An Assessment of the Effects of 5-HT6 Receptor Antagonists in Rodent Models of Learning

Antagonists of serotonin 6 (5-HT6) receptors have been reported to enhance cognition in animal models of learning, although this finding has not been universal. We have assessed the therapeutic potential of the specific 5-HT6 receptor antagonists, Ro 04-6790 and SB-271046, in rodent models of cognitive function. Although mice express the 5-HT6 receptor and the function of this receptor has been investigated in mice, all reports of activity with 5-HT6 receptor antagonists have utilized rat models. In the present study, receptor binding revealed that the pharmacological properties of the mouse receptor are different from the rat and human receptor: Ro 04-6790 does not bind to the mouse 5-HT6 receptor, so all in vivo testing included in the present report was conducted in rats. We replicated previous reports that 5-HT6 receptor antagonists produce a stretching syndrome previously shown to be mediated through cholinergic mechanisms, but Ro 04-6790 and SB-271046 failed to attenuate scopolamine-induced deficits in a test of contextual fear conditioning. We also failed to replicate the significant effects reported previously in both an autoshaping task and in a version of the Morris water maze. The results of our experiments are not consistent with previous reports that suggested that 5HT6 antagonists might have therapeutic potential for cognitive disorders. In our experiments, reference 5-HT6 receptor antagonists failed to demonstrate any significant effects suggestive of utility as cognition enhancing agents. JPET #56002 4 The 5-HT6 receptor was first isolated from rat striatal mRNA in 1993. It is localized almost exclusively in the CNS, including areas important for learning and memory, such as the cerebral cortex and been associated with clinical disorders such as Alzheimer's, bipolar affective disorder, and schizophrenia (Tsai et al., 1999a; Tsai et al., 1999b; Vogt et al., 2000), all of which are characterized by at least some degree of cognitive deficit. The suggestion that 5-HT6 receptor antagonists may have therapeutic potential as novel treatments for cognitive deficits is supported by reports that they facilitate cholinergic and glutamatergic neurotransmission. Antagonists of 5-HT6 receptors produce a behavioral syndrome of yawning/stretching/chewing, which is characteristic of cholinergic agonists (Bourson et al., and they reduce the number of rotations produced in rats by cholinergic antagonists (Bourson et al., 1998). 5-HT6 receptor antagonists have also been shown to enhance extracellular levels of glutamate in the frontal cortex and hippocampus as revealed during microdialysis (Dawson et al., 2000; Dawson et al., 2001). In addition, there is suggestive evidence …