The brain serotonin (5-hydroxytryptamine; 5-HT) system is a powerful modulator of emotional processes and a target of medications used in the treatment of psychiatric disorders. To evaluate the contribution of serotonin 5-HT 1A receptors to the regulation of these processes, we have used gene-targeting technology to generate 5-HT 1A receptormutant mice. These animals lack functional 5-HT 1A receptors as indicated by receptor autoradiography and by resistance to the hypothermic effects of the 5-HT 1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Homozygous mutants display a consistent pattern of responses indicative of elevated anxiety levels in open-field, elevated-zero maze, and novel-object assays. Moreover, they exhibit antidepressant-like responses in a tail-suspension assay. These results indicate that the targeted disruption of the 5-HT 1A receptor gene leads to heritable perturbations in the serotonergic regulation of emotional state. 5-HT 1A receptor-null mutant mice have potential as a model for investigating mechanisms through which serotonergic systems modulate affective state and mediate the actions of psychiatric drugs. The brain serotonin (5-hydroxytryptamine; 5-HT) system has been strongly implicated in the neural regulation of mood and anxiety state. Accordingly, many commonly used antidepressant and antianxiety medications target this system (1). The complex physiological actions of serotonin are mediated by a heterogeneous family of at least 14 distinct receptor subtypes (2). Although the relative contributions of individual receptor subtypes to the serotonergic regulation of mood are incompletely understood, particular attention has focused on the 5-HT 1A receptor subtype. Partial agonists at this receptor, such as buspirone, are in clinical use as anxiolytics (3), and 5-HT 1A receptor antagonists are reported to accelerate the therapeutic effects of antidepressant medications (4).These compounds produce complex effects on brain function through interactions with functionally distinct populations of 5-HT 1A receptors. 5-HT 1A receptors located on serotonergic neuronal cell bodies and dendrites are the predominant somatodendritic autoreceptors of these neurons; their activation suppresses serotonergic neuronal activity (5, 6). In addition, postsynaptic 5-HT 1A receptors are expressed in numerous serotonergic projection sites such as the cerebral cortex, septal nuclei, hippocampus, and amygdala (7). The relatively selective 5-HT 1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and antagonist WAY 100635 (8) have been used as pharmacological probes of 5-HT 1A receptor function. Systemic administration of 8-OH-DPAT produces hyperphagia, hypothermia, and an anxiolytic-like effect in rodents (9-12). The behavioral and physiological effects of 8-OH-DPAT are blocked by pretreatment with WAY 100635 (12-14).To complement pharmacological approaches to the study of 5-HT 1A receptor function, we have used a gene-targeting strategy to generate a line of m...

Central serotonin (5-hydroxytryptamine, 5-HT) systems have been implicated in the pathophysiology and treatment of anxiety disorders, which are among the world's most prevalent psychiatric conditions. Here, we report that the 5-HT 2C receptor (5-HT 2C R) subtype is critically involved in regulating behaviors characteristic of anxiety using male 5-HT 2C R knockout (KO) mice. Specific neural substrates underlying the 5-HT 2C R KO anxiolytic phenotype were investigated, and we report that 5-HT 2C R KO mice display a selective blunting of extended amygdala corticotropin-releasing hormone neuronal activation in response to anxiety stimuli. These findings illustrate a mechanism through which 5-HT 2C Rs affect anxietyrelated behavior and provide insight into the neural circuitry mediating the complex psychological process of anxiety.