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)

Corticotropin-releasing hormone (CRH) and catecholamines are suggested to play a significant role in the pathophysiology of depression. In the present study we investigated gene expression of CRH in the hypothalamic paraventricular nucleus (PVN) and tyrosine hydroxylase (TH) in the locus coeruleus (LC) in an experimental model of depression. A chronic mild stress model was applied in rats of both genders for a three-week period. Anhedonic behaviour, a typical sign of depression-like state, was measured by a sucrose preference test. The chronic mild stress induced a decrease in sucrose preference in both genders. The body weight gain was reduced in males only. The total activity in the open field test was unchanged, however, male rats exposed to chronic mild stress showed enhanced locomotor activity during the first minute of the session, suggesting increased anxiety. Basal plasma corticosterone levels, thymus and adrenal weights measured on the third day after cessation of the stress regimen, were not affected by the stress procedure. Evaluation of CRH mRNA levels in the PVN by in situ hybridisation revealed a significant rise in response to chronic mild stress in males. In females, the basal CRH mRNA levels were higher compared to those in males, but the stress-induced rise was absent. Chronic mild stress resulted in a decrease in TH mRNA levels in the LC. These data demonstrate that chronic mild stress model of depression induces a specific stress response with a reduction of TH gene expression in the LC and clear gender differences in gain of body weight, anxiety-like behaviour, and CRH mRNA levels in the PVN.
 ...
PMID:Corticotropin-releasing hormone mRNA levels in response to chronic mild stress rise in male but not in female rats while tyrosine hydroxylase mRNA levels decrease in both sexes. 1107 Mar 36

Synaptic transmission in the superior cervical ganglion (SCG) is mediated by nicotinic acetylcholine receptors (nAChR). After transection of the postganglionic nerves of the SCG in the adult rat, the transcript levels of four of the five nAChR subunits present in the ganglion, alpha3, alpha5, alpha7, and beta4, decrease dramatically. In the present study, the effect of axotomy on nAChR subunit expression was examined at the protein level, focusing on the alpha7 and beta4 subunits. Immunohistochemistry with monoclonal antibody mAb306 (for the alpha7 subunit) and polyclonal antibody 4886 (for the beta4 subunit) showed that immunoreactivities for both alpha7 and beta4 subunits were concentrated in neurons in the intact ganglion. Results from double staining with antibodies to these subunits and to tyrosine hydroxylase, the enzyme that catalyzes the rate-limiting step in the biosynthesis of the sympathetic neurotransmitter norepinephrine, demonstrated that most neurons in the SCG express both the alpha7 and beta4 subunits. Three days after axotomy, the number of immunolabeled neurons and the intensity of the immunostaining per labeled neuron were decreased for both subunits. Decreases in subunit levels were also observed by Western blot analysis. Observing changes in these subunits over time after surgery revealed that, while the protein level of the alpha7 subunit recovered substantially within 2 weeks after the lesion, that of the beta4 subunit stayed low. These data demonstrate that decreases in nicotinic receptor subunits are among the changes in proteins that occur in axotomized sympathetic neurons, and suggest that these decreases may contribute to the depression in ganglionic synaptic transmission observed in axotomized ganglia.
 ...
PMID:Nicotinic acetylcholine receptor subunit proteins alpha7 and beta4 decrease in the superior cervical ganglion after axotomy. 1116 4

Chronic mild or moderate stress elicits an adaptive change in central nervous systems that function to maintain homeostasis. The principal components of stress response are the extrahypothalamic corticotropin-releasing hormone (CRH) and the locus coeruleus (LC)-norepinephrine (NE) systems. CRH is known to produce various stress-, anxiety- and arousal-associated behaviors in animals. Moreover, CRH causes an increase in the firing rate and activity of tyrosine hydroxylase in the LC, and NE release in LC projection areas. It is thought that chronic inescapable and unpredictable stress can result in a sustained dysregulation of both CRH neuronal activity and LC-NE systems. One may hypothesize that the NE-CRH interaction occurs in the terminal projection of forebrain NE systems, the hypothalamic paraventricular nucleus (PVN), the bed nucleus of the stria terminalis (BNST) and the central nucleus of the amygdala (CeA) where NE stimulates CRH release. Such CRH-NE-CRH feed-forward systems elicit progressive augmentation of stress responsivity with repeated exposure. The beta-adrenergic receptor down-regulation is induced by acute and chronic exposure to moderate and predictable stress, implying an adaptation to stress. However, chronic unpredictable (variable) stress (CVS), a model for depression, up-regulated the beta-AR. In our laboratory, we found that concurrent treatment with the selective serotonin reuptake inhibitor (SSRI) citalopram caused beta-R down-regulation in the frontal cortex of rats treated with CVS for 14 days. As previously reported by the authors, an increase in 5-HT availability plays a role in preserving beta-R down-regulation by NE potentiating agents. In depressed patients, hyperactivation of the CRH-NE systems caused by the CRH-NE feed-forward system is thought to be involved in generating anxiety, sympathetic activation and hyperarousal. Moreover, a decrease in the 5-HT turnover in depressed patients has been reported. Accordingly, it is proposed that an increase in 5-HT availability by SSRI might contribute to normalize beta-R down-regulation as an adaptive regulatory mechanism against excessive CRH-NE neurotransmission under a "stressful" situation.
 ...
PMID:[Influences of chronic stress on central nervous systems]. 1121 56

