Use of Mice with Targeted Genetic Inactivation in the Serotonergic System for the Study of Anxiety

Excerpt

The first knockout of a 5-HT receptor was published more than 10 years ago and since then most of the 5-HT receptors have been genetically inactivated in mice. Reviewing the anxiety-related behavior of individual receptor knockout lines, it is apparent that genetic inactivation of some receptors, including the 5-HT_2A and 5-HT₃ receptors, reproduced the phenotype elicited by the acute pharmacological blockade of the receptor. This indicates that signaling through some 5-HT receptors is directly involved in the regulation of anxiety states. In other cases, however, the genetic inactivation and pharmacological blockade of the receptor resulted in different and sometimes opposing behaviors. For example, the genetic inactivation of the 5-HT transporter results in increased anxiety whereas chronic pharmacological blockade of the 5-HT transporter by SSRIs leads to reduced anxiety. Mice null for the 5-HT_1A receptor show increased anxiety, while selective pharmacological inhibitors of the receptor do not have a measurable effect on anxiety in adult mice. These are interesting findings because the genetic inactivation of the receptor could be similar to inherited conditions characterized by a loss of function mutation of the receptor/transporter. Indeed, 5-HT transporter knockout in mice may reproduce the s polymorphism in humans. Also, certain individuals have a reduced expression of the 5-HT_1A receptor that, if present from early life, is similar to the null mutation of the receptor in mice. Therefore, the 5-HT_1A receptor and 5-HT transporter knock-out mouse strains may represent disease models that can be used to understand how a receptor or transporter deficiency leads to an anxiety-like phenotype.