propylthiouracil and cyclothiazide

The role of glutamate receptors in the inferior colliculus (IC) in audiogenic and audiogenic-like seizures was investigated in adult rats with transient neonatal hypothyroidism by 0.02% propylthiouracil (PTU) treatment through mother's milk (PTU rats) and in naive rats treated intracisternally with N-methyl-d-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid (AMPA), or cyclothiazide, an inhibitor of rapid AMPA receptor desensitization. All rats showed audiogenic or audiogenic-like seizures characterized by running fit (RF) and generalized tonic-clonic seizures (GTCS). While systemically administered MK-801 inhibited GTCS, intracisternally administered NBQX inhibited RF and GTCS in both audiogenic and audiogenic-like seizures. Auditory stimulation shortened the latency to GTCS induced by AMPA, but not NMDA, at a subclinical dose and further elongated the shortened duration of RF, but not GTCS, induced by MK-801 pretreatment. Furthermore, Northern blot analysis was used to evaluate the expression of the immediate-early gene c-fos in the IC following induction of audiogenic or audiogenic-like seizures. The significant induction of c-fos mRNA by audiogenic seizures in PTU rats or by AMPA- or cyclothiazide-induced seizures in naive rats was prominent in the IC. MK-801 suppressed c-fos mRNA expression in the IC induced by audiogenic seizures in PTU rats or by AMPA-induced seizures in naive rats. NBQX suppressed the expression of c-fos mRNA in the IC induced by AMPA-induced seizures but did not suppress c-fos mRNA in PTU rats or rats with cyclothiazide-induced seizures. Auditory stimuli failed to affect c-fos mRNA induction by AMPA. The present study suggests that audiogenic-like seizures can be reproduced by glutamate receptor agonists in which AMPA receptors are primarily linked to the initiation of audiogenic seizures (RF) while NMDA receptors presumably located within the IC are involved in the propagation of GTCS in audiogenic seizures.

Topics: Acoustic Stimulation; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Animals, Suckling; Benzothiadiazines; Dizocilpine Maleate; Drug Administration Routes; Excitatory Amino Acid Antagonists; Female; Hypothyroidism; Inferior Colliculi; Injections, Intraventricular; Male; Maternal Exposure; N-Methylaspartate; Propylthiouracil; Proto-Oncogene Proteins c-fos; Quinoxalines; Rats; Rats, Sprague-Dawley; Reaction Time; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; RNA, Messenger; Seizures

Rats neonatally treated with 0.02% propylthiouracil (PTU) through mother's milk showed a high incidence of audiogenic seizures after maturation. These audiogenic seizures were differently modified by MK-801 and NBQX; while intraperitoneal MK-801 equally inhibited running fit (RF) and generalized tonic-clonic seizure (GTCS), NBQX administered into cisterna ambiens significantly inhibited RF but not GTCS. The possible involvement of glutamate receptors in the inferior colliculus was further investigated using naive Sprague-Dawley rats injected with NMDA, AMPA or cyclothiazide, known as an inhibitor of desensitization of AMPA action. All drugs tested successfully induced RF followed by GTCS, resembling audiogenic seizures in PTU-treated rats. However, sound stimulation could augment AMPA-induced, but not NMDA-induced GTCS. Systemic administration with MK-801 potently blocked GTCS induced by AMPA/cyclothiazide, but the same drug failed to block RF after intracisternal injection with AMPA/cyclothiazide. Furthermore, intracisternal administration with NBQX significantly inhibited only RF induced by AMPA/cyclothiazide. The present study suggests that: 1) glutamate receptors in the brainstem, possible in the inferior colliculus, play a crucial role in audiogenic seizures, namely the initiation of RF and propagation into GTCS; and 2) the initiation mechanism is regulated by both NMDA and AMPA receptors, whereas propagation is mainly controlled by NMDA receptors.

Topics: Acoustic Stimulation; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Anticonvulsants; Benzothiadiazines; Brain Stem; Dizocilpine Maleate; Epilepsy, Tonic-Clonic; Excitatory Amino Acid Agonists; Inferior Colliculi; N-Methylaspartate; Neuroprotective Agents; Propylthiouracil; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate; Seizures