The amygdaloid 5-HT2C receptor in anxiety-like behavior

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DESCRIPTION (provided by applicant): Anxiety disorder is one of the most common mental health problems in the United States. It also accompanies with other affective disorders such as depression. The etiology for anxiety disorders is still unknown and may be complicated. Furthermore, current therapeutic approaches suffer from serious deficiencies. Therefore, it is essential to study the etiology of anxiety disorders and develop better therapeutic approaches for anxiety disorders. Serotonin2c (5- HT2c) receptors play a role in the regulation of anxiety behaviors. Studies, from both humans and rodents, indicate that activation of 5-HT2c receptors produces an anxiogenic effect. Increased sensitivity of 5-HT2c receptors was found in patients with panic disorder. Conversely, 5-HT2c receptor antagonists produce anxiolytic effect. However, little is known regarding the neural circuitry and the cellular and molecular mechanisms that mediate the effect of 5-HT2c receptors on the regulation of anxiety behaviors. The objective of the current application is to determine the role of amygdaloid 5-HT2c receptors in the regulation of anxiety-like behaviors. Our hypothesis is that 5-HT2c receptors in the amygdala play an important role in the regulation of anxiety-like behaviors. The amygdala is known as a fear center and it contains a high density of 5-HT2c receptors. We recently found that serotonin transporter knockout mice show increased anxiety-like behaviors and that the density of 5-HT2c receptors is increased in the amygdala of these mice. To test the hypothesis, we will pursue 2 specific aims: 1) We will characterize recombinant adenovirus containing 5-HT2c sense and antisense sequences, so that they can be used to manipulate the expression of 5-HT2c receptors; and 2) We will determine the effect of 5-HT2c receptors in the amygdala on anxiety-like behaviors. Anxiety like behavior of the animals will be assessed by elevated plus maze, open field and fear conditioning tests. The outcome of the studies will be the first line of evidence for the location of 5-HT2c receptors that are involved in the regulation of anxiety behavior, which will be the foundation for the future studies on the neuronal circuitries and the cellular and molecular mechanisms mediating 5-HT2c receptor-involved regulation of anxiety behaviors. Furthermore, the proposed studies have a high potential of leading to the development of novel drugs to treat anxiety disorders.