The α-5 subunit-containing GABA-A receptor: a target for the treatment of cognitive defects
Abhishta Pierre Bhandari
Sunday, March 29th, 2015
Amnesic effects of benzodiazep
The α-5 subunit-containing GABA-A receptor: a target for the treatment of cognitive defects
Abhishta Pierre Bhandari
Sunday, March 29th, 2015
Amnesic effects of benzodiazepines are in part the result of the activity of α5-subunit containing GABAA receptors (GABRA5). Negative modulators at this receptor could improve cognition. In order to explore this beneficial effect, this article reviews the evidence on the effects of GABRA5 negative modulators and searches potential uses for such drugs. A literature search found a number of GABRA5 negative modulators. These drugs generally improve hippocampal-dependant learning via an increase in longterm potentiation (LTP) in the hippocampus. Passive avoidance learning was also improved. In addition, the compounds examined demonstrated minimal side effects partly due to lack of binding to different alpha subunit-containing GABAA types. Due to its beneficial properties, there is potential for such a drug in treating Alzheimer’s, alcohol-related amnesia and Down syndrome. Despite the myriad animal studies that utilised GABRA5 negative modulators, only three human studies were found. Due to its cognitive enhancing properties and minimal side effects, further human trials should be conducted in order to ascertain the potential of such drugs in treating cognitive deficits.
γ-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain and is responsible for regulating neuronal excitability. There are at least three different receptors that it targets — GABAA, GABAB and GABAC.  The GABAA receptor is the main target for the popular class of drugs, the benzodiazepines. This receptor is an ionotropic membrane receptor, which facilitates the movement of chloride into cells. In neurons, this increases the threshold needed to excite them. Benzodiazepines are positive modulators at this receptor and exert their effects by binding to the interface between the γ2 and α subunits on the GABAA receptor.  Since they are modulators and not agonists, they do not work in the absence of GABA.  They only bind to the receptors containing the α5, α3, α2, and α1 subunits.  Each of these subunits mediates different effects. In knockout mice, the α1 subunit has shown hypnotic/sedative effects, whilst the α3, α2 and α5 subunits have anti-anxiolytic effects and these have been exploited for therapeutic use.
Despite their uses in treating various conditions, traditional benzodiazepines have numerous side effects. The main side effects associated with therapeutic use are amnesia, confusion, impaired coordination and dizziness. There may be tolerance due to rapid escalation in the dose needed to provide the required effect. There are also long-term issues with dependence. In acute overdose the most life-threatening effect is respiratory depression, especially when combined with alcohol. 
Interestingly, it is thought that positive modulators at the α5 subunit-containing GABAA receptors (GABRA5) produce the anterograde amnesia associated with benzodiazepine use.  Most of these receptors are found in the hippocampus (a brain region associated with memory) and provide tonic inhibition in this region.  The exploitation of this receptor has led to the increasing use of the infamous ‘date rape’ drug flunitrazepam, which is a positive modulator at the GABRA5 in addition to its other functions. Because of its amnestic effects, victims are unable to recall events following intoxication and this provides a major challenge for prosecutors.  Despite these negative properties, by using a GABRA5 negative modulator the opposite effect might The α5 subunit-containing GABAA receptor: a target for the treatment of cognitive defects be achieved and cognition improved. The use of such a drug could potentially improve the quality of life for those living with cognitive defects and could also counteract drug-induced amnesia (for example, alcoholic ‘blackout’). However, this must be balanced with the inverse activity of non-selective negative modulators which c