Elevated anxiety and antidepressant-like responses in serotonin 5-HT1A receptor mutant mice

The brain serotonin (5-hydroxytryptamine; 5-HT) system is a powerful modula tor of emotional processes and a target of medications used in the treatmen t of psychiatric disorders. To evaluate the contribution of serotonin 5-HT1 A receptors to the regulation of these processes, we have used gene-targeti ng technology to generate 5-HT1A receptor-mutant mice, These animals lack f unctional 5-HT1A receptors as indicated by receptor autoradiography and by resistance to the hypothermic effects of the 5-HT1A receptor agonist 8-hydr oxy-2- (di-n-propylamino)tetralin (8-OH-DPAT), Homozygous mutants display a consistent pattern of responses indicative of elevated anxiety levels in o pen-field, elevated-zero maze, and novel-object assays. Moreover, they exhi bit antidepressant-like responses in a tail-suspension assay. These results indicate that the targeted disruption of the 5-HT1A receptor gene leads to heritable perturbations in the serotonergic regulation of emotional state. 5-HT1A receptor-null mutant mice have potential as a model for investigati ng mechanisms through which serotonergic systems modulate affective state a nd mediate the actions of psychiatric drugs.