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)

Serotonin type 3 (5-HT3) antagonists, which find an unflinching place in the management of nausea and emesis are presently screened for their neuro-pharmacological potential in various animal models. In the present study, 2-(4-methyl piperazin-1-yl)-1,8-naphthyridine-3-carbonitrile (NA-2) with an optimal log P and pA2 value comparable to that of ondansetron was screened in rodent models of depression. The acute and chronic (14 days) treatment of the synthetic compound exhibited antidepressant-like effects at the lower dose levels in mice forced swim test (FST). A typical and similar dose-immobility profile was observed in both mice FST and tail suspension test (TST). Interaction studies in FST revealed the reversal of mCPP induced immobility, attenuation of antidepressant effects of fluoxetine and desipramine. Chronic NA-2 treatment restored the behavioural deficits in olfactory bulbectomized (OBX) rats as indicated by reduction in hyperactivity in novel open field test. This preliminary study points to a serotonergic mechanism behind the antidepressant-like effects of NA-2 and invigorates further investigation of analogous compounds in various other models of depression.
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PMID:Potential antidepressants: pharmacology of 2-(4-methyl piperazin-1-yl)-1,8-naphthyridine-3-carbonitrile in rodent behavioural models. 1821 43

The olfactory bulbectomized (OBX) rat model of depression has been widely used in studies on the behavioral and neurochemical aspects of human depression. The objective of the present investigation was to assess open field (OF) activity and the brain regional 5-HT(1A) receptor densities of the sham operated (SHX) and OBX rats treated with saline (SHX-SAL, OBX-SAL), and either 10 mg/(kg day) (SHX-B10, OBX-B10) or 20 mg/(kg day) (SHX-B20, OBX-B20) of buspirone for 14 days, delivered by a subcutaneous osmotic minipump. Adult Sprague-Dawley rats were used for this experiment. The surgery was performed on the first day of the experiment and the rats were randomly assigned to either the SHX or OBX groups. The results of the OF tests were organized in eight groups. Following 14 days of treatment and the final OF tests, the rats were sacrificed and the brains were used for 5-HT(1A) receptor autoradiography using [(3)H]8-OH-DPAT. The data showed that the OF activities, 14 days following surgery, in the OBX rats were significantly elevated when compared to the SHX rats. In the OBX rats, only the 14-day treatment with 20mg/(kgday) of buspirone normalized the elevated OF activity, the same dose shown previously to be needed for the normalization of the regional 5-HT synthesis. A significant reduction in the number of 5-HT(1A) receptor sites was found in most brain regions in the OBX rats when compared to the SHX rats. Data also show that the regional density of the 5-HT(1A) receptors in OBX-SAL treated rats is lower than that of the SHX-SAL rats. The 14-day treatment with either 10 or 20 mg/(kg day) of buspirone reduced the 5-HT(1A) receptors in most brain regions of the SHX rats, without an obvious dose-dependent effect of the buspirone. The comparison between the OBX-B20 and control (SHX-B20) rats suggests that the buspirone treatment resulted in a regional balance in the 5-HT(1A) sites. A dose dependent reduction in the density of 5-HT(1A) sites was observed in the sham rats, but the buspirone treatment had very little effect on the density of the 5-HT(1A) receptors in the OBX rats. From these observations, we conclude that the antidepressant effects of buspirone in the OBX rat model of depression are likely mediated through the fine tuning of the regional imbalance of 5-HT(1A) receptors with even increases of about 20% in some limbic regions. The data suggest that the neurochemical effects of antidepressants should be studied in animal models of depression rather than in normal rats.
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PMID:Chronic buspirone treatment normalizes open field behavior in olfactory bulbectomized rats: assessment with a quantitative autoradiographic evaluation of the 5-HT1A binding sites. 1835 30

