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. 2011 Sep 29:192:761-72.
doi: 10.1016/j.neuroscience.2011.06.045. Epub 2011 Jun 22.

Changes in postnatal norepinephrine alter alpha-2 adrenergic receptor development

J D Sanders  1 , H K Happe, D B Bylund, L C Murrin
Affiliations

Changes in postnatal norepinephrine alter alpha-2 adrenergic receptor development

J D Sanders et al. Neuroscience. .

Abstract

Alpha-2 adrenergic receptors (A2AR) regulate multiple brain functions and are enriched in developing brain. Studies demonstrate norepinephrine (NE) plays a role in regulating brain maturation, suggesting it is important in A2AR development. To investigate this we employed models of NE absence and excess during brain development. For decreases in NE we used N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP4), a specific noradrenergic neurotoxin. Increased noradrenergic terminal density was produced by methylazoxymethanol acetate (MAM) treatment. A2AR density was assayed with [(3)H]RX821002 autoradiography. DSP4 lesions on postnatal day (PND) 3 produce A2AR decreases in many regions by PND 5. A2AR recover to control levels by PND 15 and 25 and there is no further change in total receptor density. We also assayed A2AR in brains lesioned with DSP4 on PND 13, 23, 33 and 43 and harvested 22 days post-lesion. A2AR levels remain similar to control at each of these time points. We examined A2AR functionality and high affinity state with epinephrine-stimulated [(35)S]GTPγS and [(125)I]p-iodoclonidine autoradiography, respectively. On PND 25, control animals and animals lesioned with DSP4 on PND 3 have similar levels of [(35)S]GTPγS incorporation and no change in high affinity state. This is in contrast to increases in A2AR high affinity state produced by DSP4 lesions of mature brain. We next investigated A2AR response to increases in norepinephrine levels produced by MAM. In contrast to DSP4 lesions, increasing NE results in a large increase in A2AR. Animals treated with MAM on gestational day 14 had cortical [(3)H]RX821002 binding 100-200% greater than controls on PND 25, 35, 45, 55 and 65. These data indicate that NE regulation of A2AR differs in developing and mature brain and support the idea that NE regulates A2AR development and this has long term effects on A2AR function.

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Figures

FIGURE 1
FIGURE 1
Reduction in NET parallels reduction in norepinephrine levels in DSP4 treated animals. Neonatal treatment with DSP4 reduces NET and norepinephrine levels in cortex and hippocampus at PND 32 to <5% of control levels. NET was quantified by [3H]nisoxetine binding. NE levels were measured by HPLC. ctx = cortex, hip=hippocampus. Data are mean ± SEM, n = 4. All DSP4 values were significantly different from the corresponding saline controls, p<0.001.
FIGURE 2
FIGURE 2
Effects of neonatal DSP4 lesion on development of NET and A2AR. DSP4 treatment on PND 3 greatly reduces NET from PND 5 to PND 25 as measured by [3H]nisoxetine binding. A2AR density, as measured by [3H]RX821002 binding, is reduced in some regions two days later (PND 5) but recovers and is not significantly changed compared to controls from PND 15 on. Data for frontal cortex (fr ctx) and septum (sep) are from coronal level 0.7 mm anterior to the bregma while data for parietal cortex (par ctx), amygdala (amy) and hippocampus (hip) are from coronal level 3.3 mm posterior to the bregma, corresponding to plates 15 and 33 in Paxinos and Watson (1998). fr ctx=frontal cortex; sep=lateral septum. Data are mean ± SEM, n = 4–12. Groups significantly different from saline control, * − p < 0.05; # − p < 0.01.
FIGURE 3
FIGURE 3
Effects of DSP4 lesion on A2AR agonist high affinity state in developing and mature brain. DSP4 treatment on PND 3 produces no significant change in the level of high affinity state A2AR on PND 25 (A) or PND 60 (B). In contrast, DSP4 treatment on PND 48 produces significant increases in levels of high affinity state A2AR on PND 62 (C). Data are expressed in fmol/mg tissue and are mean ± S.E.M., n=3–8. Data for frontal cortex (fr ctx) and septum (sep) are from the coronal level 0.7 mm anterior to the bregma (3A, 3C) while data for parietal cortex (par ctx), amygdala (amy) and hippocampus (hip) are from coronal level 3.3 mm posterior to the bregma (3A, 3B, 3C: Paxinos and Watson, 1998). For 3B amygdaloid tissue was lost during processing. * - significantly different from corresponding saline control, p < 0.02.
FIGURE 4
FIGURE 4
Linkage of A2AR to G proteins is not affected by neonatal DSP4 lesion. Rats were treated with DSP4 at PND 3 and linkage of A2AR to Gi/o was examined at PND 25 using the [35S]GTPγS assay as described in Methods. Treatment with epinephrine (Epi) increased [35S]GTPγS binding in all brain regions, similar to previously published studies in adults. Neonatal treatment with DSP4 did not alter [35S]GTPγS binding in either control or DSP4 treated animals. There were no significant differences between control (saline) and DSP4 treated animals within any treatment. n= 10–16. * - significantly different from the corresponding control, RX and Epi+RX, p < 0.001.
FIGURE 5
FIGURE 5
Comparison of the effects of developmental noradrenergic depletion and excess on NET and A2AR. NET was assayed with [3H]nisoxetine and A2AR with [3H]RX821002. MAM was administered to pregnant dams on E14 and offspring brains harvested at PND 25, 35, 45, 55 and 65. DSP4 was administered 22 days prior to each of the experimental ages. NE hypoinnervation during development due to DSP4 lesions reduced NET levels to near zero but had no effect on A2AR, in contrast to similar lesions in adults. NE hyperinnervation during development due to MAM lesions significantly increased both NET and A2AR levels in cortex. Data are mean ± SEM, n = 4–6. * - significantly different from the corresponding control, p < 0.01.
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