Grant: Operating Grant

Major depression is the second most debilitating disease in Western countries after heart disease. Drugs used to treat depression target the serotonin system, but require weeks to be effective and are not always successful, often leading to suicide attempts. The serotonin-1A (5-HT1A) receptor mediates antidepressant actions, but also inhibits serotonin activity. Drugs that inhibit the 5-HT1A receptor on serotonin neurons potentiate antidepressant actions; however these compounds completely inhibit the receptor, leading to adverse events. We propose to elucidate 5-HT1A receptor structure in order to generate an entirely new type of blocker that is specific for the relevant receptor signal. We have identified two key structural portions of the 5-HT1A receptor (the i2 and i3 loops) and mutated them. Single mutations of these loops block selective signals of the receptor, rather than blocking all of its actions as with current drugs. We will expand this characterization to determine which 5-HT1A mutants affect specific brain signals of the receptor. We will examine the ability of the wild-type or the 5-HT1A mutant receptors to "rescue" the abnormal anxiety behavior of mice lacking 5-HT1A receptors. These studies will be the first to clarify which 5-HT1A receptor signals are important for behavior and should be targeted for antidepressant development. If a 5-HT1A mutant is found that prevents inhibition of serotonin neurons but preserves the beneficial actions of the receptor, we will design compounds based on the structure of the 5-HT1A i2 and i3 loops of that mutant to enhance antidepressant activity. Thus by targeting the 5-HT1A i2 and i3 loops, we hope to generate inhibitors that are specific for key inhibitory brain signals of the receptor. If successful, selective compounds to inhibit discrete signals could serve as a prototype a wide variety of therapeutic drugs.