The responses of olfactory bulbectomized (OBX) rats to antidepressant treatment are similar to those of depressed patients since chronic administration of an antidepressant reverses OBX-induced behavioral and physiological changes. Previously, using several animal models, it was demonstrated that single treatment with delta-opioid receptor agonists produced an antidepressant-like effect. This study examined the antidepressant effects resulting from subchronic exposure for 8 days to the delta-opioid receptor agonist SNC80 in an OBX rat model of depression. The olfactory bulbs were removed by suction. The emotionality of rats was measured by scoring their responses to given stimuli, i.e., attack, startle, struggle, and fight responses. The OBX rats chronically treated with vehicle for 7 days at 14 days following surgery showed a significant increase in emotionality score and a decrease in the time spent and entries in the open arm of a plus-maze. In the case of OBX rats, these changes were dose- and time-dependently reversed by chronic SNC80 treatment (1-10 mg/kg, s.c.) for 7 days, as same as desipramine (10 mg/kg, i.p.). Moreover, the concentration of 5-HT and its metabolite 5-HIAA in the frontal cortex, hippocampus, and amygdala were decreased in OBX rats, and these changes were also normalized by SNC80 treatment, rather than desipramine treatment. In addition, SNC80 also significantly reversed the loss of TH-positive cells produced by OBX in the dorsal raphe. In conclusion, we demonstrated that subchronic SNC80 treatment could completely reverse OBX-induced behavioral abnormalities and defects in serotonergic function.
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PMID:Antidepressant-like effects of the delta-opioid receptor agonist SNC80 ([(+)-4-[(alphaR)-alpha-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-methoxyphenyl)methyl]-N,N-diethylbenzamide) in an olfactory bulbectomized rat model. 1838 Dec 8

The olfactory bulbectomized (OBX) rat is an extensively investigated animal model of depression. In the present study the effects of olfactory bulbectomy in drug-naive adult male Sprague-Dawley rats (200-240 g) on global (gCGU) and regional cerebral glucose (rCGU) utilization was evaluated. Two weeks following surgery, the autoradiographic measurement of CGU using [14C]-2-deoxyglucose was employed. The levels of CGU in the OBX and sham-operated rats were compared in 40 brain regions. Statistical methods indicate significantly lower levels of global (overall) CGU in the OBX group than in the sham group. Discriminant analysis was done on the z-scores to remove animal to animal variability. The following thirteen regions were identified by the stepwise discriminant analysis of the z-scores as significantly contributing to the differences between the sham and OBX: amygdala, cingulate cortex, caudate putamen at the level of globus pallidus, caudate putamen-lateral part, dorsal subiculum, dorsal thalamus, hypothalamus, median raphe, somatosensory cortex, substantia nigra, ventral hippocampus, ventral tegmental area and the ventral thalamus. The pattern of changes in the rCGU following OBX does not completely correlate with the pattern of connectivity of the olfactory bulbs, however, many regions with direct connection to the olfactory bulbs (e.g., amygdala, hypothalamus, ventral hippocampus, and ventral tegmental area) were found to be important for differentiation. No left to right asymmetries in the rCGU were found. The data suggest that there are very important regional differences in glucose utilization between the OBX and sham operated rats, which points to the need to study antidepressants in an animal model of depression rather than in normal animals.
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PMID:Olfactory bulbectomy reduces cerebral glucose utilization: 2-[14C]deoxyglucose autoradiographic study. 1853 56

In this study, we compared the depression-like symptoms induced by olfactory bulbectomy (OBX) in the two inbred Wistar and Long Evans rat strains. We also analyzed the self-regulated oral intake of nicotine in these strains and the effect of nicotine on the depression-like symptoms of olfactory bulbectomy. Furthermore, we compared the antidepressant-like effects of nicotine on Wistar rats to those of transcranial magnetic stimulation (TMS), which has emerged as a therapeutic alternative for depression management. Our results show that Wistar rats develop depression-like symptoms, demonstrated by the forced swim test (FST), 4 weeks after OBX. However, in bulbectomized Long Evans rats these symptoms cannot be assessed due to a higher degree of variability of the swimming behavior of this strain. These results suggest that there are some innate differences in susceptibility to stress between these two rat strains. In Wistar rats, voluntary oral nicotine intake (1.2 mg/(kg day) for 14 days) as well as nicotine administered as a single daily i.p. injection (1.5 mg/(kg day) for 14 days) decrease the depression-like symptoms of OBX. Daily transcranial magnetic stimulation (60 Hz and 0.7 mT for 2h/day for 14 days) also decreases depression-like symptoms but is less effective than nicotine. In conclusion, our results support the idea that there are possible innate differences for depression susceptibility and that nicotine and TMS may be useful in the treatment of this syndrome.
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PMID:Antidepressant-like effects of nicotine and transcranial magnetic stimulation in the olfactory bulbectomy rat model of depression. 1858 40

