Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A variety of biologic studies have demonstrated abnormal regulation of the norepinephrine (NE) system in patients with major depression, suggesting a role for NE in the etiology of depression. Brain NE and dopamine levels can be rapidly reduced by blocking synthesis with the tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine (AMPT). In the current investigation, AMPT was administered to drug-free depressed patients to evaluate the effect on mood of diminished catecholamine levels. Seventeen drug-free patients meeting DSM-III-R criteria for major depressive episode were tested with AMPT and an active placebo control, diphenhydramine. Testing was accomplished in a double-blind, crossover fashion, with random assignment to test conditions. Each test included baseline evaluation, 2 days with administration of either AMPT or diphenhydramine, and a follow-up day. Diphenhydramine was used as an active control because of the significant sedation associated with AMPT. Behavioral ratings, including visual analogue scales for a variety of feeling states, the Hamilton Depression Rating Scale (HDRS), and plasma for 3-methoxy-4-hydroxyphenelethyleneglycol (MPHG) and homovanillic acid (HVA) levels, were obtained. AMPT significantly reduced plasma HVA by 70% and MHPG by 50%, but it had no significant effects on the HDRS. AMPT also significantly increased visual analogue ratings of "tired" and decreased ratings of "energetic." Diphenhydramine significantly decreased HDRS scores, but the change was small and was not clinically apparent. The lack of AMPT effects on depressed mood, in conjunction with a prior report that large reductions in plasma tryptophan do not systematically alter depressed mood, indicate that monoamine deficiency by itself is insufficient explanation of the cause of depression. The role of the noradrenergic system needs to be considered in relationship to the many other neurobiologic factors that could be involved in the pathophysiology of depression.
 ...
PMID:Effects of alpha-methyl-para-tyrosine (AMPT) in drug-free depressed patients. 886 98

The effect of pinealectomy, superior cervical ganglionectomy and melatonin replacement on diurnal variations in submaxillary lymph node ornithine decarboxylase activity, tyrosine hydroxylase activity and [3H]choline conversion to [3H]acetylcholine were examined in rats subjected to pinealectomy, bilateral superior cervical ganglionectomy or their respective sham-operations, and treated with Freund's complete adjuvant or its vehicle. In both immunized and nonimmunized sham-operated rats, significant diurnal variations in ornithine decarboxylase activity were detectable, with a maximum at 13.00 h (vehicle) or at 17.00 h (Freund's adjuvant). In rats subjected to pinealectomy, ornithine decarboxylase activity decreased by about half, still exhibiting significant diurnal variations with a maximum at 13.00 h. Abolition of circadian rhythmicity and depression of ornithine decarboxylase activity to about one third of controls were found in submaxillary lymph nodes of bilaterally superior cervical ganglionectomized rats. Administration of melatonin (30 micrograms/animal) in the late evening during 11 days counteracted the depressed levels and suppressed the amplitude of diurnal rhythmicity of ornithine decarboxylase in pinealectomized or bilaterally superior cervical ganglionectomized rats, as well as augmented enzyme activity in sham-operated controls. The amplitude and mean levels of 24-hour rhythms in submaxillary lymph node tyrosine hydroxylase activity and [3H]choline conversion to acetylcholine (that attained their maxima at 21.00-1.00 and 13.00-17.00 h, respectively) decreased significantly after pinealectomy, these effects being significantly counteracted by melatonin injection. Melatonin augmented tyrosine hydroxylase activity and acetylcholine synthesis in sham-pinealectomized rats. The results are compatible with the view that the pineal gland plays a role in circadian changes of immune responsiveness in lymphoid tissue via an immunopotentiating effect of melatonin on lymph node cell proliferation.
 ...
PMID:Diurnal rhythms in ornithine decarboxylase activity and norepinephrine and acetylcholine synthesis and acetylcholine synthesis of rat submaxillary lymph nodes: effect of pinealectomy, superior cervical ganglionectomy and melatonin replacement. 894 25

