Common effects of chronically administered antipanic drugs on brainstem GABAA receptor subunit gene expression

Abstract

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 (␣1-6, ␤1-3, ␥1-3) steady-state mRNA levels investigated, we observed an increase in the levels of the ␣3-, ␤1-and ␥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 ␣3␤1␥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. Molecular Psychiatry (2001) 6, 404-412.

Role of GABA in anxiety and depression

“…In contrast, chronic antidepressants upregulated a1, a3, b1, b2, and g2 genes in rat brainstem [Tanay et al, 1996[Tanay et al, , 2001, while altered anxiety and depression-related behavior was found in mutant mice lacking B1 and B2 receptors [Mombereau et al, , 2005. A recent human study showed that severe treatment-resistant depression with anxiety was linked to a mutation in the b1 subunit of GABA-A receptor [Kosel et al, 2004].…”

“…Elevated cortical GABA after AD treatment in rats [Yang and Shen, 2005]. Increased brainstem GABA-A a1, a3, b1, b2 and g2 subunits mRNA levels [Tanay et al, 1996[Tanay et al, , 2001] and hippocampal GABA-B1 expression [Sands et al, 2004] after chronic AD treatment in rats. Increased Cl À uptake in submissive rats after AD treatment [Malatynska et al, 1995[Malatynska et al, , 2000.…”

Regulation of GABAAReceptor Subunit Expression by Pharmacological Agents

“…Long-term treatment with abecarnil, diazepam, imidazenil, and zolpidem in vivo had no effect on ␣2 mRNA expression in any brain region quantified Holt et al, 1996;Impagnatiello et al, 1996) (Table 2). Long-term treatment with alprazolam up-regulated ␣2 mRNA in the brainstem by 76% (Tanay et al, 2001). Of all brain regions studied, the caudateputamen was the only one in which flurazepam downregulated ␣2 mRNA (Tietz et al, 1999a).…”

“…Holt et al, 1996Holt et al, , 1997a, with the exception of diazepam given as daily injections (Arnot et al, 2001). Long-term alprazolam had no effect on ␤3 mRNA expression in the brainstem (Tanay et al, 2001). Withdrawal from flurazepam for 2 days downregulated ␤3 mRNA expression in all hippocampal subregions (Tietz et al, 1993(Tietz et al, , 1999a (Table 5).…”

“…␤2 Subunit. A reduction in ␤2 mRNA expression in vivo was found after long-term treatment with abecarnil in the cerebral cortex (Holt et al, 1996), with alprazolam in the brainstem (Tanay et al, 2001), with flurazepam in the cerebral cortex, cerebellum, and hippocampus (Zhao et al, 1994a), and with triazolam in the interpeduncular nucleus (Ramsey-Williams and Carter, 1996) (Table 3). No effects on ␤2 mRNA expression in any brain region studied were found after long-term treatment with diazepam, flurazepam (Tietz et al, 1999a), imidazenil, or zolpidem , 1996, 1997aImpagnatiello et al, 1996) (Table 3).…”