Clinical and experimental studies on the pathogenesis of depression

doi:10.1016/0306-4530(77)90017-8

Psychoneuroendocrinology

Volume 2, Issue 2, 1977, Pages 115-130

https://doi.org/10.1016/0306-4530(77)90017-8 Get rights and content

Abstract

(1) Serum TSH responses to TRH showed abnormal patterns in terms of diminished, delayed and exaggerated responses in more than one third of the depressed patients. (2) These findings suggest the pathogenetic importance of the hypothalamo-pituitary dysfunction in depressed patients. Because of this, a number of patients, especially those with diminished and delayed TSH responses to TRH, are prone to develop latent hypothyroidism which might make them resistant to antidepressants. (3) To elucidate the underlying mechanism of these clinical findings, changes in brain monoamines of ‘depression model rats’ were examined by the histochemical fluorescence method. (4) Fluorescence intensity in nerve cells of the ascending NA system (A1, A2, A5, A6, A7) was markedly increased and fluorescence intensity in cell bodies (A12) and nerve terminals (ext. ME) of the tubero-infundibular DA system was decreased.

References (22)

M. Fujiwara et al.
Histochemical demonstration of noradrenaline in rat salivary glands
Jap. J. Pharmacol.
(1965)
T. Maeda et al.
Projections ascendantes du locus coeruleus et d'autres neurones aminergiques pontiques au niveau du prosencephale du rat
Brain Res.
(1972)
L. Olson et al.
Further mapping out of central noradrenaline neuron projections of the ‘subcoeruleus’ area
Brain Res.
(1972)
R.H. Roth et al.
Noradrenergic neurons: allosteric activation of hippocampal tyrosine hydroxylase by stimulation of the locus coeruleus
Biochem. Pharmacol.
(1974)
R.E. Zigmond et al.
Increased tyrosine hydroxylase activity in the locus coeruleus of rat brain stem after reserpin treatment and cold stress
Brain Res.
(1974)
J. Avni et al.
Comparative study of imipramine, amitriptyline and their desmethyl analogues in the hypothyroid rat
Psychopharmacologia, Berlin
(1967)
I.J. Chopra et al.
An improved radioimmunoassay of triiodothyronine in serum: its application to clinical and physiological studies
J. Lab. clin. Med.
(1972)
J.A. Coppola et al.
Induction of pseudopregnancy in rats by depletors of endogenous catecholamines
Endocrinology
(1965)
A. Dahlstrom et al.
Evidence for the existence of monoamine containing neurones in the central nervous system. I. Demonstration of monoamines in the cell bodies of brain stem neurons
Acta physiol. scand.
(1964)
M. Endo et al.
Endocrine studies in depression

B. Falck et al.

Fluorescence of catecholamines and related compounds condensed with formaldehyde

J. Histochem. Cytochem.

(1962)

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Persistent depressive state after chronic stress in rats is accompanied by HPA axis dysregulation and reduced prefrontal dopaminergic neurotransmission
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Exposure to stress is thought to play an important role in the etiology of depression. Dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis characterized by glucocorticoid negative feedback resistance is frequently observed in human depressives. Additionally, dysfunctions of the dopaminergic and serotonergic systems in the prefrontal cortex (PFC) are thought to be involved in the development of a depressive state. In rats, chronic stress induces a behaviorally depressive state, concomitant with dysregulation of the HPA axis and reductions in dopaminergic and serotonergic transmissions in the PFC. Considering that dysregulation of the HPA axis is associated with relapse and persistency of depression, it is possible that the chronic stress-induced depressive state persists during long-term rest after its exposure. In the present study, we examined this possibility in rats and found that the behaviorally depressive state in the rotarod test, negative feedback resistance in the dexamethasone suppression test, and a decrease in the extracellular concentration of dopamine but not serotonin in the PFC persisted for 3 months following a 4-week stress session. These results suggest that dysregulation of the HPA system and reduced dopaminergic transmission in the PFC underlies persistent behavioral depression following chronic stress.
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Hypersecretion of corticotropin-releasing factor (CRF) has been hypothesized to occur in depression. To investigate CRF receptor (CRFR) response to the increased production of CRF in chronically stressed rats, we measured by in situ hybridization the expression of CRFR mRNA in the locus coeruleus (LC) concomitant with measuring plasma adrenocorticotropin (ACTH). The expression of both CRFR mRNA in the LC and the plasma level of ACTH increased significantly in “depression-model rats” which exhibit reduced activity following exposure to 14 days forced walking stress (FWS), but not in “spontaneous recovery rats” whose activity was restored after the long-term stress. These results suggest that the LC neurons continue to be stimulated by CRF, and that the hypothalamic-pituitary-adrenal (HPA) axis is hyperfunctioning in the depression-model rats.
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  Clonidine, an alpha2 agonist, was administered immediately after a single session of 8 min immobilization stress in a restraining box, followed by locomotion measurement on day 1, day 7, and day 14 after the stress session.
- 3.
  In the saline-treated control group, locomotion on day 1, day 7, and day 14 after the 8 min stress session was significantly reduced to about 80 % in comparison with that before the stress. This finding confirmed the previous report that a single stressful event could lead to long-lasting behavioral changes. When clonidine was administered, locomotion reduction was not observed on any post-stress day.
- 4.
  The results suggest that early intervention by noradrenergic inhibition to stressful events may have a preventive effect on subsequent behavioral change which may be considered as an animal model of post-traumatic stress disorder.

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Symposium paperClinical and experimental studies on the pathogenesis of depression

Abstract

Jap. J. Pharmacol.

Brain Res.

Brain Res.

Biochem. Pharmacol.

Brain Res.

Comparative study of imipramine, amitriptyline and their desmethyl analogues in the hypothyroid rat

Psychopharmacologia, Berlin

An improved radioimmunoassay of triiodothyronine in serum: its application to clinical and physiological studies

J. Lab. clin. Med.

Induction of pseudopregnancy in rats by depletors of endogenous catecholamines

Endocrinology

Evidence for the existence of monoamine containing neurones in the central nervous system. I. Demonstration of monoamines in the cell bodies of brain stem neurons

Acta physiol. scand.

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Fluorescence of catecholamines and related compounds condensed with formaldehyde

J. Histochem. Cytochem.

Symposium paper
Clinical and experimental studies on the pathogenesis of depression