This study was designed to determine the behavioral effects of a reduction in catecholamine and indoleamine function in healthy subjects. Eight healthy subjects received the tyrosine hydroxylase inhibitor, alpha-methyl-para-tyrosine (AMPT) in combination with a full-strength tryptophan-depleting amino acid drink during one 4-day test session, and AMPT and tryptophan-supplemented amino acid drink (n = 2), or a 25% strength tryptophan-depleting amino acid drink (n = 6) during a second 4-day test session. The combined administration of AMPT and the tryptophan-free amino acid drink did not produce statistically significant or even clinically noticeable changes in mood among the healthy subjects. The implications of these observations for the monoamine hypotheses of depression are discussed.
 ...
PMID:Lack of behavioral effects of monoamine depletion in healthy subjects. 898 96

Previous data have clearly suggested that the posterior pituitary (PP), consisting of neural lobe (NL) and intermediate lobe (IL), has a role in the control of anterior pituitary PRL secretion. However, basic aspects of this regulatory mechanism like (1), the role of an intact hypothalamic innervation of the PP as well as (2) the site of production of previously found PRL releasing substance(s) have not yet been characterized. Denervation of the PP (PPD) is an effective method for having a selective lesion of the innervation of PP, indeed, PPD results in a disappearance of neurosecretory materials from NL and tyrosine hydroxylase (TH) immunoreactivity from IL, leaving blood supply of all three lobes intact. Blood samples were taken from freely moving sham an PP-denervated lactating rats before and after 4-h separation from their pups and during the suckling stimulus. PPD blocks separation-induced depletion but only attenuates suckling induced release of PRL. Furthermore, it doubles plasma level of alpha-MSH during the entire sampling period, which has been used as a marker for in vivo secretory activity of IL cells. Lack of the separation-induced depression in plasma PRL of PPD animals can be partially restored by normalizing the diabetes insipidus with treatment of a vasopressin analogue, 1-desamino-8-D-arginine-vasopressin (dDAVP). In contrast, dDAVP, neither alone nor in combination with oxytocin (OXY), can change PPD-induced elevation of plasma alpha-MSH as well as attenuation of PRL response induced by suckling. It is concluded that: (1) contribution of the THDA system parallel to the confirmed role in the regulation of alpha-MSH seems to be crucial for the depletion of plasma PRL induced by separation but not for the elevation due to suckling stimulus, (2) intact hypothalamic innervations of both NL and IL, regulating water intake and the secretion of alpha-MSH, respectively, are necessary for normal secretory responses of AL during lactation, (3) as well as for the presence of PRF activity in PP, (4) which does not solely responsible for suckling-induced PRL release. Therefore, an interplay between several substances produced by NIL of the pituitary gland must have been responsible for the intact regulation of PRL secretion during lactation.
 ...
PMID:Effect of posterior pituitary denervation (PPD) on prolactin (PRL) and alpha-melanocyte-stimulating hormone (alpha-MSH) secretion of lactating rats. 922 42

The loss of nigrostriatal tyrosine hydroxylase (TH), dopamine and dopaminergic neurons are the major pathology of Parkinson's disease (PD). These catecholaminergic changes are responsible for the symptoms of tremor, hypokinesia and rigidity. Depression is also a major symptom in PD, but the cause is unknown. The impairments of catecholaminergic fibers in the frontal lobe may be involved, because the frontal lobe of the cerebrum is involved in the regulation of mood, and decreased catecholaminergic activity in the frontal lobe is related to behavioral depression. The changes that damage the nigrostriatal dopamine system and induce motor impairments may also damage the forebrain catecholamine fibers and induce depression. It means that manipulations that damage the nigrostriatum (NS) and induce parkinsonism may also deplete TH in the frontal cortex. Such an effect would suggests a basis for the depression seen in PD. The injection of S-adenosyl-L-methionine (SAM), the biological methyl donor, into the brain of rats damaged the NS, depleted TH and caused tremor and hypokinesia. SAM may interfere also with the forebrain TH, which may help to explain the occurrence of depression in PD. Experiments were designed to test such a hypothesis. The results showed that SAM caused a loss of immunoreactive nerve fibers and it decreased the intensity of TH-immunoreactivity (IR) in the frontal cortex. These changes were accompanied with the loss of cells and the depletion of TH-IR from nerve fibers in the SN and the caudate nucleus. Other studies showed that SAM depletes DA and since SAM induces PD-like changes the results may be relevant to the co-occurrence of PD symptoms and depression. A single biological manipulation may impair the nigrostriatal dopaminergic neurons as well as the frontal cortex catecholaminergic fibers.
 ...
PMID:Depletion of nigrostriatal and forebrain tyrosine hydroxylase by S-adenosylmethionine: a model that may explain the occurrence of depression in Parkinson's disease. 924 19

