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Pilot Studies on the Novel Hypothesis that TSPO (Peripheral Benzodiazepine Receptor) Is Involved in Benzodiazepine/“Z-Drug” Physical Dependence and/or Withdrawal

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Pharmacology & Pharmacy 2023年第3期14卷 72-83页

作者： Cheyenne Moffett Katherine J. Kost Austen Thompson Joseph V. Pergolizzi Jr. Tally M. Largent-Milnes Robert B. Raffa todd vanderah Department of Pharmacology and Comprehensive Pain and Addiction Center University of Arizona Tucson AZ USA NEMA Inc. Naples FL USA Neumentum Inc. Summit NJ USA Enalare Therapeutics Naples FL USA School of Pharmacy Temple University Philadelphia PA USA College of Pharmacy (Adjunct) University of Arizona Tucson AZ USA

Benzodiazepines and other benzodiazepine receptor agonists, such as the “Z” drugs, are widely prescribed medications mainly used for treating anxiety and seizures, and for inducing sedation. Unfortunately, despite their popularity, benzodiazepine prescribing often exceeds recommendations and the consequences can be severe. On September 23, 2020, the United States FDA announced a new requirement for a Boxed Warning for benzodiazepines prescribing. Along with this announcement, the FDA stated that relevant information regarding the initiation, continuation, and discontinuation of benzodiazepines is lacking. Here, we describe initial pilot studies intended to investigate the questions 1) can animal models be developed that demonstrate benzodiazepine physical dependence and/or withdrawal symptoms, and 2) determine whether translocator protein (TSPO) plays a role in benzodiazepine dependence and/or withdrawal processes. The former was demonstrated, methodological limitations prevented the latter.

关键词： Benzodiazepine TSPO Rats In Vivo Tests Western-Blot Analysis

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The FDA Mandate to Reassess Benzodiazepines: Alprazolam Induces a Positive Conditioned Place-Preference in Male Rats

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Journal of Biosciences and Medicines 2021年第3期9卷 1-8页

作者： Cheyenne Moffett Katherine J. Kost Austen Thompson Michael H. Ossipov Joseph V. Pergolizzi Junior Sumiyo Umeda-Raffa Robert B. Raffa Tally M. Largent-Milnes todd vanderah Department of Pharmacology and Comprehensive Pain and Addiction Center University of Arizona Tucson AZ USA Department of Pharmacology and Comprehensive Pain and Addiction Center University of Arizona Tucson AZ USA Neumentum Inc. Morristown NJ USA Enalare Therapeutics Naples FL USA Pharmaceutical Sciences (Form. Faculty) Hokkaido University of Science Hokkaido Japan Temple University School of Pharmacy (Prof Em.) Philadelphia PA USA College of Pharmacy (Adjunct) University of Arizona Tucson AZ USA

On September 23, 2020, in order “To address the serious risks of abuse, addiction, physical dependence, and withdrawal reactions, the U.S. Food and Drug Administration (FDA) is requiring the Boxed Warning be updated for all benzodiazepine medicines”. With this announcement, the FDA proclaimed that much more needs to be known about the initiation, continuation, and discontinuation of these widely-used drugs. Unfortunately, relevant information is lacking, since for many years, there has been a notable sparsity in the funding and conduct of basic and clinical research on these drugs. In order to begin to fill the void, it is valuable to (re)examine animal models. We here describe a model of conditioned place-preference (CPP) for rats and for the first time, to our knowledge, show that the representative benzodiazepine alprazolam induces positive place-preference in male rats.

关键词： Benzodiazepines Conditioned Place-Preference Alprazolam Reinforcement Affective State

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Pharmacology & Pharmacy 2021年第5期12卷 100-108页

作者： Cheyenne Moffett Katherine J. Kost Austen Thompson Michael H. Ossipov Joseph V. Pergolizzi Jr. Sumiyo Umeda-Raffa Robert B. Raffa Tally M. Largent-Milnes todd vanderah Department of Pharmacology and Comprehensive Pain and Addiction Center University of Arizona Tucson AZ USA NEMA Inc. Naples FL USA Neumentum Inc. Morristown NJ USA Enalare Therapeutics Naples FL USA Pharmaceutical Sciences (Form. Faculty) Hokkaido University of Science Hokkaido Japan School of Pharmacy (Prof Em.) Temple University Philadelphia PA USA College of Pharmacy (Adjunct) University of Arizona Tucson AZ USA

The benzodiazepines were introduced into medical practice during the 1960s. At the time, they represented a safer alternative to extant therapies used for anxiety, such as the barbiturates. However, on September 23, 2020, the United States FDA indicated that more is needed to be known about the initiation, continuation, and discontinuation of the use of these widely-used drugs with publication of the announcement “to address the serious risks of abuse, addiction, physical dependence, and withdrawal reactions, the U.S. Food and Drug Administration (FDA) is requiring the Boxed Warning be updated for all benzodiazepine medicines.” Because for many years, there has been a sparsity of research on these drugs, relevant information is unfortunately lacking at this critical time. It is therefore valuable to (re)establish animal models and begin to collect relevant data. We here use a model of conditioned place

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