Neurosteroids anxiolytic effects

GABA for their action, but their maximal modulatory efficacy never surpasses the maximal response elicited by GABA in the same receptor channel [Puia et al. 1990]. This explains why neurosteroids do and benzodiazepines do not possess anesthetic properties surpassing their anxiolytic effect. 

Further evidence concerning anxiolytic effects of neurosteroids involves its action on the prefrontal cortical dopamine system. This system has been identified as one of the neuroanatomically involved CNS areas in stress and anxiety responses, where increases in dopamine metabolism are observed following a variety of stressors [A. Y. Deutch and Roth 1990]. Grobin et al. [1992] demonstrated that intracerebroventricularly administered allo-THDOC effectively reduced dopamine metabolism in rats, thereby antagonizing stress-induced activation of the prefrontal cortical dopamine innervation. 

Among ai-, a2- and as-point-mutated mice, only the ai(HlOlR) mutants were resistant to the depression of motor activity by diazepam and zolpidem (Rudolph et al. 1999 Low et al. 2000 Crestani et al. 2000). This effect was specific for ligands of the benzodiazepine site, since pentobarbital or a neurosteroid remained as effective in ai(HlOlR) mice as in wild-type mice in inducing sedation. An ai(HlOlR) mouse line was also generated by McKernan et al. (2000), confirming that sedation is finked to ai GABAa receptors and differs mechanistically from the anxiolytic action of benzodiazepines. 

A further issue is raised with regard to dose-dependent effects, suggesting dual or U-shaped psychotropic responses, because recent studies have indicated that neurosteroids may induce anxiogenic or anxiolytic responses in relation to the dosage used and subsequent metabolizing steps involved [Melchior and Ritzmann 1994a, 1994b]. 

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