Effect of antidepressant drugs on the hypothalamic-pituitary-adrenal axis activity and glucocorticoid receptor function

Hyperactivity of hypothalamic-pituitary-adrenal (HPA) axis is the main biochemical change, besides disturbed monoaminergic neurotransmission, observed in the patients suffering from a major depression. High incidence of depression in Cushing's syndrome as well as antidepressant effects of adrenocortical enzyme inhibitors in major depression support hypothesis that hyperactivity of HPA axis may be involved in pathogenesis of depression.     

Effect of antidepressant drugs on serotonergic and adrenergic receptors

Summary We examined eight tricyclic antidepressants (doxepin, amitriptyline, clomipramine, imipramine, trimipramine, nortriptyline, desipramine and protriptyline) and four nontricyclic antidepressants (mianserin, nomifensin, iprindole and zimelidine) in terms of their effects on serotonergic and adrenergic receptors by direct binding assays.³H-WB-4101 (0.22 nM) served as a label for postsynaptic alpha receptors while³H-clonidine (0.2 nM) served to label presynaptic alpha receptors in the frontal cortex of the calf.³H-dihydroalprenolol (³H-DHA) (0.5 nM) was used to label the beta₁ adrenoceptors in the calf frontal cortex and beta₂ adrenoceptors in the calf cerebellar cortex.³H-d-Lysergic acid diethylamide (³H-LSD) (2 nM) and³H-serotonin (³H-5HT) (0.5 nM) were used to label the serotonergic receptors in the calf frontal cortex.The results show that at drug concentrations which occur clinically in the plasma water, most of the tertiary amine tricyclics significantly inhibited³H-WB-4101,³H-LSD and³H-5HT binding. None of the antidepressants tested had any significant effect on³H-DHA binding. The secondary amine tricyclics as a group were not potent in inhibiting the binding of all four radiolabelled ligands. The nontricyclic antidepressant mianserin was potent in inhibiting the binding of³H-WB-4101,³H-clonidine,³H-LSD and³H-5HT. We suggest that the differences between the effects of the antidepressants on adrenergic and serotonergic receptors may be responsible for the differences in their therapeutic efficacies and side effects.Supported by the Canada Medical Research Council and the Ontario Mental Health FoundationA preliminary report of this work was presented at the 9th annual meeting of the Society for Neuroscience, Atlanta, 1979     

Increased glucocorticoid receptor gene promoter activity after antidepressant treatment.

We have tested the hypothesis that antidepressants affect the expression of the glucocorticoid receptor gene, by looking at glucocorticoid receptor gene promoter activity, glucocorticoid receptor mRNA levels, and glucocorticoid-binding activity after treatment of different cell lines with desipramine. Treatment of LTK- cells or Neuro 2A cells with desipramine produced a 50-200% increase in chloramphenicol acetyltransferase activity transcribed from a 2.7-kilobase glucocorticoid receptor gene promoter region. In cell lines derived from both neuronal and non-neuronal sources, glucocorticoid receptor mRNA concentration doubled after desipramine treatment, and this was associated with a 2-fold higher functional glucocorticoid binding capacity and increased glucocorticoid sensitivity, as measured with the reporter plasmid pMMTVCAT. Antidepressant-induced increases in glucocorticoid receptor gene promoter activity, glucocorticoid receptor mRNA levels, and functional glucocorticoid binding activity suggest a novel mechanism of action for these drugs on the hypothalamic-pituitary-adrenal axis.     

Effect of tricyclic antidepressant drugs on lymphocyte membrane structure

Tricyclic antidepressant-induced perturbations of murine splenic lymphocyte membranes and cell surface concanavalin A receptor mobility have been investigated using the fluorescent probes diphenylhexatriene and fluorescein-conjugated concanavalin A. Results of these studies illustrate the possible relationship between tricyclic antidepressant-induced membrane perturbations and tricyclic antidepressant-induced suppression of the normal murine lymphocyte mitogen response. Tricyclic antidepressant effects on murine splenic lymphocyte membranes are dose-, time- and temperature- dependent. Murine lymphocyte concanavalin A cell surface receptor mobility is not apparently altered by the tricyclic antidepressants.     

