- Publikační typ
- abstrakt z konference MeSH
Evidence from clinical and preclinical studies implicates dysfunction of N-methyl-D-aspartate receptors (NMDARs) in schizophrenia progression and symptoms. We investigated the antipsychotic effect of two neuroactive steroids in an animal model of schizophrenia induced by systemic application of MK-801. The neuroactive steroids differ in their mechanism of action at NMDARs. MS-249 is positive, while PA-Glu is a negative allosteric NMDAR modulator. We hypothesized that the positive NMDA receptor modulator would attenuate deficits caused by MK-801 co-application more effectively than PA-Glu. The rats were tested in a battery of tests assessing spontaneous locomotion, anxiety and cognition. Contrary to our expectations, PA-Glu exhibited a superior antipsychotic effect to MS-249. The performance of MS-249-treated rats in cognitive tests differed depending on the level of stress the rats were exposed to during test sessions. In particular, with the increasing severity of stress exposure, the performance of animals worsened. Our results demonstrate that enhancement of NMDAR function may result in unspecific behavioral responses. Positive NMDAR modulation can influence other neurobiological processes besides memory formation, such as anxiety and response to stress.
- MeSH
- antipsychotika farmakologie MeSH
- bicyklické sloučeniny heterocyklické metabolismus MeSH
- chování zvířat účinky léků MeSH
- dizocilpinmaleát farmakologie MeSH
- HEK293 buňky MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- potkani Long-Evans MeSH
- potkani Wistar MeSH
- pregnenolon metabolismus farmakologie MeSH
- receptory N-methyl-D-aspartátu antagonisté a inhibitory metabolismus MeSH
- schizofrenie farmakoterapie metabolismus MeSH
- steroidy farmakologie MeSH
- test vyvýšeného křížového bludiště MeSH
- úleková reakce účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Antidepresivní účinek ketaminu je typický rychlým nástupem a je popsán i u pacientů trpících farmakorezistentní depresí. Na druhé straně nevýhodou ketaminu jsou jeho psychotomimetické účinky. Ketamin je nekompetitivním antagonistou NMDA (N-methyl-D-aspartát) receptorů, které mají důležitou úlohu v neurofyziologických procesech. Potlačení aktivity těchto receptorů má vliv nejen na hladiny glutamátu a excitotoxické procesy, ale také na modulaci funkcí jiných receptorových systémů. Ketamin má vliv i na neuroplasticitu, přičemž jeho efekt lze modulovat opakovanou aplikací, případně koaplikací s jinými látkami. Cílem této práce je shrnout současný pohled na mechanismy účinku ketaminu, jeho vliv na synaptoplasticitu i možnosti modulace jeho antidepresivního účinku. Lepší porozumění mechanismu antidepresivního účinku ketaminu může vést k vývoji bezpečnějších antidepresiv s vyšší účinností.
Ketamine showing a rapid antidepressant effect was demonstrated to be effective also in patients suffering from treatment-resistant depression. The main disadvantage of ketamine as an antidepressant is its psychotomimetic effect. Ketamine is an antagonist of the NMDA receptors, which have an important influence in brain activity. Through antagonism of this receptor, a large amount of processes can be affected, such as glutamate levels, excitotoxicity, or density and activity of other receptors. In addition ketamine influences synaptic plasticity and its effect can be modulated by repeated application, or co-application with other drugs. The aim of this work is to summarize possible ketamine´s mechanisms of action, its effect on synaptic plasticity and possibilities of modulation of antidepressant effect. Better understanding of mechanism of ketamine´s antidepressant effect may lead to development of safer antidepressants with increased efficacy.
