UMLS:C0011570 - FACTA Search

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Query: UMLS:C0011570 (depression)
172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Immobility induced by forced swimming is well known as an animal model of depression. To develop an animal model for the negative symptoms of schizophrenia, in particular the depressive symptoms, the effect of phencyclidine (PCP) on immobility in the forced swimming test was investigated in mice, since PCP produces such negative symptoms in humans. 2. Repeated treatment with PCP (10 mg kg-1 day-1, s.c., once a day for 14 days) prolonged the immobility time in the forced swimming test 24 h after the final injection compared with saline treatment; the effect was not obtained by single or 5 treatments with PCP (10 mg kg-1, s.c.), or by repeated treatment with methamphetamine (0.5 and 1 mg kg-1 day-1, s.c., once a day for 14 days). 3. The enhancing effect of PCP (10 mg kg-1 day-1, s.c.) on the immobility persisted for at least 21 days after the withdrawal of the drug. 4. Haloperidol (0.3 and 1 mg kg-1, p.o.), ritanserin (3 and 10 mg kg-1, p.o.), risperidone (0.1-1 mg kg-1, p.o.), and clozapine (3 and 10 mg kg-1, p.o.) failed to attenuate the immobility induced by the forced swimming in mice repeatedly treated with saline when the drugs were administered 1 h before the forced swimming test. However, ritanserin (30 mg kg-1) and clozapine (30 mg kg-1) did attenuate this immobility. 5. The enhancing effect of PCP on the immobility was attenuated by ritanserin (3 and 10 mg kg-1, p.o.), risperidone (0.3 mg kg-1, p.o.), and clozapine (3 and 10 mg kg-1, p.o.), whereas haloperidol (0.3 and 1 mg kg-1, p.o.) had no effect. 6. These results suggest that the enhancement of immobility in the forced swimming test brought about by repeated PCP treatment could be used as a model of the negative symptoms, particularly the depression, of schizophrenia. This effect of PCP appeared to be mediated, at least in part, via 5-HT2A receptors.
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PMID:Enhancement of immobility in a forced swimming test by subacute or repeated treatment with phencyclidine: a new model of schizophrenia. 858 Dec 95

There are conflicting results on the function of 5-HT in anxiety and depression. To reconcile this evidence, Deakin and Graeff have suggested that the ascending 5-HT pathway that originates in the dorsal raphe nucleus (DRN) and innervates the amygdala and frontal cortex facilitates conditioned fear, while the DRN-periventricular pathway innervating the periventricular and periaqueductal gray matter inhibits inborn fight/flight reactions to impending danger, pain, or asphyxia. To study the role of the DRN 5-HT system in anxiety, we microinjected 8-OH-DPAT into the DRN to inhibit 5-HT release. This treatment impaired inhibitory avoidance (conditioned fear) without affecting one-way escape (unconditioned fear) in the elevated T-maze, a new animal model of anxiety. We also applied three drug treatments that increase 5-HT release from DRN terminals: 1) intra-DRN microinjection of the benzodiazepine inverse agonist FG 4172, 2) intra-DRN microinjection of the excitatory amino acid kainic acid, and 3) intraperitoneal injection of the 5-HT releaser and uptake blocker D-fenfluramine. All treatments enhanced inhibitory avoidance in T-maze. D-Fenfluramine and intra-DRN kainate also decreased one-way escape. In healthy volunteers, D-fenfluramine and the 5-HT agonist mCPP (mainly 5-HT2C) increased, while the antagonists ritanserin (5-HT2A/2C) and SR 46349B (5-HT2A) decreased skin conductance responses to an aversively conditioned stimulus (tone). In addition, D-fenfluramine decreased, whereas ritanserin increased subjective anxiety induced by simulated public speaking, thought to represent unconditioned anxiety. Overall, these results are compatible with the above hypothesis. Deakin and Graeff have suggested that the pathway connecting the median raphe nucleus (MRN) to the dorsal hippocampus promotes resistance to chronic, unavoidable stress. In the present study, we found that 24 h after electrolytic lesion of the rat MRN glandular gastric ulcers occurred, and the immune response to the mitogen concanavalin A was depressed. Seven days after the same lesion, the ulcerogenic effect of restraint was enhanced. Microinjection of 8-OH-DPAT, the nonselective agonist 5-MeO-DMT, or the 5-HT uptake inhibitor zimelidine into the dorsal hippocampus immediately after 2 h of restraint reversed the deficits of open arm exploration in the elevated plus-maze, measured 24 h after restraint. The effect of the two last drugs was antagonized by WAY-100135, a selective 5-HT1A receptor antagonist. These results are compatible with the hypothesis that the MRN-dorsal hippocampus 5-HT system attenuates stress by facilitation of hippocampal 5-HT1A-mediated neurotransmission. Clinical implications of these results are discussed, especially with regard to panic disorder and depression.
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PMID:Role of 5-HT in stress, anxiety, and depression. 872 50

