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Highlights • Ageing of populations worldwide is leading to an unprecedented increase in cancer cases and fatalities. • Spalax ehrenbergi superspecies are considered an excellent model for ageing and, additionally, for cancer research. • Spalax mechanisms to prevent cell damage provide useful clues to improve the quality of human life. Abstract Cancer and ageing can be regarded as two different manifestations of the same underlying process—accumulation of cellular damage—and therefore both are closely linked. Nowadays, the ageing of populations worldwide is leading to an unprecedented increase in cancer cases and fatalities, and therefore the understanding of links between cancer and ageing is more important than ever. Spalax is considered an excellent model for ageing and, additionally, for cancer research, due to not show clear age-related phenotypic changes and not develop spontaneous tumours, despite its relatively long lifespan (∼20 years in captivity). Thereby, the purpose of this review is to summarize the recent knowledge on Spalax, with a particular emphasis on the molecular mechanisms associated with their longevity and cancer resistance. [ABSTRACT FROM AUTHOR]

This study develops a new proxy for Quaternary temperature change in tropical Africa through analysis of size variation in East African mole-rat ( Tachyoryctes splendens ). In modern mole-rats, mandibular alveolar length is unrelated to annual precipitation, precipitation seasonality, temperature seasonality, or primary productivity. However, it is inversely correlated with mean annual temperature, in agreement with Bergmann's rule. This relationship is observed at temperatures below ∼17.3 °C, but not at higher temperatures. We apply these observations to late Quaternary mole-rats from Wakondo (∼100 ka) and Kisaaka (∼50 ka) in the Lake Victoria region and Enkapune ya Muto (EYM; ∼7.2–3.2 ka) in Kenya's central rift. The Lake Victoria mole-rats are larger than expected for populations from warm climates typical of the area today, implying cooler temperatures in the past. The magnitude of temperature decline needed to drive the size shift is substantial (∼4–6 °C), similar in magnitude to the degree of change between the Last Glacial Maximum and Holocene, but is consistent with regional temperature records and with scenarios linking equatorial African temperature to northern hemisphere summer insolation. Size changes through time at EYM indicate that rising temperatures during the middle Holocene accompanied and potentially contributed to a decline in Lake Naivasha and expansion of grassland vegetation. [ABSTRACT FROM AUTHOR]

The Nrf2–Keap1 pathway is crucial for the cellular antioxidant and hypoxia response in vertebrates. Deciphering its modifications in hypoxia-adapted animals will help understand its functionality under environmental stress and possibly allow for knowledge transfer into biomedical research. The blind mole rat Spalax , a long-lived cancer-resistant rodent, lives in burrows underground and is adapted to severely hypoxic conditions. Here we have conducted a bioinformatical survey of Spalax core genes from the Nrf2–Keap1 pathway on the coding sequence level in comparison to other hypoxia-tolerant and -sensitive rodents. We find strong sequence conservation across all genes, illustrating the pathway's importance. One of the central players however, Spalax Keap1, shows a non-conservative amino acid substitution from tyrosine to cysteine in its intervening region (IVR) domain. Cysteines in this location have been shown to be of high functional relevance to the binding and degradation of Nrf2. Therefore, this peculiar substitution could influence the cellular Nrf2 levels in Spalax and, thereby, downstream gene expression in the antioxidant pathway, contributing to the special adaptive phenotype of the blind mole rat. [ABSTRACT FROM AUTHOR]

Abstract: Rhizomys, one of the most derived genera within the tribe Rhizomyini (Rhizomyinae, Spalacidae, Rodentia), comprises three species: Rhizomys sinensisGray, 1831, R. pruinosusBlyth, 1851 and R. sumatrensis (Raffles, 1821). A detailed description of the morphology and wear pattern of the cheek teeth of this taxon is provided based on the study of 41 skulls. The variability tracked is due primarily to wear, control of which facilitates comparison of different individuals, fossil or not, at different wear stages. For the first lower and upper molars, six stages of wear (0–5) are recognized. The second lower and upper molars show five stages of wear (0–4), whereas the third ones have four (0–3). The dental wear pattern in Rhizomys is comparable to that of the Pliocene Brachyrhizomys shansiusTeilhard de Chardin, 1942. [Copyright &y& Elsevier]

Abstract: Until recently, zokors (Myospalacinae) were assigned to the Cricetidae family. However, analysis of mitochondrial and nuclear genes suggests a sister relationship between zokors and subterranean rodents of the Spalacidae family, namely blind mole rats (Spalacinae) and bamboo rats (Rhizomyinae). Here, we cloned and sequenced copies of the B1 short interspersed element (SINE) from the genome of zokor Myospalax psilurus. The consensus nucleotide sequence of zokor B1 was very similar to spalacids and rhizomyids, but not cricetids. Similar to spalacids (Spalax microphthalmus) and rhizomyids (Tachyoryctes splendens), zokor contained two variants of the 4.5SI small nuclear RNA. The longer variant (L-variant, 104 nucleotides) was found only in zokor, spalacids and rhizomyids. The short, or S-variant (98 nucleotides), had a wider distribution; however, analysis of the nucleotide sequences of S-variants of 4.5SI RNA confirmed that zokors are closely related to spalacids and rhizomyids, but not to cricetids. The evolution of the 4.5SI RNA genes and pseudogenes is discussed. [Copyright &y& Elsevier]

