Abstract
Objectives: Noradrenaline reduces neuronal excitability [1], has anticonvulsant effects [2] and is protective against seizure onset. We investigated the role of α2 adrenoceptors in a neonatal domoic acid (DOM) rat model of epilepsy and studied the effects of neuroinflammation.
Methods: Male Sprague-Dawley rats (n=6-7 per group) were injected (s.c.) daily from postnatal day 8-14 with saline or one of two low sub-convulsive doses, 20µg/kg [DOM20] or 60µg/kg [DOM60] of DOM, an AMPA/kainate receptor agonist. The behaviour of the rats was observed in an open field test, a social interaction test and the forced swim test at day 50, 75 and 98, respectively. At ~120 days of age 3-4 rats per group were injected with [11C]yohimbine, an α2 adrenergic receptor antagonist, and scanned in a Mediso micro positron emission tomography (PET) scanner, to measure α2 adrenoceptor binding. The volume of distribution (VT) was obtained by Logan plot, using the arterial plasma curve from the rat as the input curve. The rats (n=1-3 per group) were later scanned with [11C]PK11195, a tracer of activated microglia, and standardized uptake values, corrected for injected dose and body weight, were used for simple semi-quantitative analysis. MicroPET images were analyzed using PMOD software and registered to an average Sprague-Dawley rat MRI brain atlas to acquire data in limbic and cortical regions of interest.
Results: In behavioural testing DOM60, and to a lesser extent DOM20 rats, spent more time in the periphery during the open field test and less time struggling in the forced swim test compared to the saline treated rats. Analysis of the microPET data revealed that relative to saline treated rats, DOM60 rats had a 40-47 % reduction in [11C]yohimbine binding in the hypothalamus, amygdala, hippocampus, cingulate cortex and medial and orbital prefrontal cortex. Preliminary data further suggest that DOM60 rats may have a marked increase in [11C]PK11195 retention in the whole brain.
Conclusion: We conclude that neonatal administration of DOM combined with the potential stress associated with behavioural testing results in a significant decrease in [11C]yohimbine binding in limbic and cortical brain regions. We suggest that the observed downregulation of α2 adrenoceptors is a result of elevated extracellular noradrenaline which may represent a form of preconditioning to decrease seizure susceptibility of the brain.
References:
1. Barry, D.I., et al., Grafted noradrenergic neurons suppress seizure development in kindling-induced epilepsy. Proc Natl Acad Sci U S A, 1987. 84(23): p. 8712-5.
2. Loscher, W. and S.J. Czuczwar, Comparison of drugs with different selectivity for central alpha 1-and alpha 2-adrenoceptors in animal models of epilepsy. Epilepsy Res, 1987. 1(3): p. 165-72.
Methods: Male Sprague-Dawley rats (n=6-7 per group) were injected (s.c.) daily from postnatal day 8-14 with saline or one of two low sub-convulsive doses, 20µg/kg [DOM20] or 60µg/kg [DOM60] of DOM, an AMPA/kainate receptor agonist. The behaviour of the rats was observed in an open field test, a social interaction test and the forced swim test at day 50, 75 and 98, respectively. At ~120 days of age 3-4 rats per group were injected with [11C]yohimbine, an α2 adrenergic receptor antagonist, and scanned in a Mediso micro positron emission tomography (PET) scanner, to measure α2 adrenoceptor binding. The volume of distribution (VT) was obtained by Logan plot, using the arterial plasma curve from the rat as the input curve. The rats (n=1-3 per group) were later scanned with [11C]PK11195, a tracer of activated microglia, and standardized uptake values, corrected for injected dose and body weight, were used for simple semi-quantitative analysis. MicroPET images were analyzed using PMOD software and registered to an average Sprague-Dawley rat MRI brain atlas to acquire data in limbic and cortical regions of interest.
Results: In behavioural testing DOM60, and to a lesser extent DOM20 rats, spent more time in the periphery during the open field test and less time struggling in the forced swim test compared to the saline treated rats. Analysis of the microPET data revealed that relative to saline treated rats, DOM60 rats had a 40-47 % reduction in [11C]yohimbine binding in the hypothalamus, amygdala, hippocampus, cingulate cortex and medial and orbital prefrontal cortex. Preliminary data further suggest that DOM60 rats may have a marked increase in [11C]PK11195 retention in the whole brain.
Conclusion: We conclude that neonatal administration of DOM combined with the potential stress associated with behavioural testing results in a significant decrease in [11C]yohimbine binding in limbic and cortical brain regions. We suggest that the observed downregulation of α2 adrenoceptors is a result of elevated extracellular noradrenaline which may represent a form of preconditioning to decrease seizure susceptibility of the brain.
References:
1. Barry, D.I., et al., Grafted noradrenergic neurons suppress seizure development in kindling-induced epilepsy. Proc Natl Acad Sci U S A, 1987. 84(23): p. 8712-5.
2. Loscher, W. and S.J. Czuczwar, Comparison of drugs with different selectivity for central alpha 1-and alpha 2-adrenoceptors in animal models of epilepsy. Epilepsy Res, 1987. 1(3): p. 165-72.
| Originalsprog | Engelsk |
|---|---|
| Publikationsdato | jun. 2015 |
| Status | Udgivet - jun. 2015 |
| Begivenhed | Brain & Brain PET 2015: XXVIIth International Symposium on Cerebral Blood Flow, Metabolism and Function and the XIIth International Conference on Quantification of Brain Function with PET - Vancouver Convention Centre, Vancouver, Canada Varighed: 27 jul. 2015 → 30 sep. 2015 |
Konference
| Konference | Brain & Brain PET 2015 |
|---|---|
| Lokation | Vancouver Convention Centre |
| Land/Område | Canada |
| By | Vancouver |
| Periode | 27/07/2015 → 30/09/2015 |