The anti-absence effect of mGlu5 receptor amplification with VU0360172 is maintained during and after antiepileptogenesis.

PURPOSE: Ethosuximide (ETX) is the drug of choice for the treatment of patients with absence seizures - taking into account both its efficacy, tolerability and antiepileptogenic properties. However, 47% of subjects failed in ETX-therapy, and most antiepileptic drugs have cognitive side effects. VU0360172, a positive allosteric modulator (PAM) of mGluR5, has been proposed as a new anti-absence drug. Here it is investigated whether anti-epileptogenesis induced by ETX alters the sensitivity of VU0360172, and whether cognition is affected during and after chronic ETX treatment. METHOD: EEG's were recorded before and after a challenge with VU0360172 in chronic ETX and in control WAG/Rij rats during and after treatment. Rats were also exposed to a cue discrimination learning task in a Y-maze both during and after treatment. At the end of the experiment, mGlu5 receptors were quantified by Western Blot analysis. RESULTS: Antiepileptogenesis was successfully induced by ETX and VU0360172 showed a time and dose dependent anti-absence action in the control group. VU0360172 kept its anti-absence action in chronic ETX treated rats both during and after treatment, without time and dose dependency. This anti-absence effect of VU0360172 in both groups matched the lack of differences in mGluR5 expression. Chronic ETX enhanced the number of completed trials, the number of correct choices in the Y-maze and the number of consumed sucrose pallets. SIGNIFICANCE: VU0360172 maintains its anti-absence effects after chronic treatment; as such, VU0360172 can also be used as a adjunctive therapy in patients with absence epilepsy. The enhanced motivation and cognitive performance by ETX might be mediated by the antidepressant action of ETX as expressed by an increase in the rewarding properties of sucrose pallets.

Anti-absence activity of mGlu1 and mGlu5 receptor enhancers and their interaction with a GABA reuptake inhibitor: Effect of local infusions in the somatosensory cortex and thalamus.

OBJECTIVE: Glutamate and γ-aminobutyric acid (GABA) are the key neurotransmitter systems in the cortical-thalamocortical network, involved in normal and pathologic oscillations such as spike-wave discharges (SWDs), which characterize different forms of absence epilepsy. Metabotropic glutamate (mGlu) and GABA receptors are widely expressed within this network. Herein, we examined the effects of two selective positive allosteric modulators (PAMs) of mGlu1 and mGlu5 receptors, the GABA reuptake inhibitor, tiagabine, and their interaction in the somatosensory cortex and thalamus on SWDs in WAG/Rij rats. METHODS: Male WAG/Rij rats were equipped with bilateral cannulas in the somatosensory cortex (S1po) or the ventrobasal (VB) thalamic nuclei, and with cortical electroencephalography (EEG) electrodes. Rats received a single dose of the mGlu1 receptor PAM, RO0711401, or the mGlu5 receptor PAM, VU0360172, various doses of tiagabine, or VU0360172 combined with tiagabine. RESULTS: Both PAMs suppressed SWDs regardless of the site of injection. Tiagabine enhanced SWDs when injected into the thalamus, but, unexpectedly, suppressed SWDs in a dose-dependent manner when injected into the cortex. Intracortical co-injection of VU0360172 and tiagabine produced slightly larger effects as compared to either VU0360172 or tiagabine alone. Intrathalamic co-injections of VU0360172 and subthreshold doses of tiagabine caused an antiabsence effect similar to that exhibited by VU0360172 alone in the first 10 min. At 30 min, however, the antiabsence effect of VU0360172 was prevented by subthreshold doses of tiagabine, and the combination produced a paradoxical proabsence effect at 40 and 50 min. SIGNIFICANCE: These data (1) show that mGlu1 and mGlu5 receptor PAMs reduce absence seizures acting at both thalamic and cortical levels; (2) demonstrate for the first time that tiagabine, despite its established absence-enhancing effect, reduces SWDs when injected into the somatosensory cortex; and (3) indicate that the efficacy of VU0360172 in the thalamus may be critically affected by the availability of (extra)synaptic GABA.