Functional abnormalities in the serotonin (5-HT) receptors have been consistently associated with anxiety. We have shown that inactivation of the 5-HTA receptor (5-HTAR) results in anxiety in mice. Surprisingly, we found that these mutant mice are insensitive to the anxiolytic effect of diazepam, a classical benzodiazepine (BZ). The importance of this finding is that a significant proportion of patients suffering from generalized anxiety do not respond to BZs. Also, BZs are not particularly effective in other forms of anxiety such as panic attacks and phobias. Since BZs bind and facilitate the function of the BZ sensitive gamma-aminobutyric acid receptors (GABAAR) receptors, abnormalities in these receptors could underlie the BZ-resistant anxiety and the anxiety-like behavior of the 5-HTAR mutant mice. Indeed, we found abnormalities in the subunit composition of GABAARs in mutant mice. Our data show that the 5-HT and GABA systems, two important neurotransmitter systems implicated in anxiety disorders, are mechanistically linked. The objective of this application is to elucidate key features of the 5-HTAR-mediated regulation of GABAAR subunits that have a relevance to the KO phenotype and that could be applied to the understanding of anxiety. We ask the following questions: 1) Is the expression of the GABAAR subunits sensitive to the dosage of the 5-HTA receptor? Anxiety in heterozygote KO mice suggests that GABAAR subunit expression is sensitive to 5-HTAR dosage. This would imply a pathogenic role for 5-HTAR hypofunction described in panic anxiety. 2) Are the abnormal GABAAR subunit levels in 5-HTAR KO mice caused by a developmental arrest in subunit expression? Dysregulation of GABAAR subunits may occur during development because 5-HTAR represents a developmental signal in brain. 3) Are particular regions within amygdala and hippocampus of 5-HTAR KO mice specifically associated with altered GABAAR subunit expression? 4) Is GABA and glutamate release altered in the amygdala and hippocampus of 5-HTAR KO mice? These changes may occur to compensate GABAAR subunit abnormalities. 5) Can 5-HTA receptor agonists alter the expression of GABAAR subunits? Increasing signaling through the 5-HTAR by agonists may elicit GABAAR subunit changes that are beneficial in anxiety.
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