Neonatal domoic acid increases receptor density of α2 adrenoceptors and GABAA α5 receptors in limbic brain regions of adult rats

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Background: The presymptomatic events involved in neurological disorders such as epilepsy remain elusive but represent an opportunity to understand disease development and stop the pathogenic processes leading to chronic epilepsy. Previous studies using Western blot and immunohistochemistry have found increased levels of α2 adrenoceptors in the hippocampal membrane of adult rats treated neonatally with low-dose domoic acid (DOM) along with decreased levels of both isoforms of glutamic acid decarboxylase (GAD), a catalyst of the decarboxylation of glutamate to GABA, indicating a reduction in GABAergic interneurons.
Objectives: The aim of the present study was to investigate the expression of GABAA α5 and α2 adrenoceptors in limbic brain regions in a DOM rat model of epilepsy using autoradiography.
Methods: Male Sprague-Dawley rats (N=3) were injected (s.c.) daily from postnatal day 8-14 with saline or low sub-convulsive doses of the glutamate agonist DOM (20µg/kg), weaned on day 22 and left undisturbed except for routine husbandry. At ~120 days of age the rats were euthanized by decapitation. The brains were removed, frozen in isopentane/dry ice and cut into 20 µM thick slices. Receptor autoradiography was performed using tracers of the α5 subtype of the GABAA receptor ([11C]Ro15-4513) and the α2 adrenoceptors ([3H]RX821002) to determine the total binding of these receptors in the hippocampus, amygdala and hypothalamus. High concentrations of unlabeled Ro15-4513 and phentolamine were used to assess non-specific binding in the GABAA and α2 adrenoceptor studies, respectively, and these values were subtracted from the total binding values to yield the specific binding.
Results: The specific binding of postsynaptic GABA receptors was significantly increased in the hippocampus, medial amygdala and hypothalamus of the DOM treated rats. A trend towards an increase in the density of α2 adrenoceptors was also found throughout the limbic system of the DOM treated rats compared to saline-treated controls in our small sample.
Conclusion: Although preliminary, the observed increase in postsynaptic GABA receptor concentrations in DOM-treated rats may represent a compensatory up-regulation in response to reduced GABAergic input. Further, the preliminary data supports earlier findings of increased levels of α2 adrenoceptors in DOM treated rats. Because noradrenaline reduces neuronal excitability, elevated receptor expression could be a protective mechanism that attempts to compensate for the lowered seizure threshold caused by DOM. These results indicate that low-dose neonatal DOM induces seemingly permanent changes in receptor expression that may be important in delayed-onset epilepsy.
Original languageEnglish
Publication yearApr 2015
Publication statusPublished - Apr 2015
Event56th Annual Congress of the Scandinavian College of Neuro-Psychopharmacology - Copenhagen, Denmark
Duration: 22 Apr 201524 Apr 2015


Conference56th Annual Congress of the Scandinavian College of Neuro-Psychopharmacology

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