Anxiolytics GABA receptors

Further, the removal of benzodiazepine sensitivity in a selective a subunit in a mouse using the gene knockin technique has established that the al subunit plays a major role in the sedative and amnesiac effects of benzodiazepines, part of the anticonvulsant effect and little of the anxiolytic effect the latter effects are more importantly mediated by the a2 subunit [5, 6], The 0 subunit selectivity for the drugs loreclezole (an anxiolytic) and etomidate (an anesthetic) allowed determination that a single residue in the M2 domain could account for this selectivity (02 = 03 >01). When a mouse knockin selectively removed the etomidate sensitivity of the 02 subunit, the animals showed reduced sensitivity to sedative effects of etomidate but no reduction of the true anesthetic effects. In contrast, mutation of the 03 subunit to negate etomidate sensitivity of that subunit alone resulted in a mouse with no sensitivity to the anesthesia produced by etomidate. This proved that the GABA receptor is the target of at least this one anesthetic (etomidate) and, furthermore, that the specific locations in the brain of 03 subunits are important for anesthetic action, while the... 

Buspirone is an extremely specific drug that could possibly represent a new chemical class of anxiolytics—azaspirones. As an anxiolytic, its activity is equal to that of benzodiazepines however, it is devoid of anticonvulsant and muscle relaxant properties, which are characteristic of benzodiazepines. It does not cause dependence or addiction. The mechanism of its action is not conclusively known. It does not act on the GABA receptors, which occurs in benzodiazepine use however, it has a high affinity for seratonin (5-HT) receptors and a moderate affinity for dopamine (D2) receptors. Buspirone is effective as an anxiolytic. A few side effects of buspirone include dizziness, drowsiness, headaches, nervousness, fatigue, and weakness. This drug is intended for treatment of conditions of anxiety in which stress, muscle pain, rapid heart rate, dizziness, fear, etc. are observed in other words, conditions of anxiety not associated with somewhat common, usual, and everyday stress. Synonyms for buspirone are anizal, axoren, buspar, buspimen, buspinol, narol, travin, and others. 

Mediation of the anxiolytic-like action of benzodiazepines through the enhancement of GABAergic transmission at the GABA-A/benzodiazepine receptor complex is well known. Benzodiazepines act at the y-subunit of the GABA receptor complex to enhance chloride influx and thereby cause hyperpolarization of neurons. However, there is much less known about the role of intracellular signal transduction in the actions of benzodiazepines. 

Mechanism of Action A benzodiazepine that depresses all levels of the CNS, includ-ing limbic and reticular formation, by binding to benzodiazepine receptor sites on the gamma-aminobutyric acid (GABA) receptor complex. Modulates GABA, a major inhibitory neurotransmitter in the brain. Therapeutic Effect Produces anxiolytic effect,... 

Bitran D, Hilvers RJ, Kellogg CK Anxiolytic effects of 3a-hydroxy-5a-pregnan-20-one, endogenous metabolite of progesterone that are active at the GABA receptor. Brain Res 561 157-161, 1991... 

Zolpidem and zaleplon are hypnotics that act at the omega-1 receptor of the central GABA receptor complex. This selectivity is hypothesized to be associated with a lower risk of dependence. Unlike benzodiazepines, zolpidem and zaleplon do not appear to have significant anxiolytic, muscle relaxant, or anticonvulsant properties. However, amnestic effects may occur. 

Eszopiclone is an additional hypnotic thought to act on GABA receptor complexes close to benzodiazepine receptors. No anxiolytic effect has been documented in the literature on this medication. 

Recently, Low et al. (11) found that a specific, GABA receptor subunit may mediate the therapeutic effects of the BZDs. Thus, in mice, a knock-in point mutation for the aj versus ag subunit rendered diazepam ineffective for its anxiolytic effects. This indicates that the efficacy of BZDs is mediated by a 2 GABA receptors. 

A second GABA receptor subtype, the GABA-B receptor (Fig. 8—12) is not allo-sterically modulated by benzodiazepines but binds selectively to the muscle relaxant baclofen. Its physiological role is not well known yet, but does not appear to be closely linked to anxiety disorders or to anxiolytics. 

The benzodiazepine derivatives class of antianxiety agents shares the property of binding to a benzodiazepine receptor, part of the GABA receptor-chloride channel complex whose function it modulates allosterically. Not only the anxiolytic effects of the benzodiazepines, but also the anticonvulsant, sedative, or muscle relaxant effects seem to be mediated by the GABA-related mechanism. Besides the direct involvement of the GABA system, in parallel or more downstream to this, several other neurotransmitters such as serotonin have been suggested to participate in different aspects of benzodiazepine action. 

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