This review summarizes some of the evidence implicating a dysfunction in the noradrenergic system in depression. Whereas the results of studies reporting changes in the concentration of the main noradrenaline metabolite, 3-methoxy-4-hydroxyphenylglycol, are equivocal, changes in adrenoceptor density and function and changes in adrenoceptors associated with the pituitary-adrenal axis function strongly implicate a disorder in central noradrenergic transmission in depression. This dysfunction may be caused by changes in the activity of tyrosine hydroxylase, the rate-limiting enzyme in the synthesis of catecholamines. The effect of corticotrophin releasing factor in modulating the activity of noradrenergic neurons in the locus coeruleus may provide the link between environmental trigger factors and central noradrenergic dysfunction. At the cellular level, evidence is presented of a link between noradrenaline and glutamate (via the N-methyl-aspartate receptor) and receptors. Such a link may provide a basis for the future development of novel antidepressants.
 ...
PMID:The role of noradrenaline in depression: a review. 943 32

Abnormal brain noradrenergic function is thought to cause depressive illnesses which are sometimes manifested or aggravated under stressful conditions. To investigate the effect of chronic stress on noradrenaline (NA) synthesis in the brain we used in situ hybridization to examine the expression of tyrosine hydroxylase (TH) mRNA in the locus coeruleus (LC) of "depression-model rats" that exhibit reduced activity following exposure to long-term (14 days) forced walking stress (FWS). We also examined TH mRNA expression in rats stressed for 30 minutes, 3 hours and 1, 2 (short-term), 6 or 12 (long-term) days. The expression of TH mRNA increased markedly following 1 to 12 days of FWS, but not in rats exposed to FWS for 30 minutes or 3 hours. The expression also increased significantly in the depression-model rats, but not in the "spontaneous recovery rats" whose activity was restored after long-term stress. Our results suggest that NA synthesis remains high in the FWS-induced depression-model rats because of the high levels of TH mRNA expression in the LC. Our results also suggest that FWS is initially a mild stress but gradually becomes a severe form of unadaptable stress as reflected by delayed but persistent increases in TH mRNA expression.
 ...
PMID:Tyrosine hydroxylase gene expression in the locus coeruleus of depression-model rats and rats exposed to short-and long-term forced walking stress. 962 87

