Common effects of chronically administered antipanic drugs on brainstem GABA(A) receptor subunit gene expression.
Panic disorder is an anxiety disorder that can be treated by long-term administration of tricyclic antidepressants such as imipramine, monoamine oxidase inhibitors such as phenelzine, or the selective serotonin reuptake inhibitor (SSRI) antidepressants. Clinical data also indicate that some benzodiazepines, such as alprazolam, are effective antipanic agents, and that their therapeutic onset is faster than that of antidepressants. Benzodiazepines are well known for their action at GABA(A) receptors, and preclinical data indicate that imipramine and phenelzine also interfere with the GABAergic system. In addition some clinical data lend support to decreased benzodiazepine-sensitive receptor function in panic disorder patients. Using imipramine, phenelzine and alprazolam, we investigated, in rats, the possibility that the therapeutic efficacy of antipanic agents stems from the remodeling of GABAergic transmission in the pons-medulla region. Of the 12 GABA(A) receptor subunit (alpha 1--6, beta 1--3, gamma 1--3) steady-state mRNA levels investigated, we observed an increase in the levels of the alpha 3-, beta 1- and gamma 2-subunit transcripts with all three antipanic agents tested. The effects of imipramine and phenelzine on these subunits occurred after 21 days of treatment, while alprazolam effects were observed after 3 days of administration. Histochemical data suggest that the alpha 3 beta 1 gamma 2 subunits comprise a receptor subtype in the pons-medulla region. Therefore, we conclude that these molecular events parallel the therapeutic profile of the drugs examined. We further propose that these events may correspond to a remodeling of the GABA(A) receptor population, and may be useful markers for investigation of the antipanic properties of drugs.
Tanay
V M
VM
Department of Pharmacology, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada T6G 2H7.
Greenshaw
A J
AJ
Baker
G B
GB
Bateson
A N
AN
D000525:Alprazolam / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001933:Brain Stem / Q000187:drug effects / Q000502:physiology*; D002065:Buspirone / Q000008:administration & dosage / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D007099:Imipramine / Q000008:administration & dosage / Q000494:pharmacology*; D007263:Infusions, Parenteral; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects / Q000502:physiology; D010624:Phenelzine / Q000008:administration & dosage / Q000494:pharmacology*; D011149:Pons / Q000187:drug effects / Q000502:physiology; D021122:Protein Subunits; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000235:genetics*; D013997:Time Factors
D014151:Anti-Anxiety Agents; D021122:Protein Subunits; D011963:Receptors, GABA-A; D010624:Phenelzine; D007099:Imipramine; D002065:Buspirone; D000525:Alprazolam