Chronic convection-enhanced muscimol delivery into the subthalamic nucleus produces transient anticonvulsant effects in an acute rat seizure model.

Aims : Intracerebral drug delivery is an emerging strategy for the treatment of refractory epilepsies. Recently, the GABA A receptor agonist muscimol was infused into the epileptic focus in drug-resistant epilepsy patients (Heiss et al. 2019 Neurosurgery). In seizure and epilepsy models in rats, muscimol has shown anticonvulsant potential when injected acutely into the subthalamic nucleus (STN). However, continuous administration would be required for the clinical setting. Thus, we hypothesized that chronic convection-enhanced muscimol delivery into the STN produces anticonvulsant effects in an acute rat seizure model. Methods : We examined the effects of intra-STN muscimol following a single microinjection (30 and 60 ng/250 nl) and during continuous administration via a microinfusion pump (60 and 600 ng/day over 3 weeks) on the seizure threshold of female Wistar Unilever rats. Timed intravenous pentylenetetrazole (PTZ) infusion was used as an acute seizure test particularly sensitive to GABA-potentiating manipulations. Results : Acute STN muscimol infusion significantly increased PTZ seizure thresholds compared to vehicle-injected animals. The anticonvulsant effect persisted in the first week during chronic STN inhibition and diminished in the second week, indicating tolerance. Low doses of muscimol were well tolerated and not associated with behavioral adverse effects (e.g., sedation, circling) observed after infusion of higher doses. Evaluation of the spatial distribution of BODIPY-labeled muscimol revealed behavioral adverse effects may be attributable to drug spread into adjacent regions of the STN. Conclusions : These results substantiate the STN as a key region in seizure control and indicate the potential of chronic targeted muscimol delivery for prolonged anticonvulsant effects.