![]() 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’). Despite these negative properties, by using a GABRA5 negative modulator the opposite effect might The α 5 subunit-containing GABA A receptor: a target for the treatment of cognitive defects be achieved and cognition improved. Because of its amnestic effects, victims are unable to recall events following intoxication and this provides a major challenge for prosecutors. 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. Most of these receptors are found in the hippocampus (a brain region associated with memory) and provide tonic inhibition in this region. Interestingly, it is thought that positive modulators at the α 5 subunit-containing GABA A receptors (GABRA5) produce the anterograde amnesia associated with benzodiazepine use. In acute overdose the most life-threatening effect is respiratory depression, especially when combined with alcohol. ![]() There are also long-term issues with dependence. There may be tolerance due to rapid escalation in the dose needed to provide the required effect. The main side effects associated with therapeutic use are amnesia, confusion, impaired coordination and dizziness. In knockout mice, the α 1 subunit has shown hypnotic/sedative effects, whilst the α 3, α 2 and α 5 subunits have anti-anxiolytic effects and these have been exploited for therapeutic use.ĭespite their uses in treating various conditions, traditional benzodiazepines have numerous side effects. Each of these subunits mediates different effects. They only bind to the receptors containing the α 5, α 3, α 2, and α 1 subunits. Since they are modulators and not agonists, they do not work in the absence of GABA. Benzodiazepines are positive modulators at this receptor and exert their effects by binding to the interface between the γ 2 and α subunits on the GABA A receptor. In neurons, this increases the threshold needed to excite them. This receptor is an ionotropic membrane receptor, which facilitates the movement of chloride into cells. The GABA A receptor is the main target for the popular class of drugs, the benzodiazepines. There are at least three different receptors that it targets - GABA A, GABA B and GABA C. Γ-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain and is responsible for regulating neuronal excitability. 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. Despite the myriad animal studies that utilised GABRA5 negative modulators, only three human studies were found. Due to its beneficial properties, there is potential for such a drug in treating Alzheimer’s, alcohol-related amnesia and Down syndrome. In addition, the compounds examined demonstrated minimal side effects partly due to lack of binding to different alpha subunit-containing GABA A types. Passive avoidance learning was also improved. These drugs generally improve hippocampal-dependant learning via an increase in longterm potentiation (LTP) in the hippocampus. A literature search found a number of GABRA5 negative modulators. ![]() In order to explore this beneficial effect, this article reviews the evidence on the effects of GABRA 5 negative modulators and searches potential uses for such drugs. Negative modulators at this receptor could improve cognition. Amnesic effects of benzodiazepines are in part the result of the activity of α 5-subunit containing GABA A receptors (GABRA5).
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