Effect of antidepressant drugs on the human corticotropin-releasing-hormone gene promoter activity in neuro-2A cells

In order to test if antidepressant drugs can directly influence corticotropin-releasing hormone (CRH) gene expression, their effect on CRH gene promoter activity was evaluated in neuro-2A cells stably transfected with a human CRH - chloramphenicol acetyl-transferase plasmid. Forskolin (an activator of adenylate cyclase), but not phorbol 12-myristate 13-acetate (an activator of protein kinase C), ca. 3-fold increased reporter gene activity, which confirms the critical role of the cAMP-responsive element in regulation of the CRH gene. Imipramine and fluoxetine present in the medium for 5 days, in a concentration-dependent manner (3-30 microM) inhibited the basal activity of CRH gene promoter, while tianeptine was inactive. The obtained results indicate that inhibition of the human CRH gene promoter activity by imipramine and fluoxetine, but not tianeptine, may play a role in a mechanism by which the former drugs attenuate HPA axis activity.     

Effects of antidepressant drugs on the behavioral and physiological responses to lipopolysaccharide (LPS) in rodents.

Antidepressants produce various immunomodulatory effects, as well as an attenuation of the behavioral responses to immune challenges, such as lipopolysaccharide (LPS). To explore further the effects of antidepressants on neuroimmune interactions, rats were treated daily with either fluoxetine (Prozac) or saline for 5 weeks, and various behavioral, neuroendocrine, and immune functions were measured following administration of either LPS or saline. Chronic fluoxetine treatment significantly attenuated the anorexia and body weight loss, as well as the depletion of CRH-41 from the median eminence and the elevation in serum corticosterone levels induced by LPS. Chronic treatment with imipramine also attenuated LPS-induced adrenocortical activation. In rats and in mice, which normally display a biphasic body temperature response to LPS (initial hypothermia followed by hyperthermia), chronic treatment with fluoxetine completely abolished the hypothermic response and facilitated and strengthened the hyperthermic response. The effects of antidepressants on the responsiveness to LPS are probably not mediated by their effects on peripheral proinflammatory cytokine production, because LPS-induced expression of TNFalpha and IL-1beta mRNA in the spleen (assessed by semiquantitative in situ hybridization) was not altered following chronic treatment with either fluoxetine or imipramine. The effects of antidepressants on the acute phase response may have important clinical implications for the psychiatric and neuroendocrine disturbances that are commonly associated with various medical conditions.     

Cardiotoxicity of antidepressant drugs

Most antidepressants affect the cardiovascular system adversely. They may affect blood pressure, the inotropic state of the heart and cardiac conduction. Adverse reactions may occur due to the direct action of these agents or through drug interactions.

The causes of these complications are discussed with relevance to the known action of these drugs.

As these agents may be lethal in both therapeutic dosage and after overdose a knowledge of these abnormalities is essential for safe prescribing.     

Effect of antidepressant drugs on 6-OHDA-treated mice in the FST.

There is growing evidence suggesting that dopamine could be indirectly involved in the appearance of behavioural effects of antidepressants. In this study, we induced a partial (over 70%) and non-reversible depletion of dopamine-containing neurons in mice by i.c.v. infusion of 6-OHDA. Then, we compared the antidepressant-like effect of drugs (citalopram, paroxetine, desipramine and imipramine) with or without dopamine depletion in the mice forced swimming test. Our results clearly show that lesion with 6-OHDA does not modify the response of mice to desipramine and imipramine, whereas dopamine depletion abolished the antidepressant-like effect of citalopram and paroxetine. It could then be suggested that antidepressant-like effect of selective serotonin reuptake inhibitors (paroxetine and citalopram) in the mice FST requires the activation of dopaminergic pathways to occur.     

Effect of antidepressant drugs on monoamine synthesis in brain in vivo.

