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 admi nistration of tricyclic antidepressants such as imipramine, monoamine oxida se inhibitors such as phenelzine, or the selective serotonin reuptake inhib itor (SSRI) antidepressants. Clinical data also indicate that some benzodia zepines, 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 s ystem. In addition some clinical data lend support to decreased benzodiazep ine-sensitive receptor function in panic disorder patients. Using imipramin e, phenelzine and alprazolam, we investigated, in rats, the possibility tha t the therapeutic efficacy of antipanic agents stems from the remodeling of GABAergic transmission in the pons-medulla region. Of the 12 GABA(A) recep tor subunit (alpha1-6, beta1-3, gamma1-3) steady-state mRNA levels investig ated, we observed an increase in the levels of the alpha3-, beta1- and gamm a2-subunit transcripts with all three antipanic agents tested. The effects of imipramine and phenelzine on these subunits occurred after 21 days of tr eatment, while alprazolam effects were observed after 3 days of administrat ion. Histochemical data suggest that the alpha3 beta1 gamma2 subunits compr ise a receptor subtype in the pons-medulla region. Therefore, we conclude t hat these molecular events parallel the therapeutic profile of the drugs ex amined. We further propose that these events may correspond to a remodeling of the GABA(A) receptor population, and may be useful markers for investig ation of the antipanic properties of drugs.