Increased exploratory activity and altered response to LSD in mice lackingthe 5-HT5A receptor

In order to determine the distribution and function of the 5-HT5A serotonin receptor subtype, we generated knockout mice lacking the 5-HT5A gene. Comp arative autoradiography studies of brains of wild-type (wt) and 5-HT5A knoc kout (5A-KO) mice revealed the existence of binding sites with high affinit y for [I-125]LSD that correspond to 5-HT5A receptors and that are concentra ted in the olfactory bulb, neocortex, and medial habenula. When exposed to novel environments, the 5A-KO mice displayed increased exploratory activity but no change in anxiety-related behaviors. In addition, the stimulatory e ffect of LSD on exploratory activity was attenuated in 5A-KO mice. These re sults suggest that 5-HT5A receptors modulate the activity of neural circuit s involved specifically in exploratory behavior and suggest that some of th e psychotropic effects of LSD may be mediated by 5-HT5A receptors.