Preclinical Pharmacodynamics of Anxiolytics: Effects of Chronic Benzodiazepine Administration
Benzodiazepine anxiolytics act at specific receptors located on the GABAA receptor complex on post-synaptic neurons. We developed a mouse model to assess pharmacodynamics and neuro-chemical effects during chronic benzodiazepine administration. During chronic lorazepam administration, animals developed behavioral tolerance and benzodiazepine receptor downregulation in several brain regions after 1 week of treatment. Similar results were observed for clonazepam. However, for alprazolam, these alterations occurred more rapidly, after 2–4 days, and neurochemical changes occurred primarily in cortex. In contrast to results with benzodiazepine agonists, chronic antagonist and “inverse agonist” treatment had opposite effects on behavior and were associated with receptor upregulation. After benzodiazepine agonist discontinuation, behavioral and neurochemical effects were also opposite to those observed during chronic administration, suggesting the presence of a “withdrawal” syndrome. Administration of carbamazepine after lorazepam discontinuation attenuated the behavioral and neurochemical withdrawal effects. Studies to determine the cellular mechanisms of these receptor alterations indicated that receptor increases after drug discontinuation were likely to be due to enhanced receptor production. During chronic administration, receptor mRNAs were decreased, but this change occurred after the development of tolerance and receptor downregulation.
KeywordsGABAA Receptor Inverse Agonist Neurochemical Change Receptor Downregulation Receptor Upregulation
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