title: Constitutive deletion of the serotonin-7 (5-HT(7)) receptor decreases electrical and chemical seizure thresholds.
abstract: The localization of serotonin-7 (5-HT(7)) receptors and the biological activity of ligands have suggested that 5-HT(7) receptors might be involved in pain, migraine, epilepsy, anxiety, depression, memory, and sleep. In the present study, the potential involvement of 5-HT(7) receptors in epilepsy and other seizure disorders was assessed by comparing the seizures produced by three types of electrical stimulation and three chemical convulsants in 5-HT(7) receptor-deficient (knockout, KO) mice to those seizures observed in wild-type (WT) mice. Thresholds for producing electroshock-induced clonic seizures did not differ between KO versus WT mice. However, thresholds for producing electroshock-induced tonic seizures were significantly lower in KO than in WT mice. Seizures produced by pentylenetetrazole (PTZ, a GABA(A) receptor antagonist), N-methyl-d-aspartate (NMDA, an agonist at NMDA-type glutamate receptors), and cocaine (an inhibitor of monoamine uptake) were also studied. PTZ was more potent in inducing seizures in 5-HT(7) KO mice than in wild-type mice. Likewise, cocaine was more potent in inducing seizures in 5-HT(7) KO than in WT mice; moreover, death resulted from cocaine administration in 5-HT(7) KO mice but not in WT mice. There was a similar trend for NMDA that did not reach statistical significance. The present findings point to the potential for a generalized reduction in seizure threshold with constitutive deletion of the 5-HT(7) receptor gene. Since seizures have not been reported with pharmacological blockade of the receptor, the findings suggest that adaptive changes may play a role in the low seizure thresholds in these mice. In addition, the data suggest that the lower thresholds for seizures produced by diverse mechanisms should be taken into account when interpreting other aspects of the phenotype and behavioral pharmacology of this mouse.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA. jwitkin@lilly.com
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Witkin
authors.forename: Melvyn
authors.initials: M
authors.lastname: Baez
authors.forename: Jianliang
authors.initials: J
authors.lastname: Yu
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Barton
authors.forename: Harlan E
authors.initials: HE
authors.lastname: Shannon
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D003292:Convulsants / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004597:Electroshock / Q000009:adverse effects*; D017353:Gene Deletion; D051379:Mice; D018345:Mice, Knockout; D011985:Receptors, Serotonin / Q000172:deficiency / Q000235:genetics*; D012640:Seizures / Q000209:etiology / Q000235:genetics / Q000503:physiopathology
chemical_list: D003292:Convulsants; D011985:Receptors, Serotonin; C104425:serotonin 7 receptor