GABA benzodiazepines

CC GABA/BENZODIAZEPINE RECEPTOR AND OPENING AN INTEGRAL CHLORIDE... 

Montpied P, Martin BM, Cottingham SL, Stubblefield BK, Ginns El, Paul SM. 1988. Regional distribution of the GABA /benzodiazepine receptor (a subunit) mRNA in rat brain. J Neurochem 51 1651-1654. 

Figure 2.12. Diagrammatic representation of the GABA-benzodiazepine supra-molecular complex. Compounds that increase inhibitory transmission may do so either by directly activating the GABA receptor site (e.g. muscimol) or by acting directly on the chloride ionophore (e.g. barbiturates). Benzodiazepines (e.g. diazepam) enhance the sensitivity of the GABA-A receptor to GABA. Compounds that decrease inhibitory transmission may do so by activating the picrotoxin site, which closes the chloride ionophore, or by blocking the GABA-A receptor.

Pharmacology Flumazenil antagonizes the actions of benzodiazepines on the CNS and competitively inhibits the activity at the benzodiazepine recognition site on the GABA/benzodiazepine receptor complex. 

Other than adenosine, there are several peptides which induce sleep (e.g., delta sleep inducing peptide). Together with endogenous chemicals interacting with the GABA benzodiazepine receptor site (e.g., (3-carbolines) identified in... 

Current theories suggest that hypersecretion of cortisol during stress may damage the hippocampus. Studies have demonstrated reduced hippocampal volume in trauma survivors with PTSD, compared to nontrauma tized individuals (Sapolsky, 2000 Bremner, 2001). However, hormonally regulated plasticity in the hippocampus involves multiple influences, and glucocorticoid hormones work in concert with excitatory amino acids and N-methyl-D-aspartate (NMDA) receptors, as well as other neurotransmitters and the GABA-benzodiazepine system (see McEwen, 2000a,b, for review). 

GABA/benzodiazepine Dissociation, hyperarousal, impaired information and memory processing... 

Chronic alcohol intake changes the functioning of the GABA benzodiazepine receptor complex. For example, chronic alcohol intake increases the binding [Mhatre et al. 1988] and function of benzodiazepine inverse agonists [Lister and Karanian 1987] and attenuates the effect of benzodiazepine... 

Belelh D, Lan N, Gee KW Anticonvulsant steroids and the GABA/benzodiazepine receptor-chloride ionophore complex. Neurosci Biobehav Rev 14 315-322, 1990 Bellaire W, Demisch K, Stoll K-D Carbamazepine vs. lithium. Application in the prophylaxis of recurrent affective and schizoaffective psychoses. Muenchener Medizinische Wochenschrift 132 S82-S86, 1990 Belmaker RH Receptors, adenylate cyclase, depression, and lithium. Biol Psychiatry 16 333-350, 1981... 

Gee KW Steroid modulation of the GABA/benzodiazepine receptor-hnked chloride ionophore. Mol Neurobiol 2 291-317, 1988... 

C. F. Zorumsky, K. E. Isenberg (1991). Insights into the structure and function of GABA-benzodiazepine receptors ion channels and psychiatry. Am. J. Psychiatry 148 162. 

Six benzodiazepines play prominent roles in the therapy of epilepsy (see also Chapter 22). Although many benzodiazepines are similar chemically, subtle structural alterations result in differences in activity. They have two mechanisms of antiseizure action, which are shown to different degrees by the six compounds. This is evident from the fact that diazepam is relatively more potent against electroshock and clonazepam against pentylenetetrazol (the latter effect correlating with an action at the GABA-benzodiazepine allosteric receptor sites). Possible mechanisms of action are discussed in Chapter 22. 

Like barbiturates, benzodiazepines reduce the activity of the nervous system. They do this by acting on the type-A GABA (or GABA ) receptor, which is the protein that the neurotransmitter GABA activates when it is secreted by one nerve cell onto another (refer back to Ghapter 1 for an overview of how nerve cells communicate). When this receptor binds GABA, nerve cells become less active. Thus, like GABA, benzodiazepines deactivate nerve cells. 

In this chapter we have provided clinical descriptions of anxiety and insomnia. We have also described the biological basis for anxiety and insomnia, emphasizing three neurotransmitter systems GABA-benzodiazepines, serotonin, and norepinephrine. Finally, we have discussed the treatments for anxiety and insomnia and how they play on these three neurotransmitter systems. 

Just as does the GABA-benzodiazepine receptor complex discussed in Chapter 8 (see Figs. 8-18 to 8—20), the NMDA glutamate—calcium channel complex also has multiple receptors surrounding the ion channel, which act in concert as allosteric modulators (Fig. 10—24). One modulatory site is for the neurotransmitter glycine another is for polyamines, and yet another is for zinc (Fig. 10—24). The magnesium ion can block the calcium channel at yet another modulatory site, which is presumably inside the ion channel or closely related to it. Another inhibitory modulatory site,... 

Perhaps the most well-known example is the acetylcholine receptor located on the postsynaptic membrane of the neuromuscular junction49 56 (Fig. 4-1). When bound by acetylcholine molecules, the receptor activates and opens a pore through the cell membrane, thereby increasing the permeability of the muscle cell to sodium.38 56 This action results in depolarization and excitation of the cell because of sodium influx. Another important example of a receptor-ion channel system is the gamma-aminobutyric acid (GABA)-benzodiazepine-chloride ion channel complex found on neuronal membranes in the central nervous sys-... 

Consequently, the presence of the GABA-benzodiazepine-chloride ion channel complex accounts for the specific mechanism of action of this class of sedative-hypnotics. By increasing the inhibitory effects at GABAergic synapses located in the reticular formation, benzodiazepines can decrease the level of arousal in the individual. In other words, the general excitation level in the reticular activating system decreases, and relaxation and sleep are enhanced. 

FIGURE 65.4 GABA-benzodiazepine-chloride channel complex. GABA = g-aminobutyric acid. 

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