Young (50 days old) and old (18 months old) Sprague-Dawley rats were injected with mycobacterial Freund's adjuvant to produce an inflammatory disease of the joints and were studied the day before, and on days 6, 12 and 18 after injection. At every postinjection interval examined, old rats had significantly lower circadian amplitudes of pineal melatonin content. On day 18 of arthritis development, decreased levels of pineal melatonin were also seen in young rats. A second study, carried out 18 days after the injection of Freund's complete adjuvant and after 17 daily injections of 10 or 100 microg of melatonin in the evening, indicated that melatonin treatment restored the inflammatory response in old rats (assessed plethysmographically in hind paws) to the level found in young animals. In young rats, an inflammation-promoting effect of 100 microg melatonin could be demonstrated. As a consequence of the immune reaction, submaxillary lymph node and splenic ornithine decarboxylase activity (an index of lymph cell proliferation) augmented significantly, with acrophases of 24-hour rhythms in the afternoon for lymph nodes or in the morning for spleen. Mesor and amplitude of ornithine decarboxylase rhythm were lowest in old rats, while melatonin injection generally augmented its amplitude. Lymph node and splenic tyrosine hydroxylase activity (a presynaptic adrenergic marker) reached maximal values during early night hours while maximal values of [3H]acetylcholine synthesis (a presynaptic cholinergic marker) occurred during the afternoon in lymph nodes. Amplitude and mesor of these rhythms were lowest in old rats, an effect generally counteracted by melatonin treatment. The results suggest that inflammation is accompanied by an age-dependent, significant depression of pineal melatonin synthesis during adjuvant-induced arthritis and a decreased amplitude of the circadian rhythm of immune cell proliferation and autonomic activity in lymph nodes and spleen. These effects are counteracted by injection of melatonin, mainly in old rats.
 ...
PMID:Effect of melatonin on 24-hour rhythms of ornithine decarboxylase activity and norepinephrine and acetylcholine synthesis in submaxillary lymph nodes and spleen of young and aged rats. 964 17

Methamphetamine (METH) is a major drug of abuse which causes neurotoxicity by depleting dopamine, its metabolites, high-affinity dopamine uptake sites and tyrosine hydroxylase activity in the striatum. Dopamine depletion and reduced dopamine transit are associated with depression. S-Adenosylmethionine (SAM) is the chief methyl donor used in dopamine and other neurotransmitter metabolism in mammals. Low SAM is associated with depression and other psychological and neurological disorders in humans. SAM is used to treat depression and some other neurological and psychiatric disorders. The present study was designed to determine if single or multiple doses of METH induce alterations in blood or liver SAM in mice and if these correlate with dopamine levels in the striatum. Adult male C57 mice were injected intraperitoneally with either single (1 x 40 mg/kg) or multiple (4 x 10 mg/kg) doses of METH. Animals were sacrificed at various intervals. A single injection of METH resulted in slightly higher blood SAM levels at 4 hr. Multiple doses of METH resulted in decreased hepatic and blood SAM levels at 72 hr. Blood SAM returned to control levels by 1 wk. Published work shows that dopamine levels increase hours after a single injection of METH, whereas dopamine decreases days after multiple injections of METH. These present data clearly demonstrate that METH dosing leads to significant alterations in liver and blood SAM and that these changes in SAM levels correlate with changes in striatal dopamine levels.
 ...
PMID:Methamphetamine treatment affects blood and liver S-adenosylmethionine (SAM) in mice. Correlation with dopamine depletion in the striatum. 966 77

Although stress is a major contributory factor in the development of depression, the relationship between stress and depression is still unclear. In this study, we evaluated basal mRNA levels of several genes involved in neurotransmitter biosynthesis and the effect of stress in Flinder's Sensitive Line (FSL), a genetic rat model of depression. In adrenals, basal levels of tyrosine hydroxylase (TH), dopamine beta-hydroxylase (DBH), phenylethanolamine N-methyltransferase (PNMT) and GTP cyclohydrolase I (GTPCH) mRNAs were markedly elevated in FSL rats compared to the control strain. As opposed to control strain, immobilization stress (IMO) to FSL rats, did not further raise DBH, PNMT or GTPCH mRNAs and had relatively mild effect on TH. In contrast to enzymes involved in catecholamine biosynthesis, basal NPY and its response to IMO were unchanged in FSL rats. In the brain, the two major dopaminergic nuclei displayed differences. In substantia nigra, TH mRNA levels were similar in both strains, and elevated by IMO only in FSL rats. In ventral tegmental area in FSL rats, TH mRNA was 2-fold higher than in the control strain and not further elevated by IMO. These high basal mRNA levels and abnormal response to stress in several catecholaminergic cell types in FSL rats may be related to the manifestations of depression.
 ...
PMID:Altered gene expression for catecholamine biosynthetic enzymes and stress response in rat genetic model of depression. 983 81


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>