Abstract: Changes in 5-HT1A receptor-mediated neurotransmission at the level of the median raphe nucleus (MRN) are reported to affect the expression of defensive responses that are associated with generalized anxiety disorder (e.g. inhibitory avoidance) but not with panic (e.g. escape). The objective of this study was to further explore the involvement of MRN 5-HT1A receptors in the regulation of generalized anxiety-related behaviours. Results of experiment 1 showed that intra-MRN injection of the 5-HT1A/7 receptor agonist 8-OH-DPAT (0.6nmol) in male Wistar rats impaired the acquisition of inhibitory avoidance, without interfering with the performance of escape in the elevated T-maze test of anxiety. Pre-treatment with the 5-HT1A receptor antagonist WAY-100635 (0.18nmol) fully blocked this anxiolytic-like effect. As revealed by experiment 2, intra-MRN injection of 8-OH-DPAT (0.6, 3 or 15nmol) also caused anxiolytic effect in rats submitted to the light–dark transition test, another animal model that has been associated with generalized anxiety. In the same test, intra-MRN injection of WAY-100635 (0.18, 0.37 or 0.74nmol) caused the opposite effect. Overall, the current findings support the view that MRN 5-HT neurons, through the regulation of 5-HT1A somatodendritic autoreceptors, are implicated in the regulation of generalized anxiety-associated behaviours. [Copyright &y& Elsevier]

Abstract: We evaluated whether changes in protein content and activity of PP-1 and PP-2A were the mechanism underneath the basal age-related reduction in α2/3-Na,K-ATPase activity in rats cerebella and whether this occurred through the cyclic GMP-PKG pathway. PP1 activity, but not its expression, increased with age, whereas PP-2 was not changed. The activity of α2/3-Na,K-ATPase varied with age, and there was a negative association between the PP-1 and α2/3-Na,K-ATPase activities. In young rats, the inhibition of PP-1 and PP-2A by okadaic acid (OA) increased in a dose-dependent manner α1- and α2/3-Na,K-ATPase, but had no effect on Mg-ATPase activity. A direct stimulation of PKG with 8-Br-cyclic GMP did not surmount the effect of OA. This analogue of cyclic GMP inhibited PP-1 activity only, indicating that at least part of the increase in α1- and α2/3-Na,K-ATPase activity induced by OA was mediated by the cyclic GMP-PKG-PP-1 cascade. Taking into account that PP1 inhibition increased α2/3-Na,K-ATPase activity, we propose that an age-related increase in PP-1 activity due to a decrease in cyclic GMP-PKG modulation plays a role for the age-related reduction of α2/3-Na,K-ATPase activity in rat cerebellum. [Copyright &y& Elsevier]

Abstract: Binge eating is more common in females than in males. This study investigated the effects of ovarian hormones on binge-eating behavior in a diet-related rat model. Six groups of ovariectomized Sprague–Dawley rats were used (n =13/group). All rats had continuous access to chow and water throughout the study. One half of the rats were injected every fourth day with estradiol benzoate (2 µg/100 µl sesame oil) and progesterone (500 µg/100 µl sesame oil); the other half received only the sesame oil vehicle. Three feeding protocols were tested in each hormone injection condition: (1) chow only: no additional dietary fat access; (2) low-restriction: 1-h fat access every day; (3) high-restriction: 1-h fat access on Monday, Wednesday, and Friday. As previously reported in intact male and female rats, the high-restriction groups exhibited binge-like increases in 1-h energy intake during fat access. The major new finding of this study is that 1-h energy intake was tonically, but not cyclically, reduced in the hormone-treated high-restriction (binge) rats. Specifically, both low- and high-restriction hormone-treated rats consumed significantly less energy than did the oil-treated rats during the 1-h fat period (p <0.0001) and overall (p <0.0001), indicating a tonic inhibition of eating. However, food intake during the 1-h fat access period was also cyclically reduced in the hormone-treated low-restriction rats, but not in the hormone-treated high-restriction rats. These results indicate that the normal cyclic inhibitory influence of ovarian hormones on eating, but not their normal tonic inhibitory influence, is disrupted by conditions leading to binge-type eating. [Copyright &y& Elsevier]

