Abstracts

RATIONALE: The ability of norepinephrine (NE) to modulate seizure activity is quite clear. However, it is unclear which adrenoreceptor (AR) is responsible for NEs inhibitory action since each of the four different ARs ([alpha]1, [alpha]2, [beta]1 and [beta]2) have demonstrated an anticonvulsant response in various paradigms. Genetically engineered mice that lack NE (dopamine [beta]-hydroxylase knockout mice; [italic]Dbh[/italic] -/-) were used to determine which AR subtype modulates seizures induced by the convulsant flurothyl. [alpha]2AR subtype knockout mice were used to determine which of the [alpha]2AR subtypes mediates the effects of clonidine ([alpha]2 agonist). These studies will indicate which noradrenergic receptor modulates flurothyl-induced seizures in mice with normal NE levels and in mice which lack NE, indicating how endogenous NE inhibits seizure activity.
METHODS: Flurothyl seizure thresholds were determined in [italic]Dbh[/italic] -/- and [italic]Dbh[/italic] +/- mice (controls) 30 min after the administration of different AR agonists/antagonists. To determine which [alpha]2AR subtype mediates the action of clonidine, flurothyl seizures thresholds were measured in [alpha]2A, [alpha]2C and [alpha]2AC knockout mice 30 min after clonidine or saline. To determine if the effects of clonidine were specific to mice, flurothyl-induced seizures were determined in rats at various ages after either saline, clondine or idazoxan ([alpha]2 antagonist).
RESULTS: Four important points were determined from these studies. 1. Stimulation of [alpha]2AR with clonidine is proconvulsant in [italic]Dbh[/italic] +/- and [italic]Dbh[/italic] -/- mice. This proconvulsant response of clonidine is mediated through the [alpha]2A-AR. The proconvulsant response of clonidine is also observed in rats. 2. Blockade of the [alpha]1AR is proconvulsant when endogenous NE is present, though stimulation of [alpha]1AR does not produce an anticonvulsant response in either [italic]Dbh[/italic] -/- or [italic]Dbh[/italic] +/- mice. 3. Administration of any single AR agonist does not produce an anticonvulsant response in [italic]Dbh[/italic] -/- mice, but a combination of agonists does produce an anticonvulsant effect. 4. Further stimulation of ARs does not produce an anticonvulsant response in [italic]Dbh[/italic] +/- mice.
CONCLUSIONS: These data indicate the inhibitory action of the noradrenergic nervous system against flurothyl-induced seizures is complex. The [alpha]1AR is, in part, responsible for the anticonvulsant action of endogenous NE; while stimulation of the [alpha]2AR is proconvulsant in mice and rats with normal NE and in mice lacking NE. This proconvulsant response is due specifically to the [alpha]2A-AR, which is localized both pre- and post-synaptically. In mice which lack NE, no single AR agonist produced an anticonvulsant response. A combination ([alpha]2, [beta]1 and [beta]2) of AR agonists was required to produce an anticonvulsant response. This combination of AR agonists produced an anticonvulsant response only in mice lacking endogenous NE.
[Supported by: National Alliance for Research on Schizophrenia and Depression, Pediatric Epilepsy Research Center, Department of Veterans Affairs and Howard Hughes Medical Institute.]