Dissecting the role of the serotonin system in neuropsychiatric disorders using knockout mice

Rationale: The serotonin system has an important role in the modulation of several processes relevant to psychiatry such as anxiety, affect, aggression, and drug abuse. This review summarizes the recent progress in elucidating the function of the serotonergic system using knockout mice. This review while not exhaustive, highlights recent findings of relevance to psychopharmacology. Objectives: To familiarize the reader with the technique and the findings from serotonergic knockout mice. Methods: Information included in this review was drawn from our own experience in this field and relevant publications from other investigators. Results: We have focused on three main themes that have emerged from studies with mice bearing single-gene mutations of serotonergic genes: anxiety, aggression, and drug abuse. Mice lacking the 5-HT1A have been found to be more anxious in several behavioral paradigms. Elevated levels of aggression have been reported in mice lacking the monoamine oxidase A and the 5-HT1B receptor genes. The mice lacking the 5-HT1B receptor have also been reported to exhibit an increased vulnerability to cocaine. The molecular basis of this enhanced vulnerability has been linked to compensatory changes in the nucleus accumbens. These results and their correlation with pharmacological studies will be discussed. Conclusion: Mice lacking key components of the serotonin system have provided us with important animal models of genetic vulnerability to conditions such as anxiety disorders, aggression, and drug abuse. Ongoing research with these mice may help elucidate the mechanistic functioning of this complex system.