The activity of tryptophan and tyrosine hydroxylase were estimated in vivo by measuring the accumulation during 30 min of 5-hydroxytryptophan (5-HTP) and 3,4-dihydroxyphenylalanine (DOPA), respectively, after inhibition of aromatic amino acid decarboxylase by administration of m-hydroxybenzylhydrazine (NSD 1015) (100 mg/kg, i.p.). Whereas the activity of tyrosine hydroxylase in the dopamine-rich striatum was sensitive to haloperidol, which caused a significant increase in accumulation of DOPA, there was no effect of haloperidol in the predominantly noradrenergic frontoparietal cortex, confirming that the activity of tyrosine hydroxylase, measured in the frontoparietal cortex, is essentially localized in noradrenergic neurones. In the frontoparietal cortex of the rat the in vivo activity of tryptophan and tyrosine hydroxylase were equipotently attenuated by imipramine, while the selective blocker of the uptake of noradrenaline, desipramine and the selective blocker of the uptake of serotonin, citalopram, reduced only tyrosine or tyrosine hydroxylase respectively. Milnacipran, an antidepressant which inhibits the uptake of both monoamines to a similar extent, decreased the synthesis of both monoamines equipotently. The monoamine oxidase inhibitor, clorgyline, also reduced the synthesis of both monoamines. Thus, the in vivo inhibition of the synthesis of monoamines would appear to be mediated by an increase in synaptic concentration of monoamines, resulting from the inhibition of the uptake or catabolism of monoamines. Chronic administration of citalopram led to a significant increase of the basal synthesis of 5-hydroxytryptamine (5-HT). Milnacipran, given chronically, significantly enhanced the basal synthesis of both 5-HT and noradrenaline (NA).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of antidepressant and neuroleptic drugs on respiratory function of rat heart mitochondria.

The effects of five antidepressants, two phenothiazines and one butyrophenone neuroleptic drug on respiratory functions of rat heart mitochondria were studied in vitro using four different substrates. All compounds caused uncoupling of oxidative phosphorylation with comparable no-effect levels ranging from 1 × 10^?6 to 5 × 10^?5 moles per mg mitochondrial protein. The uncoupling effect was accompanied by increased oxygen consumption. The same drugs were given orally twice daily to rats. Uncoupling of oxidative phosphorylation was observed in mitochondria isolated from hearts of the treated animals. Oxygen consumption was not altered. Serum and myocardial tissue levels were determined with one of the test compounds (protriptyline). Serum concentrations in rats were higher than those observed in patients treated therapeutically, but well below those observed in human overdose situations. The effects on heart mitochondria are considered to be an indicator of altered membrane functions resulting from an accumulation of the drugs in lipid membranes.     

Effect of repeated administration of antidepressant drugs on the isoprenaline-induced drinking in rats

The effect of acute (single dose) and repeated (twice daily, for 21 days) administration of imipramine, amitriptyline, citalopram, mianserin and rolipram (the latter drug in a dose of 5 mg/kg po, all the other drugs in a dose of 10 mg/kg po) on drinking induced by isoprenaline (50 micrograms intracerebroventricularly (icv), 2 h after the single dose, 2 and 72 h after the last does of the antidepressants) was studied in rats. It was found that repeated, but not acute, treatment with imipramine, amitriptyline and rolipram significantly reduced the response to isoprenaline. The effect of amitriptyline and rolipram was observed 2 and 72 h after their last administration, while that of imipramine only 72 h after its last dose. Citalopram and mianserin were ineffective after both acute and repeated administration.     

Neurotrophic effects of antidepressant drugs

The past decade has witnessed a growing interest in the trophic effects of antidepressant drugs. Antidepressants stimulate the production and signaling of plasticity-related proteins such as neurotrophins and cAMP response element binding protein, and neurotrophin signaling appears to be both sufficient and necessary for antidepressant action in rodents. Furthermore, several different antidepressant treatments increase neurogenesis in rodent hippocampus and this effect correlates with the behavioral effects produced by these drugs. These data suggest that antidepressants facilitate activity-dependent selection of functional synaptic connections in brain and, through their neurotrophic effects, improve information processing within neuronal networks compromised in mood disorders.