Differences in Nicotine-Induced Dopamine Release and Nicotine Pharmacokinetics Between Lewis and Fischer 344 Rats

Studies have shown a greater preference for the self-administration of drugs such as nicotine and cocaine in the Lewis rat strain than in the Fischer 344 strain. We examined some factors that could contribute to such a difference. The baseline level of extracellular dopamine in nucleus accumbens shell was about 3-times higher in Fischer rats than in Lewis rats (3.18 ± 0.26 vs. 1.09 ± 0.14 pg/sample). Nicotine (50-100 g/kg)-induced release of dopamine, expressed in absolute terms, was similar in the two strains. Dopamine release expressed in relative terms (as percent of baseline), however, was significantly greater in Lewis rats than in Fischer rats at 30 min after the first nicotine injection. We suggest that the relative increase is of more influence than the absolute level for determining preference; a lower physiological extracellular dopamine level thus represent a risk factor for increased preference. Amphetamine-induced dopamine release expressed in relative terms was not greater in the Lewis strain. In the initial time period of the microdialysis experiments, a sharper peak in nicotine-induced accumbal dopamine release in Lewis and a less but more sustained release in Fischer rats was observed. This release pattern paralleled the faster clearance of nicotine from blood of Lewis compared to Fischer rats. In tissue slices the electrically induced dopamine release was highest in the nucleus accumbens and lowest in the ventral tegmentum. A significant effect of nicotine was lowering the electrically induced release of dopamine in frontal cortex slices from Fischer brain and increasing this dopamine release in the ventral tegmentum of Lewis brain slices indicating that the ventral tegmentum, an area controlling dopamine release in the accumbens, is more responsive to nicotine in the Lewis rat. Nicotine levels tended to be more sustained in Fischer rats in different brain regions, although the difference in nicotine levels between the strains was not significant at any time period. Several factors contribute to nicotine preference, including the endogenous dopamine level, and the sensitivity of ventral tegmentum neurons to nicotine-induced dopamine release. Strain differences in pharmacokinetics of nicotine may also play a role.     

Hippocampal 8-[3H]Hydroxy-2-(Di-n-Propylamino)Tetralin Binding Site Densities, Serotonin Receptor (5-HT1A) Messenger Ribonucleic Acid Abundance, and Serotonin Levels Parallel the Activity of the Hypothalamopituitary-Adrenal Axis in Rat

We have previously demonstrated that susceptibility of the Lewis rat to inflammatory disease, compared with the relatively resistant Fischer F344/N rat, is related to a hyporesponsive hypothalamopituitary-adrenal axis to inflammatory and other stress mediators. Because serotonin (5-HT) and the 5-HT1A receptor are important stimulators of this axis, we have investigated the levels of 8-[3H]-hydroxy-2,3-(di-n-propylamino)tetralin binding sites, 5-HT1A mRNA, 5-HT, and 5-hydroxyindoleacetic acid in various brain regions of Lewis, outbred Harlan Sprague Dawley, and Fischer F344/N rats. Lewis rats expressed significantly fewer hippocampal and frontal cortical 8-[3H]-hydroxy-2,3-(di-n-propylamino)tetralin binding sites and less 5-HT1A mRNA than Harlan Sprague Dawley and Fischer F344/N rats. Adrenalectomy increased the number of 8-[3H]hydroxy-2,3-(di-n-propylamino)tetralin binding sites and 5-HT1A mRNA expression in the hippocampus of all three strains. Levels of hippocampal 5-HT in Fischer F344/N rats were significantly greater than levels detected in the same regions from Lewis and Harlan Sprague Dawley rats. Hypothalamic 5-HT and 5-hydroxyindoleacetic acid levels in Harlan Sprague Dawley rats were higher than the same area from the other two strains. Adrenalectomy increased the levels of 5-hydroxyindoleacetic acid in the hypothalamus of all three strains. We conclude that hippocampal 5-HT1A receptor densities and 5-HT levels in the rat parallel the activity and responsiveness of the hypothalamopituitary-adrenal axis.     

