In spite of use of cannabidiol (CBD), a non-psychoactive cannabinoid, in pediatric patients with epilepsy, preclinical studies on its effects in immature animals are very limited. In the present study we investigated anti-seizure activity of CBD (10 and 60 mg/kg administered intraperitoneally) in two models of chemically induced seizures in infantile (12-days old) rats. Seizures were induced either with pentylenetetrazol (PTZ) or N-methyl-D-aspartate (NMDA). In parallel, brain and plasma levels of CBD and possible motor adverse effects were assessed in the righting reflex and the bar holding tests. CBD was ineffective against NMDA-induced seizures, but in a dose 60 mg/kg abolished the tonic phase of PTZ-induced generalized seizures. Plasma and brain levels of CBD were determined up to 24 h after administration. Peak CBD levels in the brain (996 ± 128 and 5689 ± 150 ng/g after the 10- and 60-mg/kg doses, respectively) were reached 1-2 h after administration and were still detectable 24 h later (120 ± 12 and 904 ± 63 ng/g, respectively). None of the doses negatively affected motor performance within 1 h after administration, but CBD in both doses blocked improvement in the bar holding test with repeated exposure to this task. Taken together, anti-seizure activity of CBD in infantile animals is dose and model dependent, and at therapeutic doses CBD does not cause motor impairment. The potential risk of CBD for motor learning seen in repeated motor tests has to be further examined.
- MeSH
- antikonvulziva farmakologie MeSH
- epilepsie farmakoterapie MeSH
- kanabidiol farmakokinetika farmakologie MeSH
- krysa rodu rattus MeSH
- modely nemocí na zvířatech MeSH
- mozek účinky léků MeSH
- N-methylaspartát farmakologie MeSH
- pentylentetrazol farmakologie MeSH
- potkani Wistar MeSH
- záchvaty farmakoterapie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Synthetic cannabinoid compounds are marketed as "legal" marijuana substitutes, even though little is known about their behavioral effects in relation to their pharmacokinetic profiles. Therefore, in the present study we assessed the behavioral effects of systemic treatment with the two synthetic cannabinoids JWH-073 and JWH-210 and the phytocannabinoid Δ9-THC on locomotor activity, anxiety-like phenotype (in the open field) and sensorimotor gating (measured as prepulse inhibition of the acoustic startle response, PPI), in relation to cannabinoid serum levels. Wistar rats were injected subcutaneously (sc.) with JWH-073 (0.1, 0.5, or 5 mg/kg), JWH-210 (0.1, 0.5, or 5 mg/kg), Δ9-THC (1 or 3 mg/kg) or vehicle (oleum helanti) in a volume of 0.5 ml/kg and tested in the open field and PPI. Although JWH-073, JWH-210, Δ9-THC (and its metabolites) were confirmed in serum, effects on sensorimotor gating were absent, and locomotor activity was only partially affected. Δ9-THC (3 mg/kg) elicited an anxiolytic-like effect as suggested by the increased time spent in the center of the open field (p < 0.05). Our results further support the potential anxiolytic-like effect of pharmacological modulation of the endocannabinoid system.
- Publikační typ
- časopisecké články MeSH
The role of NMDA receptors in learning, memory and hippocampal function has long been recognized. Post-mortem studies have indicated that the expression or subunit composition of the NMDA glutamate receptor subtype might be related to the impaired cognitive functions found in schizophrenia patients. NMDA receptor antagonists have been used to develop animal models of this disorder. There is accumulating evidence showing that not only the acute but also the chronic application of NMDA receptor antagonists may induce schizophrenia-like alterations in behavior and brain functions. However, limited evidence is available regarding the consequences of NMDA receptor blockage during periods of adolescence and early adulthood. This study tested the hypothesis that a 2-week treatment of male Long-Evans and Wistar rats with dizocilpine (MK-801; 0.5 mg/kg daily) starting at postnatal days (PD) 30 and 60 would cause a long-term cognitive deficit and changes in the levels of NMDA receptor subunits. The working memory version of the Morris water maze (MWM) and active place avoidance with reversal on a rotating arena (Carousel) requiring cognitive coordination and flexibility probed cognitive functions and an elevated-plus maze (EPM) was used to measure anxiety-like behavior. The western blot method was used to determine changes in NMDA receptor subunit levels in the hippocampus. Our results showed no significant changes in behaviors in Wistar rats. Slightly elevated anxiety-like behavior was observed in the EPM in Long-Evans rats with the onset of treatment on PD 30. Furthermore, Long-Evans rats treated from PD 60 displayed impaired working memory in the MWM. There were; however, no significant changes in the levels of NMDA receptor subunits because of MK-801 administration. These findings suggest that a 2-week treatment starting on PD 60 in Long-Evans rats leads to long-term changes in working memory, but this deficit is not paralleled by changes in NMDA receptor subunits. These results support the face validity, but not construct validity of this model. We suggest that chronic treatment of adolescent and adult rats does not constitute a plausible animal model of schizophrenia.
- Publikační typ
- časopisecké články MeSH
Mikrodialýza (MD) v kombinaci s vysokoúčinnou kapalinovou chromatografií a hmotnostní spektrometrií (HPLC-MS) je úspěšně využí- vána k metabolomickému mapování dynamických změn v mozku. Potřeba využití těchto metod vzrůstá s rozvojem nových syntetických drog (NSD), kdy je nutné na jejich výskyt velmi rychle reagovat a určit jejich případnou nebezpečnost a jejich adiktivní potenciál. Z uvedeného důvodu by tato metodika mohla v budoucnu sloužit jako prediktivní nástroj pro určení nebezpečnosti NSD na základě metabolických změn v průběhu intoxikace. Dovolujeme si odhadnout, že tato metoda má vysoký potenciál pro rozšíření znalostí nejen o účinku nových syntetických drog (NSD) a molekulární podstatě rozvoje závislosti, ale může také posloužit k vývoji nových léčebných postupů.
In the past decades, the requirement for in vivo detection of diverse chemical substances has increased due to development of new synthetic drugs with an unknown impact on brain metabolism. Microdialysis in combination with high -performance liquid chromatography and mass spectrometry (HPLC-MS) is an efficient tool for monitoring dynamic biochemical changes in the brain. Hence, it could be used for dissecting the mechanism of action of newly appearing synthetic abusive drugs and processes involved in the development of drug addiction. Moreover, it can be optimized for diverse compounds and biological tissues and utilized, for example, for testing of novel therapeutical approaches.
- MeSH
- dopamin sekrece MeSH
- hmotnostní spektrometrie MeSH
- metabolomika MeSH
- methamfetamin farmakologie MeSH
- mikrodialýza * MeSH
- mozek metabolismus MeSH
- poruchy spojené s užíváním psychoaktivních látek * metabolismus MeSH
- potkani Wistar MeSH
- vysokoúčinná kapalinová chromatografie * MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