Olfactory bulbectomy (OBX) in rats causes several behavioral and neurochemical CNS changes, reminiscent of symptoms of human depression. Such depression-like behavior after OBX can be reversed with antidepressants. Recently, a connection between the vasopressin 1b (V1b) receptor and the development of depression has been suggested; therefore, a vasopressin V1b receptor antagonist (SSR149415) was investigated in the OBX model. Male rats received olfactory bulbectomy or sham surgery. After recovery, animals received 14 consecutive daily doses of SSR149415 (10 or 30 mg/kg), imipramine (20 mg/kg), or vehicle (5% hydroxy-propyl methylcellulose). Animals were tested in an open field after acute treatment, on days 7 and 14 of treatment and 1 week after cessation of treatment. Similar to imipramine, repeated, but not acute, administration of SSR149415 completely reversed OBX-induced hyperactivity, leaving activity in shams unaffected. This reversal of OBX-induced hyperactivity in the SSR149415 treated rats was still present 7 days after cessation of treatment. Although the behavioral effects of treatment with SSR149415 were specific for the OBX animals, adrenal gland weights were reduced in both sham and OBX animals treated with 30 mg/kg SSR149415. Chronic but not acute administration of SSR149415 normalizes OBX-induced hyperactivity up to 1 week after cessation of treatment, suggesting that a V1b receptor antagonist may have long-lasting antidepressant activity.
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PMID:SSR149415, a non-peptide vasopressin V1b receptor antagonist, has long-lasting antidepressant effects in the olfactory bulbectomy-induced hyperactivity depression model. 1866 25

Current antidepressants have a delayed onset of action and disturbing side effects, including inhibition of sexual behavior. It is hypothesized that novel drugs, hitting multiple disease-relevant targets, may yield a new generation of superior antidepressants. One such approach is simultaneous inhibition of serotonin, norepinephrine and dopamine transporters. We tested the triple uptake inhibitor (TUI), DOV 216,303 (5, 10 and 20 mg/kg) after 1, 7 and 14 days administration in the olfactory bulbectomized (OBX) rat depression model, and in a model of rat sexual behavior to detect putative sexual side effects. Chronic, but not acute treatment of DOV 216,303 (20 mg/kg) normalized OBX-induced hyperactivity in the open field, similar to the effect of imipramine (20 mg/kg). None of the doses of DOV 216,303 had any effect on sexual behavior at any time point. The results indicate that DOV 216,303 displays antidepressant efficacy and is devoid of sexual side effects.
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PMID:The triple monoaminergic reuptake inhibitor DOV 216,303 has antidepressant effects in the rat olfactory bulbectomy model and lacks sexual side effects. 1878 57

We investigated the effect of cocaine- and amphetamine-regulated transcript (CART) peptide on depression-like behavior in socially isolated and olfactory bulbectomized (OBX) rats. Administration of CART (54-102) into the lateral ventricle (50-100 ng) or central nucleus of amygdala (CeA) (10-20 ng) caused significant decrease in immobility time in the forced swim test (FST) without influencing locomotion, suggesting antidepressant-like effect. Social isolation as well as OBX models were undertaken to produce depression-like conditions. Although isolation reared (6 weeks) rats showed significant increase in immobility time in FST, OBX animals exhibited hyperactivity (increase in the ambulation, rearing, grooming, and defecation scores) on day 14 in the open-field test. The isolation- or OBX-induced depression-like phenotypes were reversed following acute or subchronic treatment of CART, respectively, given via intracerebroventricular and intra-CeA routes. Drastic reduction in CART-immunoreactivity was observed in most cells in the paraventricular (PVN), arcuate and Edinger-Westphal nuclei of the socially isolated and OBX animals. Although the fibers in the PVN showed variable response, those in ARC and prefrontal cortex did not change. The CART-immunoreactive fibers in the locus coeruleus also showed highly significant reduction. However, dramatic increase in CART-immunoreactive fibers was noticed in the CeA in both the experimental models. The response by the cells and fibers in the periventricular area and perifornical nucleus in the OBX and socially isolated rats was variable. The study underscores the possibility that endogenous CART system might play a major role in mediating symptoms of depression.
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PMID:Cocaine- and amphetamine-regulated transcript peptide plays a role in the manifestation of depression: social isolation and olfactory bulbectomy models reveal unifying principles. 1900 67