Response acquisition with delayed reinforcement in Lewis and Fischer 344 rats

Previous work has shown neurochemical and behavioral differences between Lewis rats and Fischer 344 rats. Some of this work suggests that there might be differential sensitivity to delayed reinforcement between the two strains. To further explore this possibility, Lewis (n=8) and Fischer 344 (n=8) rats were exposed to a response-acquisition task with a non-resetting 20s delay to reinforcement. A tandem fixed-ratio 1, fixed-time 20s schedule of reinforcement was programmed for one of two levers; presses on the alternate lever had no programmed consequences. A greater number of Lewis rats (5/8) acquired lever pressing compared to the Fischer 344 rats (2/8). Future work with these strains may lead to a better understanding of the genetic and/or neurochemical factors involved in temporal control of behavior.     

Region - specific alterations in tyrosine hydroxylase activity in rats exposed to lead

Previous studies from our laboratory showed that subchronic exposure to low levels of Pb resulted in significant decrease in dopamine (DA) content, attenuation of stimulus-induced release of DA in the dopaminergic projection area of nucleus accumbens (NA), and alterations in tyrosine hydroxylase (TH) activity in rat whole brain homogenates. The present study reported here was conducted to assess the functional integrity of DA synthesis in different brain regions of rats subchronically (90-days) exposed to 50 ppm Pb by measuring the activity of the rate limiting enzyme, tyrosine hydroxylase, in seven brain regions. In Pb-exposed rats, TH activity was reduced in two of the seven brain regions investigated, i.e., nucleus accumbens (42% reduction) and frontal cortex (61% reduction) when compared to controls. In contrast, Pb exposure did not affect the TH activity in cerebellum, brainstem, hippocampus, hypothalamus and striatum. The changes in TH activity in nucleus accumbens (NA) and frontal cortex (FC) in Pb-exposed rats were further confirmed by Western blot analysis using TH polyclonal antibody. Collectively, these results indicate that low level subchronic Pb exposure may affect TH protein in these brain regions.     

Orchiectomized Fischer 344 male rat models body composition in hypogonadal state

The hypogonadal state in men is accompanied by substantial decreases in muscle and bone mass and by an increase in adiposity. Most of the strains of orchiectomized (ORX) rat that have been used to model this state display substantial losses in bone, but only subtle changes in adiposity and muscle mass. In order to identify a rat model displaying a robust catabolic response to ORX, we studied three strains: Fischer 344 (F344), Brown Norway and Wistar. ORX caused a significant and sustained decrease in weight gained by F344, but only a trend toward reduced weight gain in Brown Norway rats and a modest reduction weight gain in Wistar rats that was significant only after 56days. ORX suppressed food intake in F344 rats, and to a lesser degree in Brown Norway and Wistar rats. ORX reduced muscle mass significantly in F344 rats, but not in Brown Norway or Wistar rats. ORX increased adiposity moderately in F344 rats and substantially in Wistar rats. ORX caused a marked reduction in prostate mass and increase in bone resorption in all three strains. Thus, F344 was the only strain in which ORX produced substantial decreases in food intake, body weight and muscle mass with increased adiposity and increased bone resorption. We conclude that the F344 rat displays a broad range of catabolic effects following ORX and is the best rat model for studying the androgenic pathway and strategies for reversing catabolic changes induced by hypogonadism.     

