Brain serotonin (5-HT) has been implicated in a number of physiological processes and pathological conditions. These effects are mediated by at least 14 different 5-HT receptors. We have inactivated the gene encoding the 5-HT 1A receptor in mice and found that receptor-deficient animals have an increased tendency to avoid a novel and fearful environment and to escape a stressful situation, behaviors consistent with an increased anxiety and stress response. Based on the role of the 5-HT 1A receptor in the feedback regulation of the 5-HT system, we hypothesize that an increased serotonergic neurotransmission is responsible for the anxiety-like behavior of receptor-deficient animals. This view is consistent with earlier studies showing that pharmacological activation of the 5-HT system is anxiogenic in animal models and also in humans.Brain serotonin (5-HT) is implicated in the control of a wide variety of physiological processes such as nociception, cardiovascular function, and thermoregulation, as well as in different behavioral processes including feeding, aggression, and response to stress (reviewed in refs. 1-5). The 5-HT system also appears to be involved in the etiology of neuropsychiatric disorders such as depression and anxiety (reviewed in refs. 6 and 7). In recent years, our understanding of the physiological and pathological aspects of the 5-HT system has benefited from the identification, classification, and more recently the cloning of the 5-HT receptor subtypes (8). Among the receptor subtypes that have received the most attention is the 5-HT 1A receptor (5-HT 1A R). This was because of the availability of 5-HT 1A R agonists and the implication of the 5-HT 1A receptor in anxiety (6, 9).The 5-HT 1A R, like most of the 5-HT receptors, belongs to the superfamily of G-protein coupled receptors (10, 11). It is negatively coupled to adenyl cyclase. Brain 5-HT 1A R is located both pre-and postsynaptically. Presynaptic 5-HT 1A R is found mainly in the dorsal and median raphe nuclei. Activation of these receptors by agonists causes a reduction in the firing rate of serotonergic neurons (12-14) and leads to the suppression of 5-HT synthesis, 5-HT turnover, and 5-HT release in the diverse projection areas (15, 16). Postsynaptic 5-HT 1A R is found in limbic regions (such as hippocampus and septum) and in some cortical layers. As in the case of presynaptic receptors, activation of postsynaptic 5-HT 1A R is generally believed to induce a decrease in the firing rate of the postsynaptic cell (14).The 5-HT 1A R has been extensively studied by pharmacological methods. Activation of the receptor by agonists results in an anxiolytic effect (17, 18). Correlations were found among the time and dose dependency of the anxiolytic effect, the inhibition of serotonergic firing in the dorsal raphe nuclei, and the inhibition of 5-HT release after systemic administration of agonists (19,20). The 5-HT 1A R partial agonist buspirone and a series of congeners also produce this neurochemical effect and are used clinically for...

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