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

BTS 72664, (R)-7-[1-(4-chlorophenoxy)]ethyl]-1,2,4-triazolo(1,5-alpha)pyrimidine, was identified as a drug development candidate from a research program designed to discover novel, broad-spectrum, non-sedative anticonvulsant drugs. BTS 72664 antagonized bicuculline (BIC)- and maximal electroshock (MES)-induced convulsions with ED(50) values of 1.9 and 47.5 mg/kg p.o., respectively. In rodents, it has a wide spectrum of activity preventing seizures induced by picrotoxin, pentylenetetrazol, i.c.v. 4-aminopyridine or NMDA, and audiogenic seizures in DBA-2 mice and GEPR-9 rats. BTS 72664 was also effective in preventing convulsions in amygdala-kindled rats The lack of sedative potential was predicted on the basis of wide separation between ED(50) in anticonvulsant models and TD(50) for motor impairment in mice in rotating rod and inverted horizontal grid tests. BTS 72664 is likely to produce its anticonvulsant effect by enhancing chloride currents through picrotoxin-sensitive chloride channels, and by weak inhibition of Na(+) and NMDA channels. It does not act, however, at the benzodiazepine binding site. In addition to its potential use in the treatment of epilepsy BTS 72664 may be useful in the treatment of stroke. At 50 mg/kg p.o. x 4, given to rats at 12 hourly intervals, starting at 15 min after permanent occlusion of middle cerebral artery (MCA), it reduced cerebral infarct size by 31% (measured at 2 days after insult) and accelerated recovery in a functional behavioral model. BTS 72664 prevented increases in extraneuronal concentrations of glutamate, glycine and serine brain levels induced by a cortical insult to rats (cf. cortical spreading depression). It may, therefore, have also antimigraine activity.
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PMID:BTS 72664-- a novel CNS drug with potential anticonvulsant, neuroprotective, and antimigraine properties. 1147 22

Clinical and preclinical research suggests a major role of mesocortical dopamine (DA) in psychopathology through regulation of subcortical, especially mesoaccumbens, DA functioning. In these experiments we demonstrate that the high vulnerability to stress-induced 'despair' and mesoaccumbens DA inhibition, exhibited by mice of the inbred strain C57BL/6 (C57) in a common animal model of depression, depends on their being highly susceptible to stress-induced mesocortical DA activation. Thus, C57 mice but not mice of the DBA/2 strain showed an extremely high level of immobility on their first experience with the forced swimming test (FST) as well as immediate and strong activation of mesocortical DA metabolism and inhibition of mesoaccumbens DA metabolism and release. In addition, the behavioral and the mesoaccumbens DA responses to FST in C57 mice were reduced and reversed, respectively, by bilateral mesocortical DA depletion. Finally, chronic treatment with the antidepressant clomipramine reduced immobility and eliminated both mesocortical DA activation and mesoaccumbens DA inhibition in response to FST. These results suggest that a genetically determined susceptibility to stress by the mesocortical DA system may favor the development of pathological behavioral responses through inhibition of subcortical DA transmission.
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PMID:Genetic susceptibility of mesocortical dopamine to stress determines liability to inhibition of mesoaccumbens dopamine and to behavioral 'despair' in a mouse model of depression. 1245 74

