Reduced inhibitory effect of imipramine on radiolabeled serotonin uptake into platelets in geriatric depression

doi:10.1016/0006-3223(89)90238-2

Biological Psychiatry

Volume 25, Issue 6, 15 March 1989, Pages 687-691

https://doi.org/10.1016/0006-3223(89)90238-2 Get rights and content

Abstract

Tritiated imipramine binding, uptake of radiolabeled serotonin, and inhibition of uptake by imipramine in vitro were studied in platelets obtained from four groups of subjects:

1.
(1) normal controls 50 years of age or younger,
2.
(2) patients with major depression 50 years of age or younger,
3.
(3) normal controls 60 years of age or older,
4.
(4) patients with major depression 60 years of age or older.

Depression in both age groups was associated with a substantial decrease in the number of [³H]imipramine binding sites; the elderly depressed patients exhibited a small but significant (p < 0.05) reduction in platelet [³H]serotonin uptake. However, the inhibition of serotonin uptake into platelets by imipramine was markedly reduced only in the elderly depressed patients. This reduced sensitivity to imipramine may explain the reduced responsiveness of patients with geriatric depression to the therapeutic effects of imipramine and other tricyclic antidepressants.

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Cited by (20)

Regional differences in brain monoamine oxidase subtypes in an animal model of geriatric depression: Effects of olfactory bulbectomy in young versus aged rats
2000, Brain Research
Citation Excerpt :
In geriatric populations, the biological abnormalities associated with depression, and the corresponding efficacy of standard treatments, appear to differ substantially from those in younger patients. In particular, monoamine reuptake inhibitors have a higher rate of failure in the elderly [1,5,7,8,17,24]; we found that the platelet serotonin transporter, a surrogate marker for serotonin transport in the central nervous system, is resistant to inhibition of serotonin uptake by antidepressants in elderly depressed patients [31]. Accordingly, it has been suggested that MAO inhibitors may prove more useful in geriatric depression [16].
Geriatric depression is often associated dysregulation of the hypothalamus–pituitary–adrenal (HPA) axis, and with poor responsiveness to antidepressants that work through inhibition of monoamine reuptake; accordingly, it has been suggested that MAO inhibitors may represent a therapeutic alternative in this group. In the current study, we evaluated expression of MAO subtypes in brain regions of young and aged rats subjected to olfactory bulbectomy (OBX), a procedure that reproduces many of the biochemical and functional changes associated with human depression. Activities of both MAO A and B were elevated in aged rats as compared to young rats in most regions, but not in the midbrain, and the OBX lesion failed to produce any change in this pattern. These results stand in contrast to the differential effects of glucocorticoids, which reduce brain MAO in young animals but induce activity in aged rats. Our results support the view that the aged brain possesses biochemical characteristics that distinguish its monoamine biochemistry from that of young brain, and that these distinctions may work in conjunction with HPA axis dysregulation to influence the etiology and therapy of geriatric depression. The use of appropriate animal models for depression and for disruption of HPA axis function can allow for the testing of potential human biomarkers (such as platelet MAO) that may serve to predict treatment outcome.
Effects of aging and glucocorticoid treatment on monoamine oxidase subtypes in rat cerebral cortex: Therapeutic implications
1998, Brain Research Bulletin
Dysregulation of the hypothalamus–pituitary–adrenal (HPA) axis is more common in elderly depression than in younger cohorts, resulting in elevated glucocorticoid levels. Effectiveness of antidepressant drugs is also impaired in these patients. We evaluated the effects of continuous infusions of dexamethasone on monoamine oxidase (MAO) subtypes in aged rat brain to determine whether unique interactions of glucocorticoids and aging could contribute to abnormal transmitter disposition. Aged rats given dexamethasone showed robust induction of both MAO A (threefold increase) and B (30% increase) in the frontal/parietal cortex, effects in the opposite direction from those seen in young rats treated with glucocorticoids. Our results support the view that depression in the elderly may have biologically discrete components that make it differ from depression in younger people. These distinctions may influence the etiology and therapy of depression, while at the same time providing potential biomarkers (such as platelet MAO) that may serve to predict successful treatment outcome in patient subpopulations.
Glucocorticoid-targeting of the adenylyl cyclase signaling pathway in the cerebellum of young vs. aged rats
1998, Brain Research
Glucocorticoids exacerbate aging-induced cell death, but relatively little is known about other CNS effects in senescence. We examined noradrenergic/adenylyl cyclase signaling in the cerebellum, which is a brain region that is susceptible to deterioration of synaptic function in aging. Aged control rats had increased total cyclase catalytic activity, but showed deficits in basal adenylyl cyclase. Deficits resolved when G-proteins were stimulated with GTP, GTP and fluoride, or GTP and isoproterenol, despite reductions in β-receptors. In young rats, long-term dexamethasone infusions evoked the same types of changes that had been seen in aging, including induction of cyclase catalytic activity and enhanced G-protein responsiveness. The same dexamethasone regimens given to aged rats failed to cause stimulation of these processes in the cerebellum, but did so in a peripheral tissue (kidney). These data indicate homology between the cellular events involved in noradrenergic signaling during aging and after glucocorticoid administration to young animals; the absence of glucocorticoid effects in the elderly cohort supports a convergent mechanism with aging. Given the high incidence of HPA axis dysregulation in the elderly, and particularly in elderly depression, effects of glucocorticoids on cell signaling may contribute to disrupted function and to altered drug reactivity.
Serotonin transporter expression in rat brain regions and blood platelets: Aging and glucocorticoid effects
1997, Biological Psychiatry
Hyperactivity of the hypothalamus-pituitary-adrenal axis is more common in elderly depression than in younger cohorts and glucocorticoids are known to influence serotonergic systems. The current study explores the interaction of glucocorticoids with aging on serotonin transporter expression and function. Continuous infusions of dexamethasone (26 days) reduced transporter expression in the aged brain but the ability of imipramine to inhibit synaptosomal [³H]serotonin uptake was unimpaired. These effects were unique to aged animals, as prior work with young adults found no effects of dexamethasone on transporter expression. In contrast to the effects in the brain, there were no differences in platelet transporter expression between young and old rats nor did dexamethasone treatment affect the values in the aged group: thus, the platelet may not reliably model these aspects of CNS function. The results suggest that there are basic biologic differences in the effects of glucocorticoids in aged vs. young brain that could contribute to lowered effectiveness to antidepressants in elderly depression; if transport capacity is already reduced by the effects of increased glucocorticoids, further inhibition of transport by antidepressants would have proportionally less impact on synaptic serotonin concentrations.
Do glucocorticoids contribute to the abnormalities in serotonin transporter expression and function seen in depression? An animal model
1996, Biological Psychiatry
Adrenocorticosteroids and serotonergic neurons exert reciprocal regulatory actions, and both are abnormal in depression. We evaluated whether glucocorticoids influence the serotonin transporter in rat platelets and brain by infusing dexamethasone for 26 days, sufficient for replacement of the entire platelet population. Effectiveness was verified by measurement of plasma dexamethasone levels, adrenal atrophy, and growth inhibition. At the end of the infusion, we examined [³H]paroxetine binding to platelet, hippocampal, and cerebrocortical membranes, and [³H]serotonin uptake into platelets and synaptosomes. Dexamethasone slightly reduced platelet [³H]paroxetine binding (12%) and had no effect on binding in brain. Platelet [³H] serotonin uptake was unaffected, but synaptosomal uptake was significantly reduced. In neither platelets nor synaptosomes did dexamethasone alter imipramine's ability to inhibit uptake. Thus, elevated glucocorticoids are not responsible for reduced platelet serotonin transporter expression in depression, nor for resistance to imipramine's effect in platelets in elderly depression; however, reduced synaptosomal [³H] serotonin uptake indicates that glucocorticoids can affect transport efficiency, even when the number of transporter molecules is unaltered.
Expression of mRNA coding for the serotonin transporter in aged vs. young rat brain: Differential effects of glucocorticoids
1996, Brain Research
Serotonin transporter mRNA expression in midbrain of young and aged rats was measured after long-term infusion of dexamethasone (0.01 and 0.05 mg/kg/day). Aging alone had no effect. Dexamethasone significantly decreased expression in both young and old rats but the effect was greater in the aged group. Adrenocortical dysregulation is common in elderly depression; our results suggest that glucocorticoids interact with aging to exacerbate abnormalities of serotonergic function, contributing to reduced antidepressant effectiveness.

