α2-containing GABA(A) receptors: a target for the development of novel treatment strategies for CNS disorders

Abstract

GABA(A) receptors have important physiological functions, as revealed by pharmacological studies and experiments involving gene-targeted mouse models, and are the target of widely used drugs such as the benzodiazepines. In this review, we are summarizing current knowledge about the function of α2-containing GABA(A) receptors, a receptor subtype representing approximately 15-20% of all GABA(A) receptors. This receptor subtype mediates anxiolytic-like, reward-enhancing, and antihyperalgesic actions of diazepam, and has antidepressant-like properties. Secondary insufficiency of α2-containing GABA(A) receptors has been postulated to play a role in the pathogenesis of schizophrenia, and may be involved in cognitive impairment in other disorders. Moreover, polymorphisms in the GABRA2 gene encoding the GABA(A) receptor α2 subunit have been found to be linked to chronic alcohol dependence and to polydrug abuse. Thus, α2-containing GABA(A) receptors are involved in the regulation and/or modulation of emotional behaviors and of chronic pain, and appear to be a valid target for novel therapeutic approaches for the treatment of anxiety, depression, schizophrenia and chronic pain.

Figure 1

Approximate abundance, distribution and functions of α2-containing GABA_A receptors. Left panel: Approximate abundance of major GABA_A receptor subtypes. Middle panel: Immunohistochemical distribution of the GABA_A receptor α2 subunit in a parasagittal mouse brain section (expression levels from high to low: white-yellow-red-blue). The expression of the α2 subunit is particularly strong in hippocampus, striatum, and olfactory bulb, as well as in the amygdala (not shown). Reproduced with permission from (H. Mohler, et al., 2002). Right panel: Major functions and associations of α2-containing GABA_A receptors. The lower lines in the square represent the effects of positive allosteric modulation of α2-containing GABA_A receptors in different behavioral and physiological domains with the exception of the lowest square, where “SNPs” indicates that single nucleotide polymorphisms have been found to be assosciated with alcohol dependence. The evidence regarding antidepressant-like actions via α2-containing GABA_A receptors is so far only suggestive, and the improvement of cognitive deficits in schizophrenia by allosteric modulation of α2-containing GABA_A receptors in humans is still controversial and requires further study.

Figure 2

Panels A–D: Impact of diazepam on conditioned fear in the fear-potentiated startle test in wild type and α2(H101R) mice. Mean startle amplitude measures in wild type (A) and α2(H101R) (C) mice following diazepam (0, 1, 2 mg/kg) show that both genotypes show fear-potentiation of the baseline startle response in tone+startle stimulus trials ( a=startle amplitude on Tone+Startle trials significantly different from both Leader and Startle Only trials). Diazepam reduced percent potentiation of the startle response following fear conditioning in wild type (B) but not in α2(H101R) (D) mice. Panel E: Impact of diazepam on unconditioned anxiety in the elevated plus maze test in wild type and α2(H101R) mice. Percentage of time spent in the open arms was increased significantly by diazepam administration in wild type (left) but not in α2(H101R) (right) animals. *Different from the vehicle group of the animals in the same genotype at p<0.05. **Different from the vehicle group of the animals in the same genotype at p<0.01. N = 9 - 12 per group. Figure modified from (K.S. Smith, et al., 2012).

Figure 3

Anxiety-like and depressive-like behavior of wild type mice (α2^+/+), and mice heterozygous (α2^+/−) and homozygous (α2^−/−) for the α2 knockout allele. Panel A: In the novelty-suppressed feeding test (NFST), a conflict-based test assessing anxiety-like behavior, α2^+/− mice showed greater latency to consume a food pellet in a novel environment compared to wild type mice, with the α2^−/− mice ranking in between wild type and α2^+/−. Panels B–C: In two tests of behavioral despair, the forced swim test (FST) and the tail suspension test (TST), α2^−/− mice showed greater immobility compared to wild type mice. **Different from the wild type (α2^+/+) group at p<0.01. N = 12 per group. Figure modified from (Vollenweider et al., 2011).

Figure 4

Impact of diazepam on brain stimulation reward (intracranial self-stimulation, ICSS) in wild type and α2(H101R) mice. Panel A: A reduction in reward thresholds (i.e. the lowest frequency of stimulation that the animals find rewarding) is considered to be a reward-enhancing effect and is observed following the administration of drugs of abuse and other rewarding manipulations. Diazepam dose-dependently reduced reward thresholds in wild type mice, but not in α2(H101R) mice. In α2(H101R) mice, at the highest dose, diazepam even increased the reward threshold, indicating that it had aversive properties. Panel B: Diazepam did not lead to a reduction in maximum response rates in either genotype, suggesting that it was not sedative / motor impairing at the administered doses. The increase in maximum response observed in wild type mice is an artifact of the reward-enhancing effects of diazepam, and is abolished in α2(H101R) mice. *Different from the vehicle group of the animals in the same genotype at p<0.05. **Different from the vehicle group of the animals in the same genotype at p<0.01. N = 12 per group. Figure modified from (Reynolds, et al., 2012).