Enhanced calcium signaling to bradykinin in airway smooth muscle from hyperresponsive inbred rats

Inbred Fischer 344 rats display airway hyperresponsiveness (AHR) in vivo compared with the normoresponsive Lewis strain. Fischer AHR has been linked with increased airway smooth muscle (ASM) contraction ex vivo and enhanced ASM cell intracellular Ca(2+) mobilization in response to serotonin compared with Lewis. To determine the generality of this association, we tested whether bradykinin (BK) also stimulates greater contraction of Fischer airways and greater Ca(2+) mobilization in Fischer ASM cells. Explants of Fischer intraparenchymal airways constricted faster and to a greater degree in response to BK than Lewis airways. BK also evoked higher Ca(2+) transients in Fischer than in Lewis ASM cells. ASM cell B(2) receptor expression was similar between the two strains. BK activated both phosphatidylinositide-specific phospholipase C (PI-PLC) and phosphatidylcholine-specific PLC to mobilize Ca(2+) in Fischer and Lewis ASM cells. PI-PLC activity, as measured by inositol polyphosphate accumulation, was similar in the two strains. PKC inhibition with GF109203X, Go6973, or Go6983 attenuated BK-mediated Ca(2+) transients in Fischer cells, whereas GF109203X potentiated while Go6976 and Go6983 did not affect Ca(2+) transients in Lewis cells. Enhanced Ca(2+) mobilization in ASM cells can arise from variations in PKC and may be an important component of nonspecific, innate AHR.     

Differences in dopamine responsiveness to drugs of abuse in the nucleus accumbens shell and core of Lewis and Fischer 344 rats

The use of inbred rat strains provides a tool to investigate the role of genetic factors in drug abuse. Two such strains are Lewis and Fischer 344 rats. Although several biochemical and hormonal differences have been observed between Lewis and Fischer 344 strains, a systematic comparison of the effect of different drugs of abuse on dopamine (DA) transmission in the shell and core of the nucleus accumbens of these strains is lacking. We therefore investigated, by means of dual probe microdialysis, the effect of different doses of morphine (1.0, 2.5, and 5.0 mg/kg), amphetamine (0.25, 0.5, and 1.0 mg/kg) and cocaine (5, 10, and 20 mg/kg) on DA transmission in the shell and in the core of nucleus accumbens. Behavior was monitored during microdialysis. In general, Lewis rats showed greater DA responsiveness in the NAc core compared to F344 rats except after 2.5 mg/kg of morphine and 20 mg/kg of cocaine. In the NAc shell, different effects were obtained depending on drug and dose: after 1.0 mg/kg of morphine no strain differences were observed, at 2.5 and 5.0 mg/kg Lewis rats showed greater increase in DA in the NAc shell. Following amphetamine and cocaine challenge, Lewis rats showed greater DA increase in the shell after 0.25 mg/kg of amphetamine and 20 mg/kg of cocaine. Behavioral activation was greater in Lewis rats in response to the lowest dose of morphine (1.0 mg/kg), to the highest dose of amphetamine (1.0 mg/kg) and to all doses of cocaine. These differences might be the basis for the different behavioral responses of these strains to drugs of abuse.     

Comparative study of alpha2-adrenoceptors in Fischer 344 and Lewis rats. Evidence for clonidine-induced place aversion

Fischer 344 (F344) and Lewis rat strains have been shown to exhibit different vulnerability to development or maintenance of opioid seeking behaviours probably due to differences in the endogenous opioid system. Since opioid and alpha(2)-adrenergic mechanisms closely interact in nociception and substance abuse, strain differences may be expected to affect alpha(2)-adrenoceptor-mediated events. The sensitivity of these two strains to alpha(2)-adrenoceptor-mediated antinociception has been reported to be markedly different. In this work we have further studied the function of alpha(2)-adrenoceptors in F344 and Lewis rats by means of several in vivo and in vitro procedures. Comparative studies of [(3)H]RX821002 and [(35)S]GTPgammaS binding revealed that alpha(2)-adrenoceptors could be slightly more responsive to agonist stimulation in the brain cortex of F344 rats, which is in agreement with previous antinociception studies. However, these differences were modest, not observed in the spinal cord and did not translate into functional differences concerning the effects of clonidine on vas deferens contractility and body temperature. Conditioning experiments showed that a moderate dose of clonidine, which is relevant in antinociceptive and opioid antiwithdrawal studies, induces a robust place aversion which is also equivalent in F344 and Lewis rats. This finding underlies the consistency of the effect and its independency of genetic differences between both rat strains. It seems therefore that the pharmacological properties of alpha(2)-adrenoceptors are similar in F344 and Lewis rats, and thus the previously reported differences in clonidine-induced antinociception could be attributed to other factors such as dissimilar endogenous function of specific noradrenergic pathways.     

