Majken B Thomsen1, Thea P Lillethorup1, Steen Jakobsen1, Erik H Nielsen1, Mette Simonsen1, Gregers Wegener2, Anne M Landau3,4, R Andrew Tasker2,5. 1. Department of Nuclear Medicine and PET Center, Aarhus University and Hospital, Aarhus, Denmark. 2. Translational Neuropsychiatry Unit, Aarhus University, Risskov, Denmark. 3. Department of Nuclear Medicine and PET Center, Aarhus University and Hospital, Aarhus, Denmark. alandau@clin.au.dk. 4. Translational Neuropsychiatry Unit, Aarhus University, Risskov, Denmark. alandau@clin.au.dk. 5. Department of Biomedical Sciences, University of PEI, Charlottetown, Canada.
Abstract
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 α2-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 μg/kg (DOM20) or 60 μg/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 ~120 days of age, four rats per group were injected and scanned with [11C]yohimbine, an α2-adrenoceptor antagonist, and scanned in a Mediso micro positron emission tomography (PET) scanner to measure α2-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 [11C]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 [11C]yohimbine binding in the hypothalamus, amygdala and entorhinal cortex compared to saline-treated 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 α2-adrenoceptor binding in rat brain that may have relevance to the progression of an epilepsy phenotype.
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 α2-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 μg/kg (DOM20) or 60 μg/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 ~120 days of age, four rats per group were injected and scanned with [11C]yohimbine, an α2-adrenoceptor antagonist, and scanned in a Mediso micro positron emission tomography (PET) scanner to measure α2-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 [11C]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 [11C]yohimbine binding in the hypothalamus, amygdala and entorhinal cortex compared to saline-treated 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 α2-adrenoceptor binding in rat brain that may have relevance to the progression of an epilepsy phenotype.
Authors: Catherine L Ryan; Mark A Robbins; Meghan T Smith; Ian C Gallant; Amber L Adams-Marriott; Tracy A Doucette Journal: Physiol Behav Date: 2010-11-23
Authors: Majken B Thomsen; Jan Jacobsen; Thea P Lillethorup; Anna C Schacht; Mette Simonsen; Marina Romero-Ramos; David J Brooks; Anne M Landau Journal: J Cereb Blood Flow Metab Date: 2020-06-14 Impact factor: 6.200
Authors: Rebekah Petroff; Alicia Hendrix; Sara Shum; Kimberly S Grant; Kathi A Lefebvre; Thomas M Burbacher Journal: Pharmacol Ther Date: 2021-04-28 Impact factor: 12.310