Benzodiazepines dependence mechanisms

High-potency benzodiazepines (alprazolam, clonazepam) generally are more effective in panic disorder than low-potency benzodiazepines (diazepam, lorazepam, etc.). Although less research has been done on the low-potency benzodiazepines, it is generally accepted that they frequently result in sedation prior to adequately relieving panic attacks. The reader is referred to the discussion of benzodiazepines in Chapter 8 for a detailed overview of mechanism of action. A critique of the issues of benzodiazepine dependence and appropriate use is given in Chapter 13-... 

Wafford KA. GABAa receptor subtypes any clues to the mechanism of benzodiazepine dependence Curr Opin Pharmacol 2005 5 47-52. 

The syndecan family of heparin sulfate proteoglycans (HSPGs) plays critical roles in several signal transduction pathways, and syndecan 3 intramembrane proteolysis is presenilin/y-secretase dependent (357). COX2 and COXl potentiate ABP formation through mechanisms that involve y-secretase activity. Sulindac sulfide and other NSAIDs (ibuprofen, indomethacin, R-flurbiprofen) selectively decrease the secretion of ABP independently of COX activity, probably via y-secretase inhibition (358-360). Pepstatin A methylester, sulfonamides, and benzodiazepines can also act as potent, noncompetitive, y-secretase inhibitors (335). These are but a few examples of the potential repercussions and biochemical consequences that the pharmacological manipulation of secretases in AD may bring about. 

Molecular mechanics calculations on two 6-arylpyrrolo[2,l-d][l,5]benzothia-zepines (1995JMC4730) confirmed that binding to a mitochondrial benzodiazepine receptor depends on conformational strain as well as on specific repulsive interactions involving their side-chains. 

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. 

The Y -aminobutyric acid-A receptor (GABAjJ is a macromolecular complex through which a variety of ligands act. Our understanding of this receptor complex and the mechanism of action of these ligands has expanded rapidly over recent years. This is as a consequence of substantial developments in the fields of molecular biology and immunochemistry and has been fueled by the as yet elusive quest for effective anxiolytics that do not have the problems associated with the benzodiazepines, that is, adverse effects, interaction with alcohol, and the related issues of tolerance, dependency, and problems on withdrawal. 

Similar to the barbiturates, the mode of action of benzodiazepines is thought to involve GABA receptors. They may enhance GABA binding and/or activate a feedback mechanism which curtails GABA release. Both mechanisms would result in making the nervous system more dependent upon continued... 

The underlying mechanism of zaleplon abuse and stimulating effect is unknown. However, following chronic exposure to benzodiazepines or benzodiazepine-like agents, alterations in GABAa receptor sensitivity occur, which contribute to the development of tolerance, dependence, and withdrawal [29]. 

Topiramate blocks repetitive firing of cultured spinal cord neurons, as do phenytoin and carbamazepine. Its mechanism of action, therefore, is likely to involve blocking of voltage-dependent sodium channels. Topiramate also appears to potentiate the inhibitory effect of GABA, acting at a site different from the benzodiazepine or barbiturate sites. Topiramate also depresses the excitatory action of kainate on AMPA receptors. It is possible that all three of these actions contribute to topiramate s anticonvulsant effect. 

Established interactions. These increases in bioavailability might be expected to increase the extent of the sedation and amnesia due to these benzodiazepines, but in young healthy adults this is apparently of little importance. The clinical effects of the interaction with diazepam appear not to have been investigated. The effects of midazolam and triazolam may be more enhanced than those of other benzodiazepines, because these drugs are more dependent on CYP3A4 for their metabolism (see Mechanism, abovej.What is not clear is whether other factors such as old age or liver cirrhosis might increase the risk of adverse effects with concurrent use. 

Lobeline has been reported as a useful agent to treat dependency on drugs such as cocaine, amphetamine, caffeine, pheny Icy dine, opiates, barbiturates, benzodiazepines, cannabinoids, hallucinogens, alcohol, and, especially, nicotine. Dwoskin [55] described a novel mechanism of action and potential use for lobeline as a treatment for psychostimulant abuse. 

---