Chronic electroconvulsive shock (ECS), a widely used treatment for intractable depression, increases the density of 5-HT2A receptor binding sites and mRNA in rat frontal cortex. In contrast, this treatment appears to have no significant effect on 5-HT-stimulated phosphatidyl inositol turnover in rat brain. To investigate the effect of chronic ECS on the 5-HT2 receptor family further, we determined its effects on head shakes and c-fos expression in the rat in response to the 5-HT2A/2C receptor agonist DOI [1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane]. Chronic ECS (5 electroconvulsive shocks over 10 days, via earclips under halothane anaesthesia) caused a significant enhancement in the number of head shakes counted in a 30 min period after administration of 2 or 8 mg/kg DOI. In contrast, this treatment had no effect on Fos expression, induced by either dose of DOI, in any region of rat forebrain examined. Fos expression was low-to-undetectable in the brains of animals treated with chronic ECS followed by saline and sham ECS animals that had been treated identically, but with no administration of electrocurrent. Thus the lack of any change in PI turnover, following chronic ECS administration, appears to be mirrored by the failure of this treatment to alter 5-HT2 receptor-mediated Fos expression.
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PMID:Chronic electroconvulsive shock enhances 5-HT2 receptor-mediated head shakes but not brain C-fos induction. 878 5

Changes with time after injury in behavioral deficits, as determined by the Morris swim test, and the in vivo specific binding of HEAT, a selective alpha 1-adrenoreceptor ligand, were compared with the time-course of development of cortical hypometabolism in rats with focal freezing lesions. In our trauma model, cortical hypometabolism was detectable in the lesioned hemisphere at 4 hr, became maximal (50% of normal) at 3 days and diminished towards normal on days 5 and 10 post-injury. Progressive impairment of acquisition of the Morris water maze task was demonstrated up to day 3 post-lesion with improvement thereafter. On day 3 the latency to reach criterion was 60% longer in lesioned animals than in corresponding sham-operated ones. An increase in the volume of distribution of HEAT, limited to cortical areas of the lesioned hemisphere, was demonstrable at 4 hr post-lesion and reached its maximum on day 3 (200% of normal) with subsequent return toward normal on days 5 and 10. Several types of drugs were shown previously to modify the cortical hypometabolism associated with cerebral injury. The present data indicate that the same drugs also modify the in vivo binding of HEAT and the behavioral deficits induced by brain lesions. Ibuprofen, a non-steroidal anti-inflammatory drug, p-chlorophenylalanine, an inhibitor of serotonin synthesis, ketanserin, a specific 5HT2-receptor antagonist, and prazosin, an alpha 1-adrenergic receptor blocker all normalized the in vivo binding of HEAT in the cortical areas of the lesioned hemisphere. All groups of animals treated with these drugs also showed subtle, but statistically highly significant improvements in latency to locate the platform in the Morris water maze. Taken together these results show good correlation between behavioral deficits, changes in alpha 1-noradrenergic receptor binding and cortical hypometabolism in injured brain. This supports the hypothesis that post-injury cortical hypometabolism is a reflection of cortical functional depression in which both the serotonergic and noradrenergic neurotransmitter systems play a role, compatible with their inhibitory effects in the cortex and their postulated involvement in cortical information processing.
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PMID:Cortical hypometabolism in injured brain: new correlations with the noradrenergic and serotonergic systems and with behavioral deficits. 878 17