Several studies have reported rodent strain differences in the response to antidepressants in animal models of depression. The aim of the present study was to investigate the potential contribution of genetic factors to antidepressant response in an animal model of depression: the tail suspension test (TST). For this study four mice strains (Swiss and NMRI, two outbred strains and DBA/2 and C57BL/6J Rj, two inbred strains) were submitted to the TST after acute administration of five antidepressants: the tricyclic antidepressants (TCAs) imipramine and desipramine, the selective serotonin (5-HT) reuptake inhibitors (SSRIs) paroxetine and citalopram and the dopamine reuptake inhibitor bupropion. The C57BL/6J Rj strain had a longer baseline immobility time in comparison to the other strains. All antidepressants studied in this work decreased immobility time in the Swiss and C57BL/6J Rj strains. However, the Swiss strain displayed greater sensitivity to citalopram (from 2mg/kg) and C57BL/6J Rj to paroxetine (from 0.5mg/kg). This latter presented a greater size-effect with citalopram than with other strains and reached more than 60% from 8mg/kg. Moreover the size-effect of desipramine, paroxetine and bupropion in Swiss mice was greater than in the other strains in the TST. The NMRI and DBA/2 mice only responded to 5-HT reuptake inhibitors, both selective (paroxetine, citalopram) or non-selective (imipramine). The NMRI strain was more sensitive to imipramine and presented a size-effect (43% at 8mg/kg) superior to those of other strains. DBA/2 strain was more sensitive to citalopram than paroxetine and imipramine. Our results suggest that response to an antidepressant treatment is under control of genetic factors and that the strain of mouse is an important parameter to consider.
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PMID:Antidepressant-like effects in various mice strains in the tail suspension test. 1290 45

The onset of the therapeutic response to antidepressant treatment exhibits a characteristic delay. Animal models sensitive to chronic, but not acute, antidepressant treatment are greatly needed for studying antidepressant mechanisms. We initially assessed four inbred mouse strains for their behavioral response to chronic treatment with the selective-serotonin reuptake inhibitor fluoxetine (0, 5, 10 mg/kg/day in drinking water), which is used for the treatment of mood and anxiety disorders. Only the highly anxious BALB/c strain exhibited sensitivity to fluoxetine in the forced swim test. Additionally, fluoxetine reduced locomotion in C57BL/6 and 129SvEv, but not BALB/c and DBA/2, strains. We then evaluated the effects of subchronic (approximately 4 days) and chronic (approximately 24 days) fluoxetine treatment (0, 10, 18, 25 mg/kg/day) on measures of anxiety and depression in BALB/c mice. Anxiety measures were obtained using the open field and novelty-induced hypophagia tests. Antidepressant effects were evaluated using the forced swim test. We found 18 mg/kg/day of chronic fluoxetine to be active in all three paradigms; subchronic treatment had no effect. Anxiety-related measures were reduced by 18 mg/kg/day. In the forced swim test, 10 and 18 mg/kg/day increased swimming and reduced immobility. Here we present several novel effects of chronic, but not subchronic, antidepressant treatment.
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PMID:Effects of chronic fluoxetine in animal models of anxiety and depression. 1508 85

This study aimed at investigating the relationship between anxiety-like and depressive-like behaviour in mice. Therefore, we assessed the behaviour of mice from eight different strains (FVB/NA, BALB/c, C57BL/6, DBA/2, 129/Sv, C3H/He, CBA and BA) confronted first to anxiety models (the elevated plus-maze and the free exploratory test) and then to tests of depressive-like behaviours (forced swim test and unpredictable subchronic mild stress). In the forced swim test, mice from the DBA/2, the BA and the C3H/He strains displayed higher immobility than mice from the 129/Sv, the BALB/c, the C57BL/6 and the CBA strains. In the subchronic mild stress, mice from the C57BL/6 and the CBA strains displayed low sensitivity when compared with mice from all the others strains. A stepwise multiple regression analysis suggests that behaviour in the elevated plus-maze is associated with the time of immobility in the forced swim test (20%) and with the susceptibility to the unpredictable subchronic stress procedure (31%). The behaviour in the free exploratory paradigm is slightly associated with behaviours in the two tests of depression. These results suggest that anxiety may be a factor contributing, among others, to the susceptibility to depressive-like behaviours.
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PMID:Correlations between behaviours in the elevated plus-maze and sensitivity to unpredictable subchronic mild stress: evidence from inbred strains of mice. 1547 60

