Neuropharmacology
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Comparative Study
The preferential mGlu2/3 receptor antagonist, LY341495, reduces the frequency of spike-wave discharges in the WAG/Rij rat model of absence epilepsy.
We examined the expression and function of group-II metabotropic glutamate (mGlu) receptors in an animal model of absence seizures using genetically epileptic WAG/Rij rats, which develop spontaneous non-convulsive seizures after 2-3 months of age. Six-month-old WAG/Rij rats showed an increased expression of mGlu2/3 receptors in the ventrolateral regions of the somatosensory cortex, ventrobasal thalamic nuclei, and hippocampus, but not in the reticular thalamic nucleus and in the corpus striatum, as assessed by immunohistochemistry and Western blotting. In contrast, mGlu2/3 receptor signalling was reduced in slices prepared from the somatosensory cortex of 6-month-old WAG/Rij rats, as assessed by the ability of the agonist, LY379268, to inhibit forskolin-stimulated cAMP formation. ⋯ To examine whether pharmacological activation or inhibition of mGlu2/3 receptors affects absence seizures, we recorded spontaneous spike-wave discharges (SWDs) in 6-month-old WAG/Rij rats systemically injected with saline, the mGlu2/3 receptor agonist LY379268 (0.33 or 1 mg/kg, i.p.), or with the preferential mGlu2/3 receptor antagonist, LY341495 (0.33, 1 or 5 mg/kg, i.p.). Injection of 1mg/kg of LY379268 (1 mg/kg, i.p.) increased the number of SWDs during 3-7 h post-treatment, whereas injection with LY341495 reduced the number of seizures in a dose-dependent manner. It can be concluded that mGlu2/3 receptors are involved in the generation of SWDs and that an upregulation of these receptors in the somatosensory cortex might be involved in the pathogenesis of absence epilepsy.
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Group II (mGluR2/3) metabotropic glutamate receptors have been implicated in the mechanisms of persistent pain states. In the present study, the effects of the selective group II metabotropic glutamate receptor agonists LY379268 and LY389795 were evaluated in the formalin test, carrageenan-induced thermal hyperalgesia and mechanical allodynia, and capsaicin-induced mechanical allodynia in rats. The agonists LY379268 and LY389795 produced dose-dependent decreases in formalin-induced behaviors that were antagonized by the mGlu2/3 receptor antagonist LY341495. ⋯ However, both agonists produced motor impairment on the inverted screen at doses that were analgesic. Moreover, tolerance to the analgesic effects of LY379268 developed after 4 days of once-daily repeated administration in the formalin, carrageenan, capsaicin and hot plate tests. The present findings indicate that group II (mGluR2/3) metabotropic glutamate receptors may be involved in the mechanisms of hyperalgesia and allodynia, however tolerance rapidly develops to these effects.
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Comparative Study
Magnesium-deficient diet alters depression- and anxiety-related behavior in mice--influence of desipramine and Hypericum perforatum extract.
A relation between magnesium (Mg) status and mood disorders has been suggested, but evidence remains inconsistent. Therefore, we examined in mice whether Mg-depletion would alter behavior evaluated in established animal models of depression and anxiety and whether these effects would be sensitive to antidepressants. Compared to control mice fed with normal diet, mice receiving a low Mg diet (10% of daily requirement) for several weeks displayed increased immobility time in the forced swim test, indicating enhanced depression-like behavior. ⋯ Furthermore, the increase in anxiety-related behavior of Mg-depleted mice was abolished in both the open field and light dark test by Hyp. Taken together, we report that Mg-depletion leads to enhanced depression- and anxiety-related behavior in mice, which was further validated by the reversibility of the behavioral changes by known antidepressant and anxiolytic substances. Further, the utility of Mg-depletion as a new screening model for clinically active antidepressant and anxiolytic drugs is suggested.
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The non-competitive NMDA receptor antagonists, including PCP (phencyclidine), ketamine, and MK-801 (dizocilpine) produce psychosis in humans and injure neurons in retrosplenial cortex in adult rodent brain. This study examined the effects of the metabotropic mGlu2/3 agonist LY379268 and antagonist LY341495 on cortical injury produced by systemic MK-801 (1 mg/kg i.p.) in adult female rats. ⋯ The data show that bilateral activation of mGlu2/3 glutamate receptors in cortex or anterior thalamus decreases the neuronal injury in retrosplenial cortex produced by systemic MK-801. Because antipsychotic medications decrease cortical injury produced by NMDA antagonists in rodents and decrease psychosis in humans, mGlu2/3 agonists that decrease cortical injury produced by NMDA antagonists in rodents might be evaluated for decreasing psychosis in people.
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Comparative Study
Behavioural effects of the novel AMPA/GluR5 selective receptor antagonist NS1209 after systemic administration in animal models of experimental pain.
The effects of systemic administration of the novel AMPA/GluR5 selective receptor antagonist NS1209 in animal models of experimental pain have been tested and compared with the AMPA receptor antagonist NBQX and the opiate morphine. In the mouse hot plate test, NS1209 (3-30 mg/kg, s.c. and i.p.) and morphine (3-30 mg/kg, s.c.) significantly increased the nociceptive response latency, whereas NBQX (3-30 mg/kg, i.p.) was ineffective. In the rat formalin test, a model of persistent pain, NS1209 (3 and 6 mg/kg, i.p.) and morphine (0.5 and 3 mg/kg, s.c.) produced dose-dependent reductions in second phase nociceptive behaviours, although NBQX (10 and 20 mg/kg, i.p.) was without effect. ⋯ NS1209 and morphine also reduced cold hypersensitivity in response to ethyl chloride stimulation of the injured hindpaw. At the doses associated with anti-nociceptive actions, no effects on motor performance as determined by the rotarod test were observed for any of the drugs tested. Thus, systemic administration of NS1209 at non-ataxic doses has marked analgesic actions comparable to those of morphine in a range of animal models of experimental pain.