To investigate cardiorespiratory effects of an experimental 5-hydroxytryptamine receptor antagonist (R51703) with sedative properties, intramuscular doses of the drug were studied in 6 awake dogs of mixed breed, and in 6 anesthetized beagles. Two doses (0.2 and 0.4 mg/kg) of R51703 and a saline control were studied in the awake dogs using a randomized crossover trial. Subsequently, the higher dose of R51703 was included as a component of halothane anesthesia to determine whether the halothane sparing effect of R51703 produced a beneficial alteration of hemodynamic function. Data were obtained at equipotent halothane/R51703 (H/R) and halothane/saline (H/S) doses equivalent to 1.0, 1.5 and 2.0 MAC. In awake dogs, heart rates tended to be lower in dogs sedated with R51703, significantly so at 30 min for both doses, and at 90 and 120 min for the 0.2 and 0.4 mg/kg doses, respectively (P < 0.05). The cardiac index (CI) was lower at 60 min with both doses compared to the saline control group. Both doses of R51703 reduced mean blood pressure at 30, 90 and 120 min, and diastolic pressure at 30 and 90 min after administration; however, systolic blood pressure (SBP) was not altered. Overall, the cardiovascular alterations were minimal in conscious dogs and there was no evidence of respiratory depression. In the anesthetized dogs, at equipotent MAC, CI tended to be lower with H/R than with H/S, though the difference was not significant. Heart rate and stroke volume index also tended to be lower in the dogs treated with R51703, while systemic vascular resistance tended to be higher: these changes were not significant. Mean and SBP were higher at each MAC multiple in the H/R group. It was concluded that the halothane sparing effect of R51703 did not substantially improve hemodynamic function compared to the use of halothane alone at equipotent doses.
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PMID:Cardiorespiratory effects of a 5HT2 antagonist (R51703) in awake and anesthetized dogs. 880 79

Modifications in serotonin (5-HT) neurotransmission have been associated with the physiopathology of anxiety and depression. Among the numerous 5-HT receptor subtypes, several (5-HT1A, 5-HT1B, 5-HT2 and 5-HT3) could be involved in these etiologies. By using a murine genetic model, we attempted to correlate variations in the density of receptor subtypes with modifications of anxiety-related behaviors. From a classic inbred strain (C57BL/6ByJ) and a linkage-testing inbred strain (ABP/Le), segregated F(2) populations for 3 loci located in the 4th, 7th and 9th chromosomes have been selected for their different responses in anxiety-related behavioral tests. The regional density of 5-HT1A, 5-HT1B, 5-HT2A and 5-HT2B receptors has been measured in the brains of parental strains, F(1) and F(2) populations by quantitative autoradiography. The results suggest that chromosomal fragments containing the brown, pink-eyed dilution and the short-ear loci, previously shown to be involved in anxiogenic processes, are mainly associated with a variation in the density of the 5-HT1B receptors.
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PMID:An autoradiographic study of serotonergic receptors in a murine genetic model of anxiety-related behaviors. 883 59