Gonadectomy in adult male rats induces a series of changes in cortical catecholamine innervation that begins with a large, but transient decrease in the density of tyrosine hydroxylase- but not dopamine-beta-hydroxylase-immunoreactive axons in sensory, motor, and association cortices. More recent studies have shown that estradiol maintains these presumed dopamine afferents but that supplementing acutely gonadectomized rats with dihydrotestosterone provides no protective effects for innervation. These findings suggest that the depression of mesocortical dopamine axons that follows gonadectomy is stimulated by changes in estrogen signaling. The studies presented here examined tyrosine hydroxylase and dopamine-beta-hydroxylase innervation in hormonally intact adult male rats treated for 4 days with the nonsteroidal antiestrogen tamoxifen or with the nonsteroidal antiandrogen flutamide to probe for additional evidence for this selective hormone sensitivity and for insights into the intracellular mechanisms that may govern it. Qualitative and quantitative comparisons of innervation with corresponding data from control and acutely gonadectomized rats revealed that administration of the antiestrogen tamoxifen in hormonally intact rats produced deficits in catecholamine innervation that mirrored those induced by short-term gonadectomy. The antiandrogen flutamide, however, had no discernible impact on cortical afferents. When considered within the context of the known pharmacology and sites of action of tamoxifen, these findings not only provide additional support for an initial phase of selective estrogen sensitivity among the cortical catecholamines but also suggest that it is stimulation of intracellular estrogen receptors that confers this sensitivity in the adult rat cerebrum.
 ...
PMID:Administration of tamoxifen but not flutamide to hormonally intact, adult male rats mimics the effects of short-term gonadectomy on the catecholamine innervation of the cerebral cortex. 1122 14

Corticotropin-releasing hormone (CRH) interacts with noradrenergic, dopaminergic and cholinergic systems of the brain, and these interactions are thought to be of relevance for the stress response, anxiety-related behavior, and cognitive function. CRH mediates its central effects through two high-affinity membrane receptors, CRH receptor subtypes 1 and 2. It is however unclear at present whether cholinergic or catecholaminergic cells express these receptors themselves or whether the effects of CRH are indirectly mediated through interaction with other neurotransmitter systems. Therefore, this study investigated whether choline acetyltransferase immunoreactive neurons of the murine basal forebrain and brainstem nuclei, and tyrosine hydroxylase immunoreactive neurons located within the locus coeruleus, ventral tegmental area and substantia nigra co-express CRH receptor 1, employing a double-immunocytochemical procedure. Using an antibody against the C-terminus of the CRH type 1 receptor (CRH-R1), CRH-R1-like immunoreactivity was found in all cholinergic basal forebrain nuclei except the nucleus basalis magnocellularis. In particular, the diagonal band of Broca (vertical and horizontal limbs) showed a high degree of co-localization of CRH-R1 immunoreactivity and choline acetyltransferase immunoreactivity (both limbs >90%). A less intense immunoreactivity but still high rate of co-localization was detected in the cholinergic neurons of the medial septum (80%), while lowest co-localization was observed in choline acetyltransferase immunoreactive neurons of the substantia innominata (58%). An intermediate degree of co-localization (75%) was seen in the brainstem pedunculopontine tegmental nucleus, while the other major brainstem cholinergic nucleus, the laterodorsal tegmental nucleus, showed an even higher degree of choline acetyltransferase immunoreactivity-positive cells also immunoreactive for CRH-R1 (92%). All catecholaminergic structures studied displayed a pattern of CRH-R1 immunoreactivity strongly overlapping the pattern of tyrosine hydroxylase immunoreactivity. The intensity of the CRH-R1 signal was relatively low within the ventral tegmental area and the substantia nigra pars compacta, while the CRH-R1 signal was very intense and detected in almost all of the neurons of the locus coeruleus. These results clearly demonstrate that the cholinergic and catecholaminergic systems provide direct anatomical substrates for CRH action through the CRH-R1. These findings are of particular relevance for understanding the action of recently developed CRH-R1 antagonistic drugs which may offer a new therapeutic approach to treat stress-related disorders such as anxiety and depression and their concomitant alterations in arousal and cognitive functions.
 ...
PMID:Detection of corticotropin-releasing hormone receptor 1 immunoreactivity in cholinergic, dopaminergic and noradrenergic neurons of the murine basal forebrain and brainstem nuclei--potential implication for arousal and attention. 1144 Jul 98