- Klíčová slova
- glutamátergní transmise,
- MeSH
- AMPA receptory účinky léků MeSH
- antidepresiva farmakologie MeSH
- deprese nereagující na léčbu * farmakoterapie MeSH
- depresivní poruchy * farmakoterapie MeSH
- indukce remise MeSH
- intravenózní infuze MeSH
- ketamin * farmakologie škodlivé účinky terapeutické užití MeSH
- kinasa 3 glykogensynthasy účinky léků MeSH
- lidé MeSH
- mozkový neurotrofický faktor účinky léků MeSH
- nádorové supresorové proteiny účinky léků MeSH
- receptory GABA účinky léků MeSH
- receptory metabotropního glutamátu účinky léků MeSH
- receptory N-methyl-D-aspartátu antagonisté a inhibitory MeSH
- synergismus léků MeSH
- TOR serin-threoninkinasy účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
OBJECTIVE: The aim of our study was to test whether ketamine produces an antidepressant effect in animal model of olfactory bulbectomy and assess the role of mammalian target of rapamycin (mTOR) pathway in ketamine's antidepressant effect. METHODS: Bulbectomized (OBX) rats and sham controls were assigned to four subgroups according to the treatment they received (ketamine, saline, ketamine + rapamycin, and saline + rapamycin). The animals were subjected to open field (OF), elevated plus maze (EPM), passive avoidance (PA), Morris water maze (MWM), and Carousel maze (CM) tests. Blood samples were collected before and after drug administration for analysis of phosphorylated mTOR level. After behavioral testing, brains were removed for evaluation of brain-derived neurotrophic factor (BDNF) in prefrontal cortex (PFC) and hippocampus. RESULTS: Ketamine normalized hyperactivity of OBX animals in EPM and increased the time spent in open arms. Rapamycin pretreatment resulted in elimination of ketamine effect in EPM test. In CM test, ketamine + rapamycin administration led to cognitive impairment not observed in saline-, ketamine-, or saline + rapamycin-treated OBX rats. Prefrontal BDNF content was significantly decreased, and level of mTOR was significantly elevated in OBX groups. CONCLUSIONS: OBX animals significantly differed from sham controls in most of the tests used. Treatment had more profound effect on OBX phenotype than controls. Pretreatment with rapamycin eliminated the anxiolytic and antidepressant effects of ketamine in task-dependent manner. The results indicate that ketamine + rapamycin application resulted in impaired stress responses manifested by cognitive deficits in active place avoidance (CM) test. Intensity of stressor (mild vs. severe) used in the behavioral tests had opposite effect on controls and on OBX animals.
- MeSH
- antidepresiva farmakologie MeSH
- bludiště - učení účinky léků MeSH
- bulbus olfactorius fyziologie MeSH
- hipokampus účinky léků metabolismus MeSH
- ketamin antagonisté a inhibitory farmakologie MeSH
- krysa rodu rattus MeSH
- mozkový neurotrofický faktor metabolismus MeSH
- potkani Wistar MeSH
- prefrontální mozková kůra účinky léků metabolismus MeSH
- sirolimus farmakologie MeSH
- TOR serin-threoninkinasy účinky léků metabolismus MeSH
- učení vyhýbat se účinky léků MeSH
- úzkost psychologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Publikační typ
- abstrakt z konference MeSH
- Publikační typ
- abstrakt z konference MeSH
A number of studies demonstrated a rapid onset of an antidepressant effect of non-competitive N-methyl-d-aspartic acid receptor (NMDAR) antagonists. Nonetheless, its therapeutic potential is rather limited, due to a high coincidence of negative side-effects. Therefore, the challenge seems to be in the development of NMDAR antagonists displaying antidepressant properties, and at the same time maintaining regular physiological function of the NMDAR. Previous results demonstrated that naturally occurring neurosteroid 3α5β-pregnanolone sulfate shows pronounced inhibitory action by a use-dependent mechanism on the tonically active NMDAR. The aim of the present experiments is to find out whether the treatment with pregnanolone 3αC derivatives affects behavioral response to chronic and acute stress in an animal model of depression. Adult male mice were used throughout the study. Repeated social defeat and forced swimming tests were used as animal models of depression. The effect of the drugs on the locomotor/exploratory activity in the open-field test was also tested together with an effect on anxiety in the elevated plus maze. Results showed that pregnanolone glutamate (PG) did not induce hyperlocomotion, whereas both dizocilpine and ketamine significantly increased spontaneous locomotor activity in the open field. In the elevated plus maze, PG displayed anxiolytic-like properties. In forced swimming, PG prolonged time to the first floating. Acute treatment of PG disinhibited suppressed locomotor activity in the repeatedly defeated group-housed mice. Aggressive behavior of isolated mice was reduced after the chronic 30-day administration of PG. PG showed antidepressant-like and anxiolytic-like properties in the used tests, with minimal side-effects. Since PG combines GABAA receptor potentiation and use-dependent NMDAR inhibition, synthetic derivatives of neuroactive steroids present a promising strategy for the treatment of mood disorders. Highlights: -3α5β-pregnanolone glutamate (PG) is a use-dependent antagonist of NMDA receptors.-We demonstrated that PG did not induce significant hyperlocomotion.-We showed that PG displayed anxiolytic-like and antidepressant-like properties.
- Publikační typ
- časopisecké články MeSH
