Mood disorders such as depression and bipolar disorder are common mental illnesses, affecting millions of patients worldwide. Over the past four decades, advances in in vivo brain imaging have transformed our understanding of brain mechanisms involved in mental health processes and psychiatric illnesses. These discoveries are expected to provide potential targets for new treatments. However, current mood disorder therapies are not ideal and only limitedly effective in alleviating symptoms. Thus, there is an urgent need for novel treatments that act on the mechanisms of action underlying these common psychiatric disorders. We have previously demonstrated that GABA is a key regulator of mood disorders.
Here we show that diazepam, a benzodiazepine drug with a chemical structure similar to GABA, effectively mitigates depressive behavior in mice and human subjects with high levels of depressive symptoms as determined by the Hamilton Depression Rating Scale (HDRS), the most commonly used clinical rating scale for evaluating depressive-like behavior in rodents and humans. Interestingly, diazepam treatment not only reduced the high levels of depression and anxiety but also improved anhedonia in mice that are normally depressed following chronic stress. In addition, diazepam treatment reversed depressive behavior in a mouse model of depression that is attributed to abnormal GABA tone in the medial prefrontal cortex (mPFC). In human subjects, open label administration of diazepam produced a significant reduction in depressive symptoms compared to placebo.
These findings suggest that benzodiazepines may represent a promising new class of mood disorder medications due to their ability to alleviate both anxiety-based and depressive behavior. However, diazepam is not the only benzodiazepine that has antidepressant actions; other benzodiazepines such as alprazolam and chlordiazepoxide are also effective antidepressants in animal models of depression. Since all three benzodiazepines have similar mechanisms of action and favorable adverse effects profiles, they could potentially improve mood by acting on the same central nervous system target(s). We propose that one of these possible targets is the GABAergic system, where all three benzodiazepines bind at a common site on their receptor complex.
Here we investigate the mechanism by which benzodiazepines act as antidepressants by testing diazepam’s effect on GABAA receptors in mouse and human cells. We show that diazepam reverses the hypoactivity of GABAA receptors and behavioral deficits observed in GABA receptor knockout mice. Furthermore, we demonstrate that selective antagonist AED8 is an excellent tool to test interactions between benzodiazepines and GABAA receptors. We find that AED8 is able to reverse diazepam’s effects on GABAA receptors and behaviors in GABA receptor-deficient mice, providing direct evidence that GABAA receptormediated effects of benzodiazepines are mediated via a common site on the GABA receptor complex.
Here we present the first evidence of a functional link between GABAA receptor hypoactivity and brain microcircuits underlying depression-like behavior….