Chronic triazolam and its withdrawal alters GABAA receptor subunit mRNA levels: an in situ hybridization study.
The benzodiazepine (BZ), triazolam (TRZ), results in tolerance and physical dependence. We performed in situ hybridization (ISH) experiments to gain a more complete understanding of the processes involved in mediating the effects of chronic TRZ ISH allowed us to determine whether GABAA receptor subunit mRNAs are affected by 4 weeks of TRZ administration and its withdrawal and to localize the changes to discrete brain regions. Using oligonucleotide probes directed toward the alpha 1-6, beta 1-3, and delta subunit mRNAs, we analyzed message density in 63 brain regions of TRZ-treated and control rat brains, alpha 1-4, beta 1-3, and delta subunit mRNA levels were altered by 28 days of chronic TRZ. No changes were noted in alpha 5-6 mRNA levels. Many of the changes measured were localized to neural structures within the limbic circuit of Papez, or in close communication with this pathway. After a 24 h withdrawal period from 4 weeks of TRZ treatment, the changes noted on the 28th day of treatment were reversed. Moreover, brain regions that were unaffected by the 4-week treatment were altered by the 24 h withdrawal. Our results indicate that chronic treatment and withdrawal are associated with separate processes and that chronic TRZ is correlated with limbic alterations which may be responsible for some of its chronic effects.
Ramsey-Williams
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Upjohn Company, Kalamazoo, MI 49001, USA.
Carter
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D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D005260:Female; D017403:In Situ Hybridization; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism*; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*; D013997:Time Factors; D014229:Triazolam / Q000008:administration & dosage*
D012333:RNA, Messenger; D011963:Receptors, GABA-A; D014229:Triazolam