Repeated Zolpidem Treatment Effects on Sedative Tolerance, Withdrawal, mRNA Levels, and Protein Expression

Abstract

Zolpidem and benzodiazepines (BZs) potentiate the inhibitory action of gamma-Aminobutyric acid (GABA) by allosterically binding to GABAA receptors (GABAAR). Prolonged use of GABAAR positive allosteric modulators (PAM) can lead to behavioral tolerance, the diminished response to the same drug dose with repeated use, and withdrawal, a group of symptoms that occur due to abrupt end of drug treatment. Zolpidem is a short-acting, non-BZ GABAAR PAM whose potential for tolerance and withdrawal is unclear. Zolpidem demonstrates sedative efficacy similar to BZs and has become a main treatment of insomnia in lieu of BZs. Zolpidem replaced BZs due to lower incidences of tolerance and withdrawal after prolonged treatment and discontinuation. Despite reported lower incidences, some studies find the occurrence of tolerance and withdrawal similar between zolpidem and BZs. Tolerance and withdrawal symptoms are likely caused by drug-induced neuroadaptive changes in central nervous system (CNS) functioning, and these alterations may be similar between zolpidem and BZ. Past rodent research suggests that long term use of zolpidem and BZs may produce alterations in normal inhibitory GABAergic and excitatory glutamatergic functioning in the cortex, hippocampus, amygdala, and PFC and that these alterations may underlie sedative tolerance and withdrawal symptoms. viii TABLE OF CONTENTS CHAPTER 1. INSOMNIA TREATMENT ISSUES.