In Vivo Evidence of the Specificity of Effects of GABA_A Receptor Modulating Medications

FOR HALF A CENTURY MEDICATIONS THAT ENHANCE NEURONAL INHIBITION BY BINDING TO A SITE ON THE Γ-AMINOBUTYRIC ACID (GABA) TYPE A receptor complex have dominated the pharmacologic treatment of insomnia.^1,2 These agents include a family of chemically related compounds referred to as benzodiazepines as well as a more recently available set of medications that are unrelated chemically to the benzodiazepines but that work via the same mechanism, referred to as “non-benzodiazepines.”² The medications which modulate GABA_A receptors at the benzodiazepine site generally have a number of types of clinical effects, including sedation, myorelaxation, anxiolysis, anticonvulsant effects, cognitive impairment, and motor impairment.² Although these medications are often considered to have the same types of clinical effects and to differ primarily in terms of pharmacokinetics, there is increasing evidence that their profiles of clinical effects vary to a significant degree.^3–7 This is at least partially responsible for the fact that some of these medications have been developed and are U.S. Food and Drug Administration (FDA) approved for the treatment of insomnia (examples: triazolam, temazepam, flurazepam, quazepam, estazolam, zolpidem, zolpidem CR, eszopiclone, and zaleplon), whereas others have been developed and are indicated for the treatment of anxiety disorders (lorazepam, diazepam, alprazolam, clonazepam, and chlordiazepoxide), seizures (diazepam and clonazepam), and/or myorelaxation (diazepam).²

The primary basis for the differences in the clinical effects of the GABA modulating medications is believed to be the existence of a variety of subtypes of GABA_A receptors with distinct patterns of regional expression in the brain to which these medications bind with varying affinities.^1,8–14 However, relatively little data exist that establish these differences in vivo in genetically un-modified animals, particularly among commonly used medications. These gaps in knowledge limit our ability to fully capitalize on the unique features of these GABA_A modulating medications to optimize the clinical management of patients. Better characterization of the effects of GABA_A receptor subtypes on sleep/wake mechanisms also has the potential to lead to the development of novel therapies with improved risk-to-benefit profiles over existing treatment options

The article by Hambrecht-Wiedbusch and colleagues¹⁵ in this issue of SLEEP represents an important contribution to establishing in vivo differences among medications that modulate GABA_A at the benzodiazepine binding site. These authors carried out a study in rats comparing the administration of three medications from this group (zolpidem, eszopiclone, and diazepam) to the pontine reticular formation (PRF) by microdialysis, and examined the differential effects on acetylcholine (Ach) release and changes in EEG delta power. The results are intriguing and indicate clear differences among these three agents. Zolpidem and eszopiclone increased PRF Ach release, however, diazepam did not. At the same time, zolpidem and diazepam were associated with increased EEG delta power, whereas this was not observed with eszopiclone.

The importance of this study does not lie in its suggesting what effects these medications might have on Ach release or EEG delta power in humans in clinical practice. In fact, the intravenous administration of eszopiclone in this study established that the effects of these medications when administered via PRF microdialysis are not predictive of their effects when systemically administered as would occur in clinical practice. Intravenous eszopiclone diminished Ach release and increased EEG delta power. The importance of this study lies in verifying that differences in GABA_A subtype binding observed in vitro for these medications are seen in vivo. These differences include that zolpidem has relatively high affinity for α₁ compared with α₃ subunit containing GABA_A receptors, whereas eszopiclone has greater relative effects on α₃ than α₁ subunit containing GABA_A receptors; and diazepam has relatively high affinity for the α₁, α₂, and α₅ GABA_A receptors with moderate α₃ binding.^9–11,14 Although, it is not possible for the study by Hambrecht-Wiedbusch and coworkers¹⁵ to verify the specific GABA_A subtype binding profiles noted in other studies, their findings are consistent with the observation that there are a variety of GABA_A receptor subtypes in the PRF that could mediate the differential effects observed among the medications studied.

The evidence of pharmacologic differences between zolpidem and eszopiclone observed in this study are of particular interest, given recent evidence from studies in humans suggesting that eszopiclone has a greater anxiolytic effect than zolpidem when added to selective serotonin reuptake inhibitor therapy in generalized anxiety disorder patients.^4,5 They lend support to evidence from in vitro and knockout studies suggesting that this difference between zolpidem and eszopiclone could reflect that eszopiclone has relatively greater effects at α₃ containing GABA_A receptors.^8–11,^13–14 The findings of the study by Hambrecht-Wiedbuch and coworkers¹⁵ also suggest that the PRF microdialysis model may be a useful one for future work characterizing differences in GABA_A subtype binding affinities.

While such work is of high interest, there is probably a greater need for work in humans to better characterize the clinical differences among GABA_A modulating agents and test hypotheses emerging from the basic pharmacological research. For example, there has yet to be a study convincingly demonstrating differential GABA_A subtype binding among the group of benzodiazepines and non-benzodiazepines in humans. By helping to establish that such studies in humans are worthwhile, the study by Hambrecht-Wiedbusch and coworkers¹⁵ has opened the door to an important line of research that could help to develop untapped potential of these agents to aide in optimizing individualized insomnia treatment. The aim of such work would be to identify agents with particular utility in insomnia patients with anxiety, insomnia patients with pain, insomnia patients who are at risk for substance abuse, etc. By paving the way for such work, the study of Hambrecht-Wiedbusch¹⁵ represents an important step towards exploring whether it is possible to fine-tune GABA_A modulators so that they may be used to provide even more effective therapy for insomnia patients.

DISCLOSURE STATEMENT

Dr. Krystal has consulted for Abbott, Actelion, Arena, Astellas, Axiom, AstraZeneca, BMS, Cephalon, Eli Lilly, GlaxoSmithKline, Jazz, Johnson and Johnson, King, Merck, Neurocrine, Neurogen, Novartis, Organon, Ortho-McNeil-Janssen, Pfizer, Respironics, Roche, San34ofi-Aventis, Sepracor, Somaxon, Takeda, Transcept, Astellas, and Kingsdown Inc. and he has received research support from NIH, Sanofi-Aventis, Cephalon, GlaxoSmithKline, Merck, Neurocrine, Pfizer, Sepracor, Somaxon, Takeda, Transcept, Respironics, Neurogen, Evotec, Astellas, Neuronetics, and Abbott.