Potential role of cortical 5-HT2A receptors in the anxiolytic action of cyamemazine in benzodiazepine withdrawal

The antipsychotic cyamemazine is a potent serotonin 5-HT2A receptor (5-HT2AR) antagonist. A positron emission tomography (PET) study in human patients showed that therapeutic doses of cyamemazine produced near saturation of 5-HT2AR occupancy in the frontal cortex, whereas dopamine D2 occupancy remained below the level for motor side effects observed with typical antipsychotics. Recently, numerous studies have revealed the involvement of 5-HT2AR in the pathophysiology of anxiety and a double-blind, randomized clinical trial showed similar efficacy of cyamemazine and bromazepam in reducing the anxiety associated with benzodiazepine withdrawal. Therefore, we reviewed the above articles about 5-HT2AR and anxiety in order to understand better the anxiolytic mechanisms of cyamemazine in benzodiazepine withdrawal. The 5-HT2AR is the most abundant serotonin receptor subtype in the cortex. Non-pharmacological studies with antisense oligodeoxynucleotides and genetically modified mice clearly showed that cortical 5-HT2AR signaling positively modulates anxiety-like behavior. With a few exceptions, most other studies reviewed here further support this view. Therefore, the anxiolytic efficacy of cyamemazine in benzodiazepine withdrawal can be due to a 5-HT2AR antagonistic activity at the cortical level.