Stock differences in the susceptibility of rats to learned helplessness training

Learned helplessness (LH) consists of shock escape deficits evidenced by animals previously exposed to inescapable shock. This phenomenon has shown promise as a behavioral screen for new antidepressant drugs. Unfortunately, some stocks of rats evidence low susceptibility to LH training. Accordingly, male rats from 8 different stocks were tested for susceptibility to LH training. The outbred stocks consisted of Harlan SD, Sasco Holtzman, and Charles River Holtzman. The inbred stocks (i.e. strains) tested were Lewis, Wistar Kyoto, Brown Norway, Fischer F-344, and Buffalo. The Lewis, Brown Norway, Fischer and Sasco Holtzman rats were found to be virtually non-susceptible to LH training. Harlan SD and Buffalo rats evidenced intermediate susceptibilities of 28% and 33%, respectively. Kyoto and Charles River Holtzman rats were the most susceptible at 53% and 55%, respectively. No stock differences between control animals were observed. These results indicate that wide differences in susceptibility to LH training exist in rats from different stocks or suppliers and researchers should be careful to choose subjects from a susceptible stock. Charles River Holtzman and Wistar Kyoto rats appear to be very susceptible to LH training.     

Glial Fibrillary Acidic Protein and the Mesolimbic Dopamine System: Regulation by Chronic Morphine and Lewis-Fischer Strain Differences in the Rat Ventral Tegmental Area

Abstract— In this study we demonstrate that a 51-kDa phosphoprotein, previously identified as morphine regulated and showing different basal levels among rat strains, is glial fibrillary acidic protein (GFAP). Chronic morphine increased levels of GFAP immunoreactivity by >70% in the ventral tegmental area (VTA) of outbred Sprague-Dawley rats. This increase in GFAP content was not observed in rats that were treated concomitantly with morphine and naltrexone, an opiate receptor antagonist, and did not occur in response to a single acute injection with morphine. No alterations in GFAP levels were observed in response to chronic morphine in several other regions of the CNS studied, including the substantia nigra, locus coeruleus, cerebral cortex, and spinal cord. There were also inherent differences in levels of GFAP immunoreactivity in the VTA of drug-naive Fischer 344 and Lewis rats, two inbred rat strains that differ in their relative preference for morphine and other drugs of abuse. The VTA of drug-naive Lewis rats contained more than twofold higher levels of GFAP compared with drug-naive Fischer rats. This strain difference was also apparent in the locus coeruleus but not in several other brain regions or in spinal cord. Because the mesolimbic dopamine system is thought to play a critical role in mediating the reinforcing properties of opiates and other drugs of abuse, it is possible that the opiate induction of GFAP and inherent Lewis versus Fischer strain differences in GFAP levels in the VTA may be related to the reinforcing and/or addictive properties of opiates mediated by this brain region, as well as to genetic differences in drug preference.     

Brain signaling and behavioral responses induced by exposure to (56)Fe-particle radiation

