α₁ and β₂ Adrenoreceptor Agonists Inhibit Pentylenetetrazole-Induced Seizures in Mice Lacking Norepinephrine

Abstract

It has been known for many years that norepinephrine (NE) is a potent endogenous anticonvulsant, yet there is confusion as to which receptor(s) mediate this effect. This is probably due to multiple factors, including the importance of distinct signaling pathways for different seizure paradigms, a lack of comprehensive pharmacological studies, and difficulty in interpreting existing pharmacological results due to the presence of endogenous NE. We sought to circumvent these problems by testing the anticonvulsant activity of selective agonists for most known adrenoreceptors (ARs) in dopamine β-hydroxylase knockout (Dbh −/−) mice that lack endogenous NE. Dbh −/− mice are hypersensitive to pentylenetetrazole (PTZ)-induced seizures, demonstrating that endogenous NE inhibits PTZ-induced seizures in the wild type. Pretreatment of Dbh −/− mice with an α₁AR or β₂AR, but not an α₂AR or β₁AR agonist significantly protected against PTZ-induced seizures. In contrast, only the β₂AR agonist showed anticonvulsant activity in heterozygous controls. Furthermore, an α₁AR antagonist exacerbated PTZ-induced seizures in control mice, whereas a β₂AR antagonist had no effect. We conclude that activation of the α₁AR is primarily responsible for the anticonvulsant activity of endogenous NE in the murine PTZ model of epilepsy. Endogenous NE probably does not activate the β₂AR under these conditions, but exogenous activation of the β₂AR produces an anticonvulsant effect.