Abstracts

RATIONALE: Norepinephrine (NE) is an important modulator of neuronal excitability and seizure susceptibility. Previously, dopamine-b-hydroxylase knockout (Dbh -/-) mice that lack NE are more sensitive than controls (Dbh +/-) to multiple convulsant agents. We wanted to begin to determine which of the noradrenergic receptors mediate the anticonvulsant action of NE. Agonists acting through the alpha 2 (a2) noradrenergic receptor has shown anticonvulsant activity against pentylenetetrazol (PTZ) seizures. METHODS: We administered a1 and a2 noradrenergic agonists and antagonists intraperitoneally to Dbh -/- and +/- mice mice and measured a change in PTZ and flurothyl seizure threshold. RESULTS: PTZ seizures: Clonidine (an a2 agonist) had no significant effect, although there was a proconvulsant trend; while cirazoline (an a1 agonist) reversed the enhanced seizure sensitivity of the Dbh -/- mice. Prazosin (an a1 antagonist) exacerbated seizures in control +/- mice and blocked the anticonvulsant effect of cirazoline in Dbh -/- mice. Flurothyl seizures: Clonidine had a proconvulsant effect on both Dbh +/- and -/- mice; whereas idazoxan (an a2 antagonist) had no effect on threshold for either Dbh +/- and -/- mice. In contrast to its anticonvulsant effect on PTZ seizures, cirazoline had no effect on flurothyl seizures in Dbh -/- mice and was proconvulsant in Dbh +/- mice. CONCLUSIONS: These results demonstrate that NE agonist, acting only on the a1 receptor is capable of reversing the increased PTZ sensitivity of the DBH -/- mice. We have yet to determine which receptor is anticonvulsant for flurothyl seizures. It is unclear why a2 agonists are not anticonvulsant in our experiments. One possibility is the animal strain used. Clonidine may be acting mainly on the presynaptic a2 receptors which would decrease locus coeruleus (LC) firing and NE/co-transmitter release. This reduced LC firing would result in a reduced release of NE/co-transmitter from terminals in Dbh +/- mice. In the Dbh -/- mice, which lack NE, reduce firing would reduce the release of the co-transmitters, galanin and neuropeptide Y, which are known anticonvulsant agents. [Supported by HHMI and VAMC]