Despite decades of basic and clinical research, our understanding of how benzodiazepines tend to lose their efficacy over time (tolerance) is at least incomplete. In appears that tolerance develops relatively quickly for the sedative and anticonvulsant actions of benzodiazepines, whereas tolerance to anxiolytic and amnesic effects probably does not develop at all. In light of this evidence, we review the current evidence for the neuroadaptive mechanisms underlying benzodiazepine tolerance, including changes of (i) the receptor (subunit expression and receptor coupling), (ii) intracellular changes stemming from transcriptional and neurotrophic factors, (iii) ionotropic glutamate receptors, (iv) other neurotransmitters (serotonin, dopamine, and acetylcholine systems), and (v) the neurosteroid system. From the large variance in the studies, it appears that either different (simultaneous) tolerance mechanisms occur depending on the benzodiazepine effect, or that the tolerance-inducing mechanism depends on the activated receptor subtypes. Importantly, there is no convincing evidence that tolerance occurs with α subunit subtype-selective compounds acting at the benzodiazepine site. 1. Introduction Shortly after their development in the 1960s, benzodiazepines became very popular as they exerted many desirable effects such as reduction of anxiety, anticonvulsant properties, and myorelaxation combined with a rather low toxicity [1]. However, their use is associated with many side effects precluding their long-term use, including sedation, amnesia, cognitive impairment, and ataxia. Even though guidelines generally recommend limiting benzodiazepines to short-term use, long-term use still often occurs. Chronic benzodiazepine treatment can result in the development of benzodiazepine dependence [2]. DSM-IV criteria for benzodiazepine dependence consist of various psychological (behavioral) and physical symptoms, including tolerance, withdrawal symptoms when drug intake is stopped and dose escalation [3]. Indeed, chronically treated patients become less sensitive to some effects of benzodiazepines (tolerance) which may include anticonvulsant, sedative, hypnotic, and myorelaxant effects of benzodiazepines. Also, benzodiazepine discontinuation may result in the appearance of a characteristic withdrawal syndrome with heightened anxiety, insomnia, and sensory disturbances [4]. In fact, tolerance and withdrawal could be two manifestations of the same compensatory mechanism, with withdrawal occurring when the counterbalancing benzodiazepine effect is absent [5]. This is
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