Differential effects mediated by GABAA receptors in thalamic nuclei in lh/lh model of absence seizures.
Absence seizures represent synchronized burst-firing of thalamocortical neurons, which are driven by tonic GABAergic output of nucleus reticularis thalami (NRT). Activation of GABAA receptors on NRT neurons reduces NRT output and retards thalamocortical burst-firing. Although this mechanism in NRT may underlie antiabsence effects of benzodiazepines, it does not explain observations that barbiturates can worsen absence-seizures. In this study we tested the hypothesis that clonazepam and phenobarbital produce differential effects on GABAA receptors in the lh/lh genetic model of absence seizures after microinjection into NRT compared to VLa, a prototypic relay nucleus containing thalamocortical neurons. In NRT, phenobarbital (16-1600 nmol/cannula), clonazepam (160-2200 pmol/cannula) and muscimol (8.8-263 pmol/cannula) significantly suppressed absence seizure frequency. In VLa, phenobarbital (1.6 nmol) and muscimol (0.88 pmol) increased seizure frequency, whereas higher doses (160 nmol and 88 pmol, respectively) significantly suppressed seizure frequency. In contrast, clonazepam produced no effect on seizure frequency even at a dose of 2.2 nmol; this same dose significantly suppressed absence seizures after microinjection into NRT. These findings suggest that activation of GABAA receptors in NRT may suppress absence seizures, and that phenobarbital may worsen absence seizures through actions on GABAA receptors in thalamocortical cells (VLa). Region-specific GABAA receptor isoforms may underlie the contrasting effects of clonazepam after microinjection into NRT and VLa.
Hosford
D A
DA
Department of Medicine (Neurology), Duke University Medical Center Durham, NC, USA. dhosford@acpub.duke.edu
Wang
Y
Y
Cao
Z
Z
D000818:Animals; D002998:Clonazepam / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects; D004832:Epilepsy, Absence / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D005260:Female; D018755:GABA Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D018757:GABA Modulators / Q000008:administration & dosage / Q000494:pharmacology*; D058785:GABA-A Receptor Agonists; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008845:Microinjections; D009118:Muscimol / Q000008:administration & dosage / Q000494:pharmacology; D010634:Phenobarbital / Q000008:administration & dosage / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000187:drug effects*; D013787:Thalamic Nuclei / Q000033:anatomy & histology / Q000503:physiopathology*
D018755:GABA Agonists; D018757:GABA Modulators; D058785:GABA-A Receptor Agonists; D011963:Receptors, GABA-A; D009118:Muscimol; D002998:Clonazepam; D010634:Phenobarbital