Vol. 298, Issue 3, 1042-1048, September 2001

₁ and ₂ Adrenoreceptor Agonists Inhibit Pentylenetetrazole-Induced Seizures in Mice Lacking Norepinephrine

David Weinshenker , Patricia Szot , Nicole S. Miller and Richard D. Palmiter

Howard Hughes Medical Institute (D.W., N.S.M., R.D.P.) and Departments of Biochemistry (D.W.) and Psychiatry and Behavioral Sciences (P.S.), University of Washington, Seattle, Washington; and Geriatric Research, Education, Clinical Center (GRECC), Puget Sound Health Care System, Seattle, Washington (P.S.)

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