Previous experiments have demonstrated that exposure to 56Fe-particle irradiation (1.5 Gy, 1 GeV) produced aging-like accelerations in neuronal and behavioral deficits. Astronauts on long-term space flights will be exposed to similar heavy-particle radiations that might have similar deleterious effects on neuronal signaling and cognitive behavior. Therefore, the present study evaluated whether radiation-induced spatial learning and memory behavioral deficits are associated with region-specific brain signaling deficits by measuring signaling molecules previously found to be essential for behavior [pre-synaptic vesicle proteins, synaptobrevin and synaptophysin, and protein kinases, calcium-dependent PRKCs (also known as PKCs) and PRKA (PRKA RIIbeta)]. The results demonstrated a significant radiation-induced increase in reference memory errors. The increases in reference memory errors were significantly negatively correlated with striatal synaptobrevin and frontal cortical synaptophysin expression. Both synaptophysin and synaptobrevin are synaptic vesicle proteins that are important in cognition. Striatal PRKA, a memory signaling molecule, was also significantly negatively correlated with reference memory errors. Overall, our findings suggest that radiation-induced pre-synaptic facilitation may contribute to some previously reported radiation-induced decrease in striatal dopamine release and for the disruption of the central dopaminergic system integrity and dopamine-mediated behavior.     

Quantitative magnetic resonance spectroscopy reveals a potential relationship between radiation-induced changes in rat brain metabolites and cognitive impairment

To test the efficacy of magnetic resonance spectroscopy (MRS) in identifying radiation-induced brain injury, adult male Fischer 344 rats received fractionated whole-brain irradiation (40 or 45 Gy given in 5-Gy fractions twice a week for 4 or 4.5 weeks, respectively); control rats received sham irradiation. Twelve and 52 weeks after whole-brain irradiation, rats were subjected to high-resolution MRI and proton MRS. No apparent lesions or changes in T(1)- or T(2)-weighted images were noted at either time. This is in agreement with no gross changes being found in histological sections from rats 50 weeks postirradiation. Analysis of the MR spectra obtained 12 weeks after fractionated whole-brain irradiation also failed to show any significant differences (P > 0.1) in the concentration of brain metabolites between the whole-brain-irradiated and sham-irradiated rats. In contrast, analysis of the MR spectra obtained 52 weeks postirradiation revealed significant differences between the irradiated and sham-irradiated rats in the concentrations of several brain metabolites, including increases in the NAA/tCr (P < 0.005) and Glx/tCr (P < 0.001) ratios and a decrease in the mI/tCr ratio (P < 0.01). Although the cognitive function of these rats measured by the object recognition test was not significantly different (P > 0.1) between the irradiated and sham-irradiated rats at 14 weeks postirradiation, it was significantly different (P < 0.02) at 54 weeks postirradiation. These findings suggest that MRS may be a sensitive, noninvasive tool to detect changes in radiation-induced brain metabolites that may be associated with the radiation-induced cognitive impairments observed after prolonged fractionated whole-brain irradiation.     

Strain- and sex-dependent differences in response to a single high dose of copper in the rat

Rats of either sex of the strains +/rnu, WAG/Cpb and Fischer-344 were injected i.v. with a single dose of Cu (2.5 mg/kg body weight). Hemolysis was observed in the female +/rnu and Fischer rats. Males accumulated more Cu than females in all strains. WAG/Cpb rats had higher kidney Cu concentrations. The lower hepatic Cu concentration in female Fischer rats was not caused by an increased biliary Cu excretion but by a diminished release of Cu from the blood to the liver. In both sexes the degree of hemolysis did not correlate to the Cu concentration of the erythrocytes. It is concluded that a sex-related difference exists in the metabolism of a large dose of Cu and that the Cu-induced hemolysis in females may be related to a prolonged exposure of erythrocytes to an increased Cu concentration of the plasma.     

Tyrosine hydroxylase expression and activity in the rat brain: differential regulation after long-term intermittent or sustained hypoxia.

