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 endog enous anticonvulsant, yet there is confusion as to which receptor(s) mediat e this effect. This is probably due to multiple factors, including the impo rtance of distinct signaling pathways for different seizure paradigms, a la ck 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, demonstra ting that endogenous NE inhibits PTZ-induced seizures in the wild type. Pre treatment of Dbh -/- mice with an alpha (1)AR or beta (2)AR, but not an alp ha (2)AR or beta (1)AR agonist significantly protected against PTZ-induced seizures. In contrast, only the beta (2)AR agonist showed anticonvulsant ac tivity in heterozygous controls. Furthermore, an alpha (1)AR antagonist exa cerbated PTZ-induced seizures in control mice, whereas a beta (2)AR antagon ist had no effect. We conclude that activation of the alpha (1)AR is primar ily responsible for the anticonvulsant activity of endogenous NE in the mur ine PTZ model of epilepsy. Endogenous NE probably does not activate the bet a (2)AR under these conditions, but exogenous activation of the beta (2)AR produces an anticonvulsant effect.