engleski

The Effects of Benzodiazepines during Prolonged Administration and Under the Conditions of Stress

Benzodiazepines are neuropsychoactive drugs widely prescribed for their anxiolytic, sedative- hypnotic, muscle relaxant, and anticonvulsant properties. These drugs produce most of their therapeutic effects by interaction with γ- aminobutyric acidA (GABA-A) receptors, the major fast inhibitory neurotransmitter receptors in the mammalian brain. Most of the benzodiazepines introduced into clinical practice are agonists, such as diazepam, but some, most notably flumazenil, antagonize the actions of the classical benzodiazepines. Some other compounds, including imidazopyridine zolpidem, a hypnotic used for the treatment of insomnia, clearly interact with the benzodiazepine sites on GABA-A receptor complex, although not being benzodiazepines. Prolonged occupancy of GABA-A receptors by benzodiazepines may lead to the adaptive changes in the receptor number and/or function. It has been suggested that these regulatory changes might be related to the development of tolerance and dependence, which appear in animals and humans following prolonged administration or withdrawal of benzodiazepines, thus limiting their therapeutic applications. In addition to experimental animals and primary neuronal cultures used in the studies addressing the development of benzodiazepine tolerance and dependence, recombinant expression systems were developed to facilitate the analysis of adaptive changes of individual GABA-A receptor subtypes. However, the molecular basis that underlies these phenomena is still not clear, although some mechanisms such as allosteric uncoupling of GABA and benzodiazepine binding sites have been suggested. Benzodiazepines, like many other drugs, could be abused. Their abuse usually concerns the use of very high doses often in conjunction with other abused substances. It appears that such high micromolar concentrations of benzodiazepines modulate the GABA-A receptor channel by mechanisms separable from those responsible for the action of these drugs at therapeutic concentrations. Benzodiazepine administration has also been associated with alterations in the neuroendocrine function, both in experimental animals and in humans. While diverse effects of these drugs on corticosterone and adrenocorticotropic hormone (ACTH) levels were reported under basal conditions, anxiolytic benzodiazepines were mostly found to decrease the hypothalamic-pituitary- adrenal (HPA) axis activity in stressful contexts. Besides being dependent on the dose, the effects of classical benzodiazepines such as diazepam on the HPA axis activity appear to depend on the gender of the animals. The results also suggested that in addition to central benzodiazepine receptors, the part of GABA-A receptor complex, noradrenergic system might play an important modulatory role in the effects of diazepam on the HPA axis activity. Considering the fact that the disturbances in the HPA axis activity are found in a variety of neuropsychiatric disorders in which benzodiazepines are used as an add-on therapy, such as depression, insomnia and anxiety, these findings might be relevant for the benzodiazepine therapeutic implications.However, although benzodiazepines are often used to prevent or counteract the consequences of exposure to different stressors, their interaction with stress is also not clear. Namely, the results obtained on experimental animals have demonstrated that stress could alter different properties of classical benzodiazepine diazepam. Hence, further studies are necessary to elucidate the complex mechanisms of benzodiazepine action during their long-term administration, as well as their application under the conditions of stress.

benzodiazepines, GABA-A receptor, prolonged administration, cell culture, mice, rats, stress, HPA axis, corticosterone, ACTH

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