Tyrosine hydroxylase, a hypoxia-regulated gene, may be involved in tissue adaptation to hypoxia. Intermittent hypoxia, a characteristic feature of sleep apnea, leads to significant memory deficits, as well as to cortex and hippocampal apoptosis that are absent after sustained hypoxia. To examine the hypothesis that sustained and intermittent hypoxia induce different catecholaminergic responses, changes in tyrosine hydroxylase mRNA, protein expression, and activity were compared in various brain regions of male rats exposed for 6 h, 1 day, 3 days, and 7 days to sustained hypoxia (10% O(2)), intermittent hypoxia (alternating room air and 10% O(2)), or normoxia. Tyrosine hydroxylase activity, measured at 7 days, increased in the cortex as follows: sustained > intermittent > normoxia. Furthermore, activity decreased in the brain stem and was unchanged in other brain regions of sustained hypoxia-exposed rats, as well as in all regions from animals exposed to intermittent hypoxia, suggesting stimulus-specific and heterotopic catecholamine regulation. In the cortex, tyrosine hydroxylase mRNA expression was increased, whereas protein expression remained unchanged. In addition, significant differences in the time course of cortical Ser(40) tyrosine hydroxylase phosphorylation were present in the cortex, suggesting that intermittent and sustained hypoxia-induced enzymatic activity differences are related to different phosphorylation patterns. We conclude that long-term hypoxia induces site-specific changes in tyrosine hydroxylase activity and that intermittent hypoxia elicits reduced tyrosine hydroxylase recruitment and phosphorylation compared with sustained hypoxia. Such changes may not only account for differences in enzyme activity but also suggest that, with differential regional brain susceptibility to hypoxia, recruitment of different mechanisms in response to hypoxia will elicit region-specific modulation of catecholamine response.     

Development of the vasculature of the pars distalis in a tumor-susceptible strain of rat (Fischer 344) differs from vascular development in a non-tumor-susceptible strain (Lewis)

The development of the vasculature of the pars distalis of two strains of rat, Fischer 344 (F344) and Lewis (LEW), was followed in 16-day (16d) and 20-day (20d) fetuses, and in 1-day (1d), 5d, 20d, 50d, and 6-month-old females. No differences in the two strains were apparent in 16d fetuses; and the capillaries that were present were immature, i.e., tall, non-fenestrated endothelial cells, and were surrounded by poorly delineated pericapillary spaces. Immature capillaries also were predominant in 20d fetuses of both strains. Agranular folliculo-stellate cells were identifiable, projecting endfeet to the parenchymal basal lamina in 20d F344 fetuses, but not in LEW fetuses. Postnatally, the capillaries of LEW rats became progressively more thin-walled and fenestrated, and were surrounded by a pericapillary space that was well delimited by basal laminae at 20d. In 50d and 6-month LEW rats, capillaries were intact and surrounded by well-defined pericapillary spaces. By comparison in F344 rats, the capillaries remained more immature even in 50d rats and older. In addition, in F344 rats focal disruptions in endothelial cells and disruptions in parenchymal and capillary basal laminae were present in all postnatal stages, and a dramatic accumulation of plasma was evident within the pericapillary spaces at 20d. Endfeet processes of folliculo-stellate cells were abundant at the parenchymal basal lamina of 1d and 5d F344 neonates, but only rarely were identified in LEW neonates. Some activation of folliculo-stellate cells, i.e., increased numbers of lysosomes and dilated endoplasmic reticulum, was present in 50d F344 rats. Connective-tissue cells within the pericapillary space also were numerous and activated in F344 rats. Discrete gaps in the parenchymal basal lamina were evident subjacent to the folliculo-stellate cell endfeet in F344 rats but not in LEW rats. The vascular bed of F344 rats differs in its development from that of LEW rats. Characteristic of the F344 strain is a persistence of more immature capillaries, an inherent vascular fragility, and an activated state of folliculo-stellate cells.     

α-Linolenic Acid Dietary Deficiency Alters Age-Related Changes of Dopaminergic and Serotoninergic Neurotransmission in the Rat Frontal Cortex

