Alpha(1) and beta(2) adrenoreceptor agonists inhibit pentylenetetrazole-induced seizures in mice lacking norepinephrine.

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 beta-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 alpha(1)AR or beta(2)AR, but not an alpha(2)AR or beta(1)AR agonist significantly protected against PTZ-induced seizures. In contrast, only the beta(2)AR agonist showed anticonvulsant activity in heterozygous controls. Furthermore, an alpha(1)AR antagonist exacerbated PTZ-induced seizures in control mice, whereas a beta(2)AR antagonist had no effect. We conclude that activation of the alpha(1)AR is primarily responsible for the anticonvulsant activity of endogenous NE in the murine PTZ model of epilepsy. Endogenous NE probably does not activate the beta(2)AR under these conditions, but exogenous activation of the beta(2)AR produces an anticonvulsant effect.