GABA activation

Von Keyserlingk, H.C. and Willis, R.J. (1992). The GABA-activated CL channel in insects as a target for insecticide action—a physiological study. In D. Otto and B. Weber (Eds.) Insecticides Mechanism of Action and Resistance. Andover, U.K. Intercept. 

Figure 11.3 Regulation of GAD during the synthesis of GABA. Active GAD (GAD-PLP) combines with glutamate (1) to form a complex (GAD-PLP-GLU). After decarboxylation (2) this yields GABA and GAD-PLP (3). The intermediate product (GAD-INT) can undergo an alternative reaction (4) to produce succinic semialdehyde (SSA) and pyridoxamine-5 -phosphate (PMP). PMP dissociates from GAD (5) leaving inactive enz5mie, which requires additional PLP to be reactivated (6), a process that is affected by ATP and inorganic phosphate...

Expression studies in Xenopus oocytes or transfected cell lines originally suggested that functional GABA-activated chloride channels could be formed by receptor subunits of each class in isolation. However, much better expression occurs with two or more subunit types in combination and it is likely that most native receptors contain at least three different subunits. Co-expression of a and /I subunits results in the assembly of... 

Chebib, M and Johnston, GA (2000) GABA-Activated ligand gated ion channels medicinal chemistry and molecular biology. J. Med. Chem. 43 1427-1447. 

It was found, however, that if neuroleptic administration was continued for two weeks then neuronal firing stopped. Also while the neurons could not be made to fire by the excitatory NT glutamate, the inhibitory NT GABA activated them by reducing the... 

Gabapentin Modulate calcium channels and enhance GABA activity Loading dose Not recommended due to short half-life Maintenance dose 900-3600 mg/day in 3-4 divided doses (doses up to 1 0,000 mg/day have been tolerated) Half-life Not established 5-7 hours (proportional to creatinine clearance) Apparent volume of distribution 0.6-0.8 L/kg Protein binding less than 10% Primary elimination route Renal Drowsiness, sedation Peripheral edema, weight gain... 

It is theorized that BZs ameliorate anxiety through potentiation of GABA activity. 

Agents that increase GABA activity or decrease glutamate activity are used for the treatment of mania and for mood stabilization (eg, benzodiazepines, lamotrigine, lithiurn, or valproic acid). 

Other Medications. There has been limited study of other nonbenzodiazepine agents that act by increasing GABA activity by any of several mechanisms. Please refer to Section 5.1.4 for more information regarding these agents. 

The only medication that blocks GABA activity is flumazenil (Mazicon). Flumaze-nil is used only in the emergency room or in an inpatient hospital setting to treat benzodiazepine overdose. It quickly and reliably reverses the toxic effects when a patient has accidentally or purposefully taken an overdose. Restricted to emergency situations, flumazenil is never used on a routine basis. 

Gabapentin acts by increasing GABA activity, although its exact mechanism of action is unclear. It causes dose-related sedation and dizziness. It has been shown in randomised controlled trials to be effective in social anxiety disorder (Pande et al. 1999) and to benefit some patients with panic disorder (Pande et al. 2000). Pregabalin is a related compovmd that has recently demonstrated efficacy in GAD in a phase III study (Pande et al. 2003). 

Mechanism of Action Abarbiturate that binds at the GABA receptor complex, enhancing GABA activity. Therapeutic Effect Depresses central nervous system (CNS) activity and reticular activating system. 

The benzodiazepines are probably the most clinically important class of GABA-active compounds. Benzodiazepines modify affective responses to sensory perceptions specifically, they render individuals less responsive to anxiety-producing stimuli and therefore exert a strong anxiolytic action. In addition, benzodiazepines exert sedating, anticonvulsant, and muscle relaxant effects. 

Gamma-aminobutyric acid (GABA), is present in many areas of the brain, and is inhibitory. GABA can influence sensation of pain and affects memory, mood, and coordination. GHB and benzodiazepines increase GABA activity. 

CNS agents of the 1,4 benzodiazepine class presumably exert their effects by binding at stereo specific receptors at several sites within the central nervous system (CNS). Alprazolam like other benzodiazepines exerts its anxiolytic action by potentiating GABA activity. GABA is a neurotransmitter which inhibits the CNS activity. Alprazolam acts preferentially in midbrain, ascending reticular formation (which maintains wakefulness) and on limbic system (thought and mental functions). 

GABA is a major CNS inhibitory neurotransmitter, which, among other effects, may attenuate catecholaminergic systems. VPA (perhaps by inhibition of this transmitter s degradation by GABA transaminase), CBZ, and lithium have all been reported to enhance GABA activity (see also the section Mechanism of Action in Chapter 12). 

It is best to avoid concomitant use of ivermectin and other drugs that enhance GABA activity, eg, barbiturates, benzodiazepines, and valproic acid. Ivermectin should not be used during pregnancy. Safety in children younger than 5 years has not been established. 

Most of the CNS depressants have similar actions in the brain they enhance the actions of the neurotransmitter gamma-aminobutyric acid (GABA)— neurotransmitters are brain chemicals that facilitate communication between brain cells. GABA works by decreasing brain activity. Although different classes of CNS depressants work in unique ways, it is ultimately their common ability to increase GABA activity that produces a drowsy or calming effect. 

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