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^☆: Supported in part by NIMH Grant MH-40159.

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Biological Psychiatry

Abstract

References (17)

Uptake of serotonin into rat platelets and synaptosomes: Comparative structure-activity relationships, energetics and evaluation of the effects of acute and chronic nortriptyline administration

Brain Res Bull

Commentary: Mode of action of antidepressant drugs

Biochem Pharmacol

Alteration of platelet [³H]imipramine binding in mildly depressed patients correlates with disease severity

Biol Psychiatry

The effect of drugs upon the uptake of 5-hydroxytryptamine and metaraminol by human platelets

J Pharm Pharmacol

The inhibition of the uptake of monoamines by blood platelets by phenothiazines and other drugs

Chemotherapy in Psychiatry

Drugs and the treatment of psychiatric disorders

Development of β-adrenergic receptor subsensitivity by antidepressants

Nature (Lond)

Cited by (20)

Regional differences in brain monoamine oxidase subtypes in an animal model of geriatric depression: Effects of olfactory bulbectomy in young versus aged rats

Effects of aging and glucocorticoid treatment on monoamine oxidase subtypes in rat cerebral cortex: Therapeutic implications

Glucocorticoid-targeting of the adenylyl cyclase signaling pathway in the cerebellum of young vs. aged rats

Serotonin transporter expression in rat brain regions and blood platelets: Aging and glucocorticoid effects

Do glucocorticoids contribute to the abnormalities in serotonin transporter expression and function seen in depression? An animal model

Expression of mRNA coding for the serotonin transporter in aged vs. young rat brain: Differential effects of glucocorticoids

Reduced inhibitory effect of imipramine on radiolabeled serotonin uptake into platelets in geriatric depression☆

Abstract

Brain Res Bull

Biochem Pharmacol

Biol Psychiatry

The effect of drugs upon the uptake of 5-hydroxytryptamine and metaraminol by human platelets

J Pharm Pharmacol

The inhibition of the uptake of monoamines by blood platelets by phenothiazines and other drugs

Chemotherapy in Psychiatry

Drugs and the treatment of psychiatric disorders

Development of β-adrenergic receptor subsensitivity by antidepressants

Nature (Lond)