Malfunction of the serotonergic system and dysregulation of the hypothalamo-pituitary-adrenocortical axis have been implicated in the pathophysiology of depression. Several studies provide evidence for reciprocal influences between glucocorticoids and 5-HT receptors. The effect of repeated treatment with a high dose of corticosterone (50 mg/kg s.c. twice daily for 4 days) on 5-HT receptor subtype-mediated behaviours was studied. It was found that in rats that were repeatedly treated with corticosterone the number of 2-chloro-6-(1-piperazinyl)pyrazine HCl (MK 212)-induced, 5-HT2C receptor-mediated penile erections were reduced, whereas both MK 212 and (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced 5-HT2A receptor-mediated head shakes were increased. The (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT)-induced lower lip retraction mediated by presynaptic 5-HT1A receptors was unchanged, whereas the open field activity induced by 8-OH-DPAT was enhanced in corticosterone pretreated rats. These changes in 5-HT receptor subtype-mediated behaviours were not seen after a single injection with corticosterone given 24 h or 5 days before. The results suggest that 5-HT2A, 5-HT2C and postsynaptic 5-HT1A receptor-mediated behaviour can be modulated by repeated treatment with a high dose of corticosterone.
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PMID:Modulation of 5-HT receptor subtype-mediated behaviours by corticosterone. 884 Jan 20

Serotonergic systems have been implicated in the pathogenesis of major depression in humans as well as in learned helplessness (LH), an animal model of depression. To understand the significance of neuronal responses in depression and LH that are mediated by serotonin (5-hydroxytryptamine, 5HT) receptors, we used intracerebroventricular injections to introduce a unique antisense oligonucleotide (ASO) to the 5HT2A receptor and determined its effect on LH behavior in Sprague-Dawley rats as determined by an escape-avoidance strategy. Of the rats injected with the 5HT2A receptor ASO, 8/16 rats met criteria for LH. By contrast, only 1/15 of the control group injected with 5HT2A sense oligonucleotide (SO) met criteria for LH. Quantitative receptor autoradiography revealed significant differences in 5HT2A receptor density between ASO and control sense oligonucleotides (SO), in close proximity to the injection site. Significant decreases in 5HT2A receptor density caused by oligonucleotide blockade were found in the CA3 hippocampal region. These data support the view that central 5HT, mediated by the 5HT2A receptor, participates in regulating behaviors that are affected by inescapable stress, and that the induction of behavioral depression may be specifically regulated via serotonergic pathways that terminate in this hippocampal subfield.
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PMID:Modulation of learned helplessness by 5-hydroxytryptamine2A receptor antisense oligodeoxynucleotides. 887 16

The antipsychotic drug risperidone shows high affinity for both central serotonin (5-HT)2A and dopamine (DA)-D2 receptors in vivo. By employing microdialysis in freely moving rats, the effects of acute risperidone administration on regional brain DA and 5-HT release and metabolism were compared with the corresponding effects of the atypical antipsychotic drug clozapine as well as amperozide, the selective DA-D2 receptor antagonist raclopride and the selective 5-HT2A/5-HT2C receptor antagonist ritanserin. Risperidone (0.2 or 2.0 mg/kg, SC) was found to increase DA release and metabolism to about the same extent in three major projection areas of the mesotelencephalic dopaminergic system, i.e. the nucleus accumbens (NAC), the medial prefrontal cortex (MPC) and the lateral striatum (STR). In contrast, clozapine and amperozide (both 10.0 mg/kg, SC), as well as raclopride (2.0 mg/kg, SC), were all found differentially to affect DA release and metabolism in the three projections areas. Specifically, clozapine and amperozide enhanced DA release in the MPC to a greater extent than in the NAC or the STR, whereas raclopride instead preferentially increased DA release in the NAC and the STR but not in the MPC. Ritanserin (3.0 mg/kg, SC) did not exert any major effects on DA metabolism in the three areas studied. In contrast to the regionally rather homogenous activation of brain DA systems caused by risperidone, the drug was found to enhance brain 5-HT metabolism preferentially in the MPC, as indicated by the elevated extracellular concentration of 5-hydroxyindoleacetic acid (5-HIAA) in this region. A similar elevation of the 5-HIAA level in the MPC was observed after amperozide and, to some extent, after clozapine and ritanserin administration. The risperidone-induced (2.0 mg/kg, SC) elevation of 5-HIAA concentrations in the frontal cortex was found to be paralleled by an increased 5-HT release in this brain area. Consequently, our findings demonstrate a pharmacological profile of risperidone, as reflected in brain DA metabolism, in between that of clozapine and the DA-D2 antagonists. The preferential activation of 5-HT release and metabolism in frontal cortical areas might be of particular relevance for the ameliorating effect of risperidone on negative symptoms in schizophrenia, especially when associated with depression.
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PMID:Risperidone: regional effects in vivo on release and metabolism of dopamine and serotonin in the rat brain. 893 2