Noncompetitive N-methyl-D-aspartate (NMDA) blockers induce schizophrenic-like symptoms in humans, presumably by impairing glutamatergic transmission. Therefore, a compound potentiating this neurotransmission, by increasing extracellular levels of glycine (a requisite co-agonist of glutamate), could possess antipsychotic activity. Blocking the glycine transporter-1 (GlyT1) should, by increasing extracellular glycine levels, potentiate glutamatergic neurotransmission. SSR504734, a selective and reversible inhibitor of human, rat, and mouse GlyT1 (IC50=18, 15, and 38 nM, respectively), blocked reversibly the ex vivo uptake of glycine (mouse cortical homogenates: ID50: 5 mg/kg i.p.), rapidly and for a long duration. In vivo, it increased (minimal efficacious dose (MED): 3 mg/kg i.p.) extracellular levels of glycine in the rat prefrontal cortex (PFC). This resulted in an enhanced glutamatergic neurotransmission, as SSR504734 potentiated NMDA-mediated excitatory postsynaptic currents (EPSCs) in rat hippocampal slices (minimal efficacious concentration (MEC): 0.5 microM) and intrastriatal glycine-induced rotations in mice (MED: 1 mg/kg i.p.). It normalized activity in rat models of hippocampal and PFC hypofunctioning (through activation of presynaptic CB1 receptors): it reversed the decrease in electrically evoked [3H]acetylcholine release in hippocampal slices (MEC: 10 nM) and the reduction of PFC neurons firing (MED: 0.3 mg/kg i.v.). SSR504734 prevented ketamine-induced metabolic activation in mice limbic areas and reversed MK-801-induced hyperactivity and increase in EEG spectral energy in mice and rats, respectively (MED: 10-30 mg/kg i.p.). In schizophrenia models, it normalized a spontaneous prepulse inhibition deficit in DBA/2 mice (MED: 15 mg/kg i.p.), and reversed hypersensitivity to locomotor effects of d-amphetamine and selective attention deficits (MED: 1-3 mg/kg i.p.) in adult rats treated neonatally with phencyclidine. Finally, it increased extracellular dopamine in rat PFC (MED: 10 mg/kg i.p.). The compound showed additional activity in depression/anxiety models, such as the chronic mild stress in mice (10 mg/kg i.p.), ultrasonic distress calls in rat pups separated from their mother (MED: 1 mg/kg s.c.), and the increased latency of paradoxical sleep in rats (MED: 30 mg/kg i.p.). In conclusion, SSR504734 is a potent and selective GlyT1 inhibitor, exhibiting activity in schizophrenia, anxiety and depression models. By targeting one of the primary causes of schizophrenia (hypoglutamatergy), it is expected to be efficacious not only against positive but also negative symptoms, cognitive deficits, and comorbid depression/anxiety states.
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PMID:Neurochemical, electrophysiological and pharmacological profiles of the selective inhibitor of the glycine transporter-1 SSR504734, a potential new type of antipsychotic. 1595 94

It has been reported that malaria infection impairs hepatic drug clearance and causes a down-regulation of CYP-mediated monooxygenase activities in rodents and humans. In the present study, we investigated the effects of Plasmodium berghei infection on the activity of liver monooxygenases in female DBA/2 and C57BL/6 mice. In both mouse strains, P. berghei infection decreased activities mediated by CYP1A (EROD: DBA/2 65.3%, C57BL/6 44.7%) and 2B (BROD: DBA/2 64.3%, C57BL/6 49.8%) subfamily isoforms and increased activities mediated by 2A5 (COH: DBA/2 182.4%, C57BL/6 148.5%) and 2E1 (PNPH: DBA/2 177.8%, C57BL/6 128.5%) isoforms as compared to non-infected controls. Since malaria infection also produced an increase in ALT (273.1%) and AST (354.1%) activities in the blood serum, our findings are consistent with the view that CYP2A5 activity is induced by liver injury. An almost generalized depression of CYP-mediated activities has been found with numerous infections and inflammatory stimuli but an induction of CYP2A5 had been previously noted only in some viral hepatitis and trematode (liver fluke) infections.
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PMID:Plasmodium berghei (ANKA): infection induces CYP2A5 and 2E1 while depressing other CYP isoforms in the mouse liver. 1654 Jan 9

