ABSTRACT
Acute treatment with positive allosteric modulators (PAMs) of mGlu1 and mGlu5 metabotropic glutamate receptors (RO0711401 and VU0360172, respectively) reduces the incidence of spike-and wave discharges in the WAG/Rij rat model of absence epilepsy. However, from the therapeutic standpoint, it was important to establish whether tolerance developed to the action of these drugs. We administered either VU0360172 (3 mg/kg, s.c.) or RO0711401 (10 mg/kg, s.c.) to WAG/Rij rats twice daily for ten days. VU0360172 maintained its activity during the treatment, whereas rats developed tolerance to RO0711401 since the 3rd day of treatment and were still refractory to the drug two days after treatment withdrawal. In response to VU0360172, expression of mGlu5 receptors increased in the thalamus of WAG/Rij rats after 1 day of treatment, and remained elevated afterwards. VU0360172 also enhanced mGlu5 receptor expression in the cortex after 8 days of treatment without changing the expression of mGlu1a receptors. Treatment with RO0711401 enhanced the expression of both mGlu1a and mGlu5 receptors in the thalamus and cortex of WAG/Rij rats after 3-8 days of treatment. These data were different from those obtained in non-epileptic rats, in which repeated injections of RO0711401 and VU0360172 down-regulated the expression of mGlu1a and mGlu5 receptors. Levels of VU0360172 in the thalamus and cortex remained unaltered during the treatment, whereas levels of RO0711401 were reduced in the cortex at day 8 of treatment. These findings suggest that mGlu5 receptor PAMs are potential candidates for the treatment of absence epilepsy in humans.
Subject(s)
Anticonvulsants/pharmacology , Epilepsy, Absence/drug therapy , Epilepsy, Absence/physiopathology , Excitatory Amino Acid Agents/pharmacology , Receptor, Metabotropic Glutamate 5/metabolism , Receptors, Metabotropic Glutamate/metabolism , Animals , Blotting, Western , Cerebral Cortex/drug effects , Cerebral Cortex/physiopathology , Disease Models, Animal , Drug Tolerance , Electrodes, Implanted , Electroencephalography , Male , Mice, Transgenic , Niacinamide/analogs & derivatives , Niacinamide/pharmacology , Rats , Rats, Inbred ACI , Rats, Wistar , Receptor, Metabotropic Glutamate 5/genetics , Receptors, Metabotropic Glutamate/genetics , Thalamus/drug effects , Thalamus/physiopathology , Time FactorsABSTRACT
Eight-month old WAG/Rij rats, which developed spontaneous occurring absence seizures, showed a reduced function of mGlu1 metabotropic glutamate receptors in the thalamus, as assessed by in vivo measurements of DHPG-stimulated polyphosphoinositide hydrolysis, in the presence of the mGlu5 antagonist MPEP as compared to age-matched non-epileptic control rats. These symptomatic 8-month old WAG/Rij rats also showed lower levels of thalamic mGlu1α receptors than age-matched controls and 2-month old (pre-symptomatic) WAG/Rij rats, as detected by immunoblotting. Immunohistochemical and in situ hybridization analysis indicated that the reduced expression of mGlu1 receptors found in symptomatic WAG/Rij rats was confined to an area of the thalamus that excluded the ventroposterolateral nucleus. No mGlu1 receptor mRNA was detected in the reticular thalamic nucleus. Pharmacological manipulation of mGlu1 receptors had a strong impact on absence seizures in WAG/Rij rats. Systemic treatment with the mGlu1 receptor enhancer SYN119, corresponding to compound RO0711401, reduced spontaneous spike and wave discharges spike-wave discharges (SWDs) in epileptic rats. Subcutaneous doses of 10 mg/kg of SYN119 only reduced the incidence of SWDs, whereas higher doses (30 mg/kg) also reduced the mean duration of SWDs. In contrast, treatment with the non-competitive mGlu1 receptor antagonist, JNJ16259685 (2.5 and 5 mg/kg, i.p.) increased the incidence of SWDs. These data suggest that absence epilepsy might be associated with a reduction of mGlu1 receptors in the thalamus, and that compounds that amplify the activity of mGlu1 receptors might be developed as novel anti-absence drugs. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.
Subject(s)
Epilepsy, Absence/metabolism , Receptors, Metabotropic Glutamate/metabolism , Allosteric Regulation , Animals , Ciprofloxacin/analogs & derivatives , Ciprofloxacin/pharmacology , Disease Models, Animal , Dose-Response Relationship, Drug , Electroencephalography/drug effects , Epilepsy, Absence/drug therapy , Epilepsy, Absence/genetics , Excitatory Amino Acid Antagonists/pharmacology , Male , Motor Activity/drug effects , Motor Activity/physiology , Nucleic Acid Synthesis Inhibitors/pharmacology , Quinolines/pharmacology , RNA, Messenger/metabolism , Rats , Rats, Inbred ACI , Rats, Inbred Strains , Receptors, Metabotropic Glutamate/genetics , Signal Transduction/drug effects , Thalamic Nuclei/metabolism , Thalamic Nuclei/physiopathology , Thalamus/metabolism , Thalamus/physiopathologyABSTRACT
The effect of diazepam on sensory gating was studied in rats by measuring diazepam effects on auditory evoked potentials (AEPs) elicited in a ten-tone paradigm. Trains of 10 repetitive tone-pip stimuli were presented. Rats (n = 8) received 4 mg x kg(-1) diazepam subcutaneously or vehicle, counterbalanced over two sessions. Diazepam decreased the amplitude of the middle-latency P30 component and increased the amplitudes of the late-latency N60 and P67 components. The increase in the late-latency components might be due to a diazepam-induced decrease in arousal. Stimulus repetition decreased the amplitudes of the middle-latency N18 and P30 components in both conditions. This suggests that automated neuronal recovery functions underlying sensory gating remain intact with diazepam. In the vehicle condition, the amplitude of the late-latency P67 decreased with stimulus repetition, but not in the diazepam condition. This suggests a diazepam-induced decrease of behaviourally mediated habituation.