1. Although conscious dogs have often been used for colonic motility studies with 5-hydroxytryptamine (5-HT), the effects of 5-HT on the isolated colon have not been thoroughly characterized yet. The current study was undertaken to characterize the response to 5-HT of the canine isolated colon longitudinal muscle. 2. Longitudinal strips of canine midcolon deprived of (sub)mucosa were prepared for isotonic measurement. 5-HT induced contractions from 3 nM onwards, which were not affected by selective inhibition of 5-HT re-uptake, monoamine oxidase or blockade of alpha-adrenoceptors. Tetrodotoxin (0.3 microM) did not affect the responses to 5-HT, suggesting that smooth muscle 5-HT receptors are involved. The selective 5-HT4 receptor antagonist SB 204070 (10 nM) slightly enhanced contractions to 5-HT and therefore it was included in the organ bath solution in all further experiments. The 5-HT1 and 5-HT2 receptor antagonist methysergide (0.1 microM) depressed the curve to 5-HT, but the selective 5-HT3 receptor antagonist granisetron (0.3 microM) had no effect. 3. Besides 5-HT, alpha-methyl-5-HT (alpha-Me-5-HT), 5-methoxytryptamine (5-MeOT), 2-methyl-5-HT (2-Me-5-HT) and 5-carboxamidotryptamine (5-CT) also induced contractions, with the following rank order of potency (pEC50 values in parentheses): 5-HT (6.9) = alpha-methyl-5-HT (6.9) > 2-Me-5-HT (5.8) = 5-MeOT (5.7) = 5-CT (5.6), indicative of 5-HT2 receptor involvement, alpha-Me-5-HT produced a bell-shaped curve, which was not affected by alpha-adrenoceptor blockade. 5-HT, 5-MeOT, 2-Me-5-HT and 5-CT produced a monophasic concentration-response curve, consistent with an interaction with a single receptor site. 8-Hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and tryptamine only induced contractions at a concentration exceeding 1 microM. 4. The selective 5-HT2B receptor antagonist SB 204741 (0.3 microM) did not affect the curve to 5-HT. Ketanserin, cisapride and spiroxatrine behaved as competitive antagonists with pKb values of, respectively, 8.4, 8.1 and 6.7. Spiroxatrine (1 microM) shifted the curve to 5-MeOT rightward yielding an apparent pA2 of 7.1. Other antagonists at 5-HT2A receptors also surmountably inhibited the contractions to 5-HT (apparent pA2 value in parentheses): mesulergine (8.2), cinanserin (8.2), yohimbine (6.2) and mianserin (8.6). However, as well as a rightward shift, methiothepin (8.3), pizotifen (8.6) and spiperone (8.8) also caused a depression of the curve, indicative of "pseudo-irreversible' antagonism. Taken together, the above mentioned affinity estimates most closely corresponded to literature affinity values for 5-HT2A receptors. 5. It was concluded that 5-HT induces contractions of the canine midcolon longitudinal muscle primarily by stimulation of smooth muscle 5-HT2A receptors. The presence of inhibitory 5-HT4 receptors cannot be ruled out.
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PMID:Characterization of the contraction to 5-HT in the canine colon longitudinal muscle. 905 13

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