Serotonin and anxiolytic activity

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Although the benzodiazepine anxiolytics primarily interact with the GABA receptor complex, there is ample experimental evidence to show that secondary changes occur in the turnover, release and firing of 5-HT neurons as a consequence of the activation of the GABA-benzodiazepine receptor. Similar changes are observed in the raphe nuclei where a high density of 5-HT1A receptors occurs. Such findings suggest that 5-HT may play a key role in anxiety disorders.

Undoubtedly one of the most important advances implicating serotonin in anxiety has been the development of the azaspirodecanone derivatives buspirone, gepirone and ipsapirone as novel anxiolytics. All three agents produce a common metabolite, namely 1-(2-pyrimidinyl) piperazine or 1-PP, which may contribute to the anxiolytic activity of the parent compounds. It soon became apparent that these anxiolytic agents do not act via the benzodiazepine or GABA receptors but show a relatively high affinity for the 5-HT1A sites; the 1-PP metabolite however only possesses a very low affinity for the 5-HT1A site although it may contribute to the anxiolytic effect of the parent compound by acting as an alpha2 adrenoceptor agonist. In experimental studies, these atypical anxiolytics have mixed actions, behaving as agonists in some situations and antagonists in others. For this reason they are considered to be partial agonists at 5-HT1A receptors, acting either as agonists on presynaptic 5-HT1A receptors or antagonists on postsynaptic 5-HT1A receptors.

In animal models of anxiety, 5-HT2 receptor antagonists have been shown to be active. Ritanserin appears to exhibit both anxiolytic and anxiogenic activity in different animal models. Nevertheless, in man, preliminary evidence suggests that ritanserin is an effective anxiolytic agent, although a placebo-controlled trial of the 5-HT2 antagonist ritanserin has shown no differences in the Hamilton Anxiety and the Clinical Global Impression scales between the drug-treated and placebo-treated patients.

The anxiolytic properties of 5-HT3 receptor antagonists have been demonstrated in several animal models of anxiety. In these models, the 5-HT3 antagonists mimic the anxiolytic effects of the benzodiazepines but differ from the latter in their lack of sedative, muscle relaxant and anticonvulsant action. These compounds appear to be extremely potent

(acting in the ng—ug/kg range) and, providing the initial clinical finding of their anxiolytic activity is substantiated, this group of drugs could provide a valuable addition to the non-benzodiazepine anxiolytics. Thus experimental and clinical evidence suggests that 5-HT1A receptor partial agonists and 5-HT2 and 5-HT3 antagonists may be useful and novel anxiolytic agents.

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