Previous studies using the 5alpha-reductase inhibitor finasteride suggest that progesterone metabolites, particularly the endogenous neurosteroid allopregnanolone, mediate some of the effects of ethanol. Consequently, we studied the effect of finasteride (2 x 25 mg/kg s.c., 12 h apart) pretreatment on the acquisition and expression of ethanol (2 g/kg i.p.) induced conditioned place preference and c-fos expression in DBA/2 mice; a strain known to be particularly sensitive to ethanol. Ethanol administration induced a clear conditioned place preference and widespread c-fos expression, with elements of the extended amygdala, Edinger-Westphal nucleus and paraventricular nucleus being especially sensitive. However, despite an approximately 99% decrease in whole brain allopregnanolone content, finasteride pretreatment had remarkably little effect on either ethanol-induced conditioned place preference or ethanol-induced c-fos expression. Thus, aside from a general stimulatory effect on c-fos expression in the ventral tegmental area, and generally mild depression of locomotor activity, no other effects of finasteride or interaction with ethanol effects were identifiable. Together, these studies suggest that endogenous allopregnanolone plays little part in mediating acute ethanol-induced reward or neural activation in DBA/2 mice.
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PMID:Lack of evidence of a role for the neurosteroid allopregnanolone in ethanol-induced reward and c-fos expression in DBA/2 mice. 1675 Jan 78

Neurosteroids, pregnenolone (Preg), dehydroepiandrosterone (DHEA) and their sulfates (PregS and DHEAS) are reported to exert their modulatory effects of neuronal excitability and synaptic plasticity via amino acid receptors, which affect and regulate the learning and memory process, mood, and depression. Although the brain levels of these steroids have been reported in rodents, the strain differences of the levels of these steroids have not been demonstrated. We examined the concentrations of Preg, 17-OH-Preg, DHEA, androstenediol (ADIOL) and their sulfates in whole brains from DBA/2, C57BL/6, BALB/c, ddY and ICR mice, the genetic backgrounds of which are different. No differences in the brain levels of Preg and DHEA were found among the strains. In contrast, PregS levels in DBA/2 were significantly lower than in the others, while DHEAS concentrations in DBA/2 were significantly higher than those in other strains. Strain differences were found in 17-OH-Preg, ADIOL and 17-OH-PregS but not in ADIOLS levels. The ranges of Preg and PregS levels were the highest among the steroids studied. Further, we measured serum these steroid levels. Although strain differences were also found in serum steroids, correlation study between brain and serum levels revealed that brain neurosteroids studied may not come from peripheral circulation. In conclusion, this is the first report of demonstrating mammalian brain levels of 17-OH-Preg, ADIOL, 17-OH-PregS and ADIOLS and the strain differences in neurosteroid levels in mice brains. The differences in levels may involve the strain differences in their behavior, e.g. aggression, adaptation to stress or learning, in mice.
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PMID:Strain differences of neurosteroid levels in mouse brain. 1679 26

Genetic factors and early life adversity both play a major role in the etiology of mood and anxiety disorders. Previous studies have shown that postnatal maternal separation (MS) can produce lasting abnormalities in emotion-related behavior and neuroendocrine responses to stress in rodents. The present study sought to examine the effects of repeated MS in eight different inbred strains of mice (129S1/SvImJ, 129P3/J, A/J, BALB/cJ, BALB/cByJ C57BL/6J, DBA/2J, FVB/NJ). Pups were separated from their dam and littermates for 180 min/day ('MS') or 15 min/day ('handling'), or left undisturbed ('facility-reared') from postnatal days P0-P13, and tested as adults for anxiety- and depression-related behaviors. Results demonstrated no clear and consistent effects of MS or handling on behavioral phenotypes in any of the strains tested. In all strains, MS produced an increase in maternal care on reunion with pups, which may have modified MS effects. Data demonstrate that the MS procedure employed does not provide a robust model of early life stress effects on the anxiety- and depression-related behaviors in the mouse strains tested.
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PMID:Effects of repeated maternal separation on anxiety- and depression-related phenotypes in different mouse strains. 1695 May 13


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