Regulation of limbic motor seizures by GABA and glutamate transmission in nucleus tractus solitarius

Purpose: The nucleus of the solitary tract (NTS) is a primary site at which vagal afferents terminate. Because afferent vagal nerve stimulation has been demonstrated to have anticonvulsant effects, it is likely that changes in synaptic transmission in the NTS can regulate seizure susceptibility. We tested this hypothesis by examining the influence of gamma-aminobutyric acid (GABA) ergic and glutamatergic transmission in the NTS on seizures evoked by systemic and focal bicuculline and systemic pentylenetetrazol (PTZ) in rats. Methods: Muscimol (256 pmol), a GABA(A)-receptor agonist, bicuculline methiodide (177 pmol), a GABA(A)-receptor antagonist, kynurenate (634 pmol), a glutamate-receptor antagonist, or lidocaine (100 nl; 5%), a local anesthetic, was microinjected into the mediocaudal (m)NTS. Ten minutes later, seizure activity was induced by either a focal microinfusion of bicuculline methiodide (177 pmol) into the rostral piriform cortex, systemic PTZ (50 mg/kg, i.p.), or systemic bicuculline (0.35 mg/kg, i.v.). Results: Muscimol in mNTS (but not in adjacent regions of NTS) attenuated seizures in all seizure models tested, whereas bicuculline methiodide into mNTS did not alter seizure responses. Kynurenate infusions into mNTS significantly reduced the severity of seizures evoked both systemically and focally. Anticonvulsant effects also were obtained with lidocaine application into the same region of mNTS. Unilateral injections were sufficient to afford seizure protection. Conclusions: Our results demonstrate that an increase in GABA transmission or a decrease in glutamate transmission in the rat mNTS reduces susceptibility to limbic motor seizures. This suggests that inhibition of mNTS outputs enhances seizure resistance in the forebrain and provides a potential mechanism for the seizure protection obtained with vagal stimulation.