Neonatal domoic acid alters in vivo binding of [11C]yohimbine to α2-adrenoceptors in adult rat brain

Rationale Epilepsy is a debilitating seizure disorder that affects approximately 50 million people. Noradrenaline reduces neuronal excitability, has anticonvulsant effects and is protective against seizure onset. Objective We investigated the role of alpha(2)-adrenoceptors in vivo in a neonatal domoic acid (DOM) rat model of epilepsy. Methods We injected male Sprague-Dawley rats daily from postnatal day 8-14 with saline or one of two sub-convulsive doses, 20 mu g/kg (DOM20) or 60 mu g/kg (DOM60) DOM, an AMPA/kainate receptor agonist. The rats were observed in open field, social interaction and forced swim tests at day 50, 75 and 98, respectively. At similar to 120 days of age, four rats per group were injected and scanned with [C-11] yohimbine, an alpha(2)-adrenoceptor antagonist, and scanned in a Mediso micro positron emission tomography (PET) scanner to measure alpha(2)-adrenoceptor binding. Results DOM60-treated rats spent more time in the periphery during the open field test and had a significant 26-33 % reduction in [C-11] yohimbine binding in the hypothalamus, hippocampus and orbital prefrontal cortex compared to saline-treated rats. On the other hand, DOM20 rats had a significant 34-40 % increase in [C-11] yohimbine binding in the hypothalamus, amygdala and entorhinal cortex compared to salinetreated rats, with no obvious behavioural differences. Conclusions The current data clearly indicate that low concentrations of DOM given to rats in their second week of life induces long-term changes in alpha(2)-adrenoceptor binding in rat brain that may have relevance to the progression of an epilepsy phenotype.