Glutamate Receptor Activation in the Brainstein of Audiogenic Seizure‐Susceptible Rats
Authors: Higashiyama Akiko , Ishida Nobuya , Yasuda Shin , Nishimura Tsutomu , Kato Nobumasa 
Published: August 2005

Purpose: This study was conducted to assess the effect of NMDA receptor antagonists (MK‐80 I and CPP) and a non‐NMDA receptor antagonist (NBQX), administered into inferior colliculus (IC) or into the ambient cistern on audiogenic seizures i n rats neonatally exposed to propylthiourecil (PTU). Furthermore, the role of glutamatc rcceptor subtypes i n audiogenic seizures was cxanincd by analysis of behavioral manifcstations induced hy inttacisternal injection of NMDA or AMPA in naive rats.

Methods: I. Rats were exposed to 0.02% PTU through the mother's milk from day 0 to day 19 (PTU rats). Those animals were tested for audiogcnic scizure susceptibility at the age of 10 wccks. PTU rats without generalized tonic‐clonic scizurc (GTCS) after auditory stimulation wcrc excluded i n this study. MK‐801 at doscs of 2, 20, 40 nmol/side (n = 2, I I, 5), CPP at doscs of 0.04, 0.4, 4 nmol/side (11 = I I, 5, 13), or NBQX at doscs of 2, 20 imnol/side (n = 3, 13) was bilatcrally;idministered into IC. Thiriy minutcs aftcr treatment of drugs, auditory stimulation wiis applied by ringing the emergency bell (1 12 dB) [or 80 scc. The latency to running fit (RF) and GTCS, and the duration 0 1 RF and GTCS wcrc observed i n each tested animal. MKX O I at doses of 0.02, 2, 40 nmol/brain (n = 6, 5, 5), CPP at doses of 0.04, 0.4, 4 nmol/hrain (n = 6, 6, h), or NBQX at doses of 0.5, 5 nmol/brain (n = 6, 6) was administered inio cisterna ambicncc of PTU rats. Five minutes after treatment of drugs, the audiogenic seizures wcrc obscrved as stated above.

2. Naive Spraguc‐Dawlcy rats were used at 7 weeks of age. NMDA at doscs of 10, 20 pglbrain (n = 10, 5) or AMPA at doses of 3, 6 pg/brain (11 = 6, 7) was administcrcd into cisterna ambience. After trcatincnt of NMDA or AMPA, the behavioral changes wcrc observed for 30 minutes. Furthermore, aftcr trcatment of NMDA 5 pg/hrain (n = 4) or AMPA 3 @brain (n=6), the behavioral changes were obscrvcd i n cach tested animal during 80 seconds with auditory stimulation. AMPA 3 pg/brain was administered into cisterna arnbiencc after pre‐trciitmcnt of systemic administration or MK‐801 0.5 mg/kg. The behavioral changes of the prc‐treated animals were comparcd with those of non pre‐treated animals during 80 scconds with auditory stimulation.

Results: I. In PTU rats the microinjection of CPP into 1C at 0.4, 4 nmol/side was found to exhibit significant blocking effects on both RF and GTCS. NBQX at 20 nmollside inhibited only GTCS. 2. intracisternal injection of MK‐801, CPP, or NBQX showed significant block‐ing effects on both RF and GTCS in PTU rats. 3. Thc intracistcrnal administration of NMDA or AMPA in naive rats dose‐dependently elicitcd RF lollowcd by GTCS similar to audiogenic seizurcs in PTU rats. 4. Auditory stimulation augmented both RF and GTCS induced by subclinical dose of AMPA in naive rats but failed to affect the procon vulsant action of NMDA. This augmentative effect was inhibited by MK‐80 I.

Conclusion: These results suggest that both NMDA and AMPA receptor activation arc ncccssary to induce RF. In audiogcnic scizurcs, thc auditory stimulation probably is equivalent to the activation of NMDA receptors, and thc relay mcchanism from RF to GTCS is presumably related to NMDA receptors.