Human pharmacology of positive GABA-A subtype-selective receptor modulators for the treatment of anxiety

Anxiety disordersarise from disruptions among the highly interconnected circuits that normally serve to process the streams of potentially threatening stimuli. The resulting imbalance among these circuits can cause a fundamental misinterpretation of neural sensory information as threatening and can lead to the inappropriate emotional and behavioral responses observed in anxiety disorders. There is considerable preclinical evidence that the GABAergic system, in general, and its α2- and/or α5-subunit-containing GABA(A) receptor subtypes, in particular, are involved in the pathophysiology of anxiety disorders. However, the clinical efficacy of GABA-A α2-selective agonists for the treatment of anxiety disordershas not been unequivocally demonstrated. In this review, we present several human pharmacologicalstudies that have been performed with the aim of identifying the pharmacologicallyactive doses/exposure levels of several GABA-A subtype-selective novel compounds with potential anxiolyticeffects. The pharmacologicalselectivity of novel α2-subtype-selective GABA(A) receptor partial agonistshas been demonstrated by their distinct effect profiles on the neurophysiologicaland neuropsychological measurements that reflect the functions of multiple CNS domains compared with those of benzodiazepines, which are nonselective, full GABA(A) agonists. Normalizing the undesired pharmacodynamicside effects against the desired on-target effects on the saccadic peak velocity is a useful approach for presenting the pharmacologicalfeatures of GABA(A)-ergic modulators. Moreover, combining the anxiogenicsymptom provocation paradigm with validated neurophysiologicaland neuropsychological biomarkers may provide further construct validity for the clinical effects of novel anxiolyticagents. In addition, the observed drug effects on serum prolactin levels support the use of serum prolactin levels as a complementary neuroendocrine biomarker to further validate the pharmacodynamicmeasurements used during the clinical pharmacologicalstudy of novel anxiolyticagents.