Noradrenergic and dopaminergic mechanisms have been proposed for the pathophysiology of seasonal affective disorder (SAD). We investigated the effects of catecholamine depletion using alpha-methyl-para-tyrosine (AMPT), an inhibitor of tyrosine hydroxylase, in patients with SAD in natural summer remission. Nine drug-free patients with SAD by DSM-IV criteria, in summer remission for at least eight weeks, completed a double-blind, crossover study. Behavioral ratings and serum HVA and MHPG levels were obtained for 3-day sessions during which patients took AMPT or an active control drug, diphenhydramine. The active AMPT session significantly reduced serum levels of HVA and MHPG compared with the control diphenhydramine session. The AMPT session resulted in higher depression ratings with all nine patients having significant clinical relapse, compared with two patients during the diphenhydramine session. All patients returned to baseline scores after drug discontinuation. Catecholamine depletion results in significant clinical relapse in patients with SAD in the untreated, summer-remitted state. AMPT-induced depressive relapse may be a trait marker for SAD, and/or brain catecholamines may play a direct role in the pathogenesis of SAD.
 ...
PMID:Effects of alpha-methyl-para-tyrosine-induced catecholamine depletion in patients with seasonal affective disorder in summer remission. 1168 83

Various heme-containing proteins have been proposed as primary molecular O(2) sensors for hypoxia-sensitive type I cells in the mammalian carotid body. One set of data in particular supports the involvement of a cytochrome b NADPH oxidase that is commonly found in neutrophils. Subunits of this enzyme have been immunocytochemically localized in type I cells, and diphenyleneiodonium, an inhibitor of the oxidase, increases carotid body chemoreceptor activity. The present study evaluated immunocytochemical and functional properties of carotid bodies from normal mice and from mice with a disrupted gp91 phagocytic oxidase (gp91(phox)) DNA sequence gene knockout (KO), a gene that codes for a subunit of the neutrophilic form of NADPH oxidase. Immunostaining for tyrosine hydroxylase, a signature marker antigen for type I cells, was found in groups or lobules of cells displaying morphological features typical of the O(2)-sensitive cells in other species, and the incidence of tyrosine hydroxylase-immunopositive cells was similar in carotid bodies from both strains of mice. Studies of whole cell K(+) currents also revealed identical current-voltage relationships and current depression by hypoxia in type I cells dissociated from normal vs. KO animals. Likewise, hypoxia-evoked increases in intracellular Ca(2+) concentration were not significantly different for normal and KO type I cells. The whole organ response to hypoxia was evaluated in recordings of carotid sinus nerve activity in vitro. In these experiments, responses elicited by hypoxia and by the classic chemoreceptor stimulant nicotine were also indistinguishable in normal vs. KO preparations. Our data demonstrate that carotid body function remains intact after sequence disruption of the gp91(phox) gene. These findings are not in accord with the hypothesis that the phagocytic form of NADPH oxidase acts as a primary O(2) sensor in arterial chemoreception.
 ...
PMID:Characteristics of carotid body chemosensitivity in NADPH oxidase-deficient mice. 1174 95

1. In depression, psychiatric symptoms are frequently associated with impaired cardiovascular function and perhaps also increased risk for cancer diseases. Pathophysiological basis of this comorbidity is not clearly understood. Molecular events involved, particularly factors modified by chronic stress exposure, may only be evaluated in animal models of depression. 2. Present experiments were aimed to study parameters related to cardiovascular system (tyrosine hydroxylase (TH) gene expression in adrenal glands) and carcinogenesis (retinoic acid receptors in the liver) in the chronic mild stress model of depression. 3. Chronic mild stress induced a rise in adrenal TH gene expression in both male and female rats. Gender dependent changes were found in retinoic acid receptor binding with stress-induced activation in females but not males. Ovariectomized animals exhibited higher retinoic acid receptor binding. slightly elevated TH mRNA levels and failed to respond to chronic mild stress exposure with further increase in TH mRNA levels. Similarly, chronic mild stress induced an anhedonic state manifested by decreased sucrose preference in control but not ovariectomized rats. 4. Presented data document that central neurochemical and behavioral changes in animals exposed to chronic mild stress model of depression are associated with changes in adrenal TH gene expression and with gender dependent changes in retinoic acid receptor status in the liver. Such alterations may participate in the development of pathological changes and could participate on increased risk for cardiovascular and oncologic comorbidity in depressive patients.
 ...
PMID:Altered function of peripheral organ systems in rats exposed to chronic mild stress model of depression. 1177 69