We investigated the effects of antidepressants on the gene expression profile and behavior of olfactory-bulbectomized (OBX) rats. Removal of the main olfactory bulbs in rats alters neuronal function in brain areas involved in emotional regulation, resulting in maladaptive behavioral patterns similar to the symptoms of patients with depression. Previously, we found that OBX-induced behavioral and neuronal abnormalities were completely rescued by chronic treatment with SNC80, an opioid delta agonist, as well as with classical monoaminergic antidepressants. Thus, to determine the basis for this effect, we analyzed gene expression in OBX rat frontal cortex using a GeneChip rat Genome oligonucleotide array after imipramine or SNC80 treatment. We found that imipramine and SNC80 induced the following systematic changes in OBX rats: zinc ion binding; hydrolase activity, acting on acid anhydrides, in phosphorus-containing anhydrides; protein serine/threonine kinase activity; N-acetyltransferase activity; protein modification process; regulation of cellular process; and regulation of neurotransmitter levels. Defining the roles of candidate neuronal systems in antidepressant-induced neural changes are likely to transform the course of research on the biological basis of mood disorders.
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PMID:Gene expression profiling reveals complex changes in the olfactory bulbectomy model of depression after chronic treatment with antidepressants. 1902 79

The olfactory bulbectomized (OBX) rat is considered to be a good model of the pathology of human depression and also of the functional actions of antidepressant drug therapy. It has been proposed that antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) can be accelerated by blocking 5-HT(1A/B) autoreceptors with pindolol. The underlying mechanism is thought to involve acute unrestricting of 5-HT release and, consequently, relatively enhanced 5-HT turnover throughout the forebrain serotonergic networks. The effect of this combination on 5-HT turnover in sham operated or OBX rats can be assessed at the level of 5-HT synthesis, a very important presynaptic step in serotonergic neurotransmission, using the alpha-[(14)C]methyl-l-tryptophan autoradiography method. In sham rats, acute citalopram (20mg/kg) treatment increased synthesis at almost all serotonergic terminal regions but slightly decreased synthesis at serotonergic cell body regions (i.e. dorsal and median (not significant) raphe; approximately 16%). Combining pindolol (10mg/kg) with citalopram further increased synthesis at many regions in sham rats (relative to treatment with only citalopram). In OBX rats, citalopram decreased synthesis at a few terminal regions and greatly decreased synthesis at the dorsal and median raphe ( approximately 45%; relative to OBX rats treated with saline). Combining pindolol with citalopram greatly increased synthesis at almost all regions in OBX rats (relative to treatment with only citalopram). These results suggest that acute citalopram effects result in elevated terminal 5-HT synthesis, but these effects are restrained by 5-HT(1A/B) autoreceptor feedback to different degrees in sham and OBX rats. Moreover, 5-HT(1A/B) autoreceptor feedback is stronger in OBX rats and may underlie the delay of SSRI effects in OBX rats and, correspondingly, in human depression. Pindolol acceleration and augmentation of SSRI antidepressant therapy for human depression may be mediated by attenuation of 5-HT(1A/B) autoreceptor feedback, permitting unhindered SSRI effects on serotonergic terminals.
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PMID:Acute effects of combining citalopram and pindolol on regional brain serotonin synthesis in sham operated and olfactory bulbectomized rats. 1907 28

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