oxidase inhibitors, and venlafaxine, that exert their clinical effects mainly by acting on the noradrenergic system (Subhash et al, 2003), may not be recommended to treat depression in children, whereas they are efficacious in adults (Geller et al, 1999;Hazell et al, 2000;Varley, 2003;Whittington et al, 2004). Furthermore, in 2007 the immature regulatory system for the a2-AR was proposed as one of the reasons that may explain the reduced effect of tricyclic antidepressant in pediatric populations compared with adults Deupree et al, 2007). On the other hand, long term consequences of the drugs acting on a2-AR require clinicians to pay more attention to children and adolescent populations if such populations are treated with such agents (Sanders et al, 2008) because of the age-related differences.…”

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

“…In this model using 21-day old animals, the SSRIs fluoxetine (at 10 mg/kg) and escitalopram (at 10 and 20 mg/kg) increased swimming, but not climbing, behavior just as seen in the adult (Reed et al, 2007). Escitalopram (at 20 mg/kg) also decreased immobility.…”

Pharmacological properties of the active metabolites of the antidepressants desipramine and citalopram

“…In the rat, the major metabolite of desipramine is desmethyldesipramine Chronic treatment of rats with desmethyldesipramine has been shown to down-regulate the β-adrenoceptor with a potency similar to desipramine (Argenti and D'Mello, 1994;Deupree et al, 2007). Treatment of rats with desipramine can result in the concentration of desmethyldesipramine reaching levels similar to that of the parent compound (Kozisek et al, 2007).…”