Recent studies have demonstrated a loss of cannabinoid CB1 receptors in the postmortem basal ganglia of patients affected by Huntington's disease (HD) and in transgenic mouse models for this disease. These studies have led to the notion that substances that increase the endocannabinoid activity, such as receptor agonists or inhibitors of endocannabinoid uptake and/or metabolism, might be useful in the treatment of hyperkinetic symptoms of this disease. In the present study, we employed a rat model of HD generated by bilateral intrastriatal injections of 3-nitropropionic acid (3-NP), a toxin that selectively damages striatal GABAergic efferent neurons. These rats exhibited biphasic motor disturbances, with an early (1-2 weeks) hyperactivity followed by a late (3-4 weeks) motor depression. Analysis of GABA, dopamine, and their related enzymes, glutamic acid decarboxylase and tyrosine hydroxylase, in the basal ganglia proved marked decreases compatible with the motor hyperkinesia. In addition, mRNA levels for CB1 receptor, neuronal-specific enolase, proenkephalin, and substance P decreased in the caudate-putamen of 3-NP-injected rats. There were also reductions in CB1 receptor binding in the caudate putamen, the globus pallidus, and, to a lesser extent, the substantia nigra. By contrast, mRNA levels for tyrosine hydroxylase in the substantia nigra remained unaffected. Interestingly, the administration of AM404, an inhibitor of endocannabinoid uptake, to 3-NP-injected rats attenuated motor disturbances observed in the early phase of hyperactivity. Administration of AM404 also tended to induce recovery from the neurochemical deficits caused by the toxin in GABA and dopamine indices in the basal ganglia. In summary, morphological, behavioral, and biochemical changes observed in rats intrastriatally lesioned with 3-NP acid were compatible with a profound degeneration of striatal efferent GABAergic neurons, similar to that occurring in the brain of HD patients. As expected, a loss of CB1 receptors was evident in the basal ganglia of these rats. However, the administration of substances that increase endocannabinoid activity, by inhibiting the uptake process, allowed an activation of the remaining population of CB1 receptors, resulting in a significant improvement of motor disturbances and neurochemical deficits. These observations might be relevant to the treatment of hyperkinetic symptoms in HD, a human disorder with unsatisfactory symptomatic treatment for most patients.
 ...
PMID:Alleviation of motor hyperactivity and neurochemical deficits by endocannabinoid uptake inhibition in a rat model of Huntington's disease. 1184 43

Gender-specific differences in susceptibility to a number of disorders related to catecholaminergic systems, including depression and hypertension, have been postulated to be mediated, at least in part, by estrogens. In this study, we examined if estrogens may regulate gene expression of norepinephrine biosynthetic enzymes. Administration of five injections of 15 or 40 microg/kg estradiol benzoate to ovariectomized (OVX) female rats elicited a dose-dependent elevation in mRNA levels of tyrosine hydroxylase (TH) in locus coeruleus, to as great as 3-fold over control. Dopamine beta-hydroxylase (DBH) mRNA levels were also similarly increased. To examine the mechanism, PC12 cells were cotransfected with luciferase reporter constructs under control of DBH or TH promoters [pDBH/Luc(-2,236/+21) or pTH/Luc(-272/+27 or -773/+27)] with an expression vector for estradiol receptor alpha. The cells were treated with 17beta-estradiol (E(2)) for 12-36 h. E(2) triggered a several fold increase in luciferase activity under control of the DBH promoter in a dose-dependent fashion. Omission of estrogen receptor alpha or addition of the estrogen receptor antagonist ICI 182,780 prevented the DBH promoter-driven increase in luciferase. When E(2) was given with 0.2 mM CPT-cAMP, reporter activity with pDBH/Luc(-2,236/+21) was increased greater than with either treatment alone. In contrast, addition of E(2) to cells transfected with pTH/Luc(-272/+27) elicited no change in basal luciferase activity nor in the response to 0.2 mM CPT-cAMP. These findings are the first to reveal that estrogen can stimulate DBH gene expression. Differing mechanisms may underlie the regulation of TH and DBH gene expression by estrogens.
 ...
PMID:Estradiol stimulates gene expression of norepinephrine biosynthetic enzymes in rat locus coeruleus. 1191 91


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