title: Differential alterations of GABA(A) receptor (α1, β2, γ2 subunit) expression and increased seizure susceptibility in rat offspring from morphine-addicted mothers: beneficial effect of dextromethorphan.
abstract: Although prenatal morphine exposure experimentally induces seizures in rat offspring, underlying mechanisms remain unclear. This study addresses whether prenatal morphine exposure altered subunit compositions of γ-aminobutyric acid receptor subtype A (GABA(A)R) in the hippocampal CA1 area and temporal cortex and increased seizure susceptibility of young rat offspring, at a representative age (postneonatal days 14; P14). Therapeutic efficacy of dextromethorphan (a noncompetitive antagonist of N-methyl-d-aspartate receptors (NMDARs)), in such offspring was also evaluated. From P7 to 14, Sprague-Dawley rat offspring were intraperitoneally (ip) injected a representative dose of dextromethorphan (3mg/kg) twice a day. At P14, some offspring were ip injected pentylenetetrazol to estimate seizure susceptibility, while the others were studied for GABA(A)R subunit (α1, β2, γ2) expression. Prenatal morphine exposure caused the up-regulated α1 subunit and down-regulated β2/γ2 subunit expression of GABA(A)R within hippocampus and temporal cortex in rat offspring associated to increase seizure susceptibility. The magnitudes of upregulated α1 subunit and downregulated β2 subunit expression in the hippocampus were greater than which in the temporal cortex. The use of dextromethorphan markedly reversed the prenatal morphine-induced alterations, indicating the possible therapeutic actions of dextromethorphan. These results suggest that the altered subunit compositions (α1, β2, γ2) of GABA(A)R in the hippocampal CA1 area and temporal cortex may contribute, at least in part, to the increased seizure susceptibility of rat offspring subjected to prenatal morphine exposure. More importantly, dextromethorphan may be a promising clinical agent acting against these alterations.
authors.affiliation: Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Chao-Yi
authors.initials: CY
authors.lastname: Wang
authors.forename: Chi-Hsing
authors.initials: CH
authors.lastname: Hung
authors.forename: Chien-Sheng
authors.initials: CS
authors.lastname: Lin
authors.forename: Hai-Hsiang
authors.initials: HH
authors.lastname: Lee
authors.forename: Chun Hwa
authors.initials: CH
authors.lastname: Yang
authors.forename: Yuh-Jyh
authors.initials: YJ
authors.lastname: Jong
authors.forename: San Nan
authors.initials: SN
authors.lastname: Yang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003915:Dextromethorphan / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D009021:Morphine Dependence / Q000150:complications* / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000096:biosynthesis* / Q000187:drug effects; D012640:Seizures / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control
chemical_list: D018691:Excitatory Amino Acid Antagonists; D011963:Receptors, GABA-A; D003915:Dextromethorphan