Abstract: The effects of α-linolenic acid diet deficiency on rat dopaminergic and serotoninergic neurotransmission systems were investigated in the frontal cortex, striatum, and cerebellum of male rats 2, 6, 12, and 24 months of age. The diet deficiency induced a severe decrease in the 22:6n-3 fatty acid levels in all regions and a compensatory increase in n-6 fatty acid levels. A recovery in the levels of 22:6n-3 was observed in deficient rats between 2 and 12 months of age; however, this recovery was lower in frontal cortex than in striatum and cerebellum. In the striatum and the cerebellum, dopaminergic and serotoninergic receptor densities and endogenous dopamine and serotonin levels were affected by aging regardless of the diet. In contrast, a 40–75% lower level of endogenous dopamine in the frontal cortex occurred in deficient rats according to age. The deficiency also induced an 18–46% increase in serotonin 5-HT₂ receptor density in the frontal cortex during aging, without variation in endogenous serotonin level, and a 10% reduction in density of dopaminergic D₂ receptors. Monoamine oxidase-A and -B activities showed specific age-related variations but regardless of the diet. Our results suggest that a chronically α-linolenic-deficient diet specifically affects the monoaminergic systems in the frontal cortex.     

High IFN－α expression is associated with the induction of experimental autoimmune uveitis （EAU） in Fischer 344 rat

INTRODUCTIONThe CD4 T cells can be subdivided intoTh1 and Th2 subsets based on their secreted cy-tokine profile. Th1 cells characteristical1y secreteInterferonry (IFN--ry), whereas Th2 cells maiuly pro--duce IL--4[1]. IL-12 po1arizes the differentiation ofnaitre, CD4 T cells towards Th1 pathWay, in con-trast IL--4 directs T cell differentiation towards Th2pathWay The broken balance between Th1 and Th2immune responses and predominant Th1 responseare crucial factors in initiation…     

Resistance of Fischer 344 rats to deoxycorticosterone hypertension

Implantation of one 40 mg pellet of DOCA causes hypertension in the majority of young female Sprague-Dawley rats within three weeks without removal of a kidney or adding salt to the diet. Similar identically-treated Fischer 344 rats remain normotensive. If one kidney is removed and 1% saline is given to drink, the hormone dosage causes hypertension in rats of both strains, although even here Fischer 344 rats develop the disorder more slowly and less severely. It is concluded that for rat strains resistant to mineralocorticoid hypertension, sensitization is necessary for its induction, whereas for susceptible strains it is not. Fischer 344 rats appear to have higher levels of resting serum renin activity than Sprague-Dawley rats, but the relationship that this bears to hypertension susceptibility is unknown.     

Selective brain responses to acute and chronic low-dose X-ray irradiation in males and females

Radiation exposure is known to have profound effects on the brain, leading to precursor cell dysfunction and debilitating cognitive declines [Nat. Med. 8 (2002) 955]. Although a plethora of data exist on the effects of high radiation doses, the effects of low-dose irradiation, such as ones received during repetitive diagnostic and therapeutic exposures, are still under-investigated [Am. J. Otolaryngol. 23 (2002) 215; Proc. Natl. Acad. Sci. USA 97 (2000) 889; Curr. Opin. Neurol. 16 (2003) 129]. Furthermore, most studies of the biological effects of ionizing radiation have been performed using a single acute dose, while clinically and environmentally relevant exposures occur predominantly under chronic/repetitive conditions. Here, we have used a mouse model to compare the effects of chronic/repetitive and acute low-dose radiation (LDR) exposure (0.5Gy) to ionizing radiation on the brain in vivo. We examined the LDR effects on p42/44 MAPK (ERK1/ERK2), CaMKII, and AKT signaling-the interconnected pathways that have been previously shown to be crucial for neuronal survival upon irradiation. We report perturbations in ERK1/2, AKT, and CREB upon acute and chronic/repetitive low-dose exposure in the hippocampus and frontal cortex of mice. These studies were paralleled by the analysis of radiation effects on neurogenesis and cellular proliferation. Repetitive exposure had a much more pronounced effect on cellular signaling and neurogenesis than acute exposure. These results suggest that studies of single acute exposures might be limited in terms of their predictive value. We also present the first evidence of sex differences in radiation-induced signaling in the hippocampus and frontal cortex. We show the role of estrogens in brain radiation responses and discuss the implications of the observed changes.