Abstract: The purpose of the present study was to examine the impact of nutritional supplementation with essential omega 3 and 6 fatty acids on CA1 neuronal death and recovery of functional impairments following global ischemia. Groups of Wistar male rats were randomly assigned to four experimental conditions determined by the consumed diet and surgical condition. Rats either received a standard diet (SD; Purina 5012) or a 15% PUFA supplemented diet (FO+CO) prepared by adding 11.5% (w/w) fish oil from menhaden fish and 3.5% corn oil to standard rat chow. Diet conditions were initiated in 30 day old rats and maintained for an 18-week period (pre- and post-surgery). Sham or 8-min global ischemic surgeries occurred during the 13th feeding week and behavioral testing took place following reperfusion for an additional 4 weeks, after which all rats were euthanized. Our findings revealed significant loss of pyramidal CA1 neurons 31 days post ischemia in ischemic as compared to sham-operated rats but no difference between ischemic animals fed the SD or PUFA supplemented diets. In the radial arm maze, SD ischemic rats took longer time to complete the task and made significantly more working memory errors than PUFA ischemic and sham-operated animals. Independent of the diet, ischemic animals appeared less anxious in the elevated plus maze, spending considerably more time in the open arms as compared to sham-operated rats. Taken together, these results suggest that fish oil supplemented diet exerts beneficial effect on ischemia-induced spatial memory deficits despite protective effects on CA1 hippocampal neurons. [Copyright &y& Elsevier]

Abstract: Artichoke is a plant with antioxidant properties. In this study, we investigated the effect of artichoke extract pretreatment on carbon tetrachloride (CCl4)-induced oxidative stress and hepatotoxicity. Rats were given artichoke leaf extract (1.5g/kg/day) by gavage for 2 weeks and after then CCl4 (1ml/kg; i.p.) was applied. All rats were killed 24h after the CCl4 injection. CCl4 administration resulted in hepatic necrosis and significant increases in plasma transaminase activities as well as hepatic malondialdehyde (MDA) and diene conjugate (DC) levels in the liver of rats. Glutathione (GSH) and vitamin C levels decreased, but vitamin E levels increased in the liver of CCl4-treated rats. Hepatic superoxide dismutase (SOD) activities remained unchanged, but glutathione peroxidase (GSH-Px) and glutathione transferase (GST) activities decreased following CCl4 treatment. In rats pretreated with artichoke extract, significant decreases in plasma transaminase activities and amelioration in histopathological changes in the liver were observed following CCl4 treatment as compared to CCl4-treated rats. In addition, hepatic MDA and DC levels decreased, but GSH levels and GSH-Px activities increased without any change in other antioxidant parameters following CCl4 treatment in artichoke-pretreated rats. The present findings indicate that in vivo architoke extract administration may be useful for the prevention of oxidative stress-induced hepatotoxicity. [Copyright &y& Elsevier]

Abstract: Rats have an inborn preference for sweet taste and learn to prefer flavors associated with sweetness. They are also strongly attracted to the taste of glucose polymers (e.g., Polycose). This “poly” taste differs in quality from the sweet taste of sugar. To determine if poly taste, like sweet taste, conditions flavor preferences rats were trained with a distinctive flavor (CS+) added to 2% Polycose solution and a different flavor (CS−) added to plain water. In a subsequent two-bottle test the rats did not prefer the CS+ to CS− when both flavors were presented in water. In contrast, other rats significantly preferred a CS+ flavor that had been paired with 2% sucrose. Adding saccharin to a flavored Polycose solution did not improve CS+ flavor learning; rather, Polycose appeared to overshadow saccharin-induced conditioning. Flavor conditioning by a 16% Polycose solution was assessed using a sham-feeding procedure to prevent post-oral reinforcement. Although the rats sham-fed substantial amounts of the CS+ flavored Polycose solution, they failed to prefer the CS+ to the CS− flavor. This contrasts with the preference other rats displayed for a CS+ paired with sham-fed sucrose. Why attractive sweet and poly tastes differ in their ability to condition flavor preferences is not certain, although some findings suggest that they differentially activate dopamine and/or serotonin circuits involved in flavor learning. [Copyright &y& Elsevier]

Abstract: The need to obtain data from individual laboratory animals has forced many researchers to singly-house small animals. This is costly to the researcher and isolation can adversely affect animal physiology and behavior which in turn may threaten the validity and generalization of experiment results to humans. We assessed the practical use of a housing device – dubbed “Buddy Barrier” (BB) – that allows social stimulation in a paired-housing situation while at the same time permitting the collection of individual measures that traditionally require individual-housing. To assess stress responses to the BB, adult male rats were single or pair-housed for several days with and without a BB in the cage. Fecal corticosterone metabolites (fCORT), food intake and body weight were monitored daily. Plasma CORT and adrenal catecholamine levels were assessed at the end of the housing manipulation. Stress hormone measures did not differ in paired vs. singly-housed rats and paired rats quickly habituated to introduction and removal of the BB. Barring a trend for paired rats to eat more in the first 4 h of the dark, there was no difference in 24 h intakes or body weight gain between singly and paired-housed rats. While the BB attenuated 24 h intakes in both groups, intakes normalized to non-BB conditions by the third BB reintroduction. A device such as the BB can enhance the welfare of animals by providing social enrichment without compromising the integrity of experimental protocols traditionally requiring single-housing. In times of lagging research funding it can also substantially reduce housing costs. [Copyright &y& Elsevier]

Abstract: Ketamine is a selective NMDA glutamate receptor antagonist that disrupts cognitive and behavioral function. Evidence exists that NMDA receptors play a role in lateral cortical connections, suggesting involvement in integrating information across the cortex. To investigate NMDA receptors'' role in cortical integration at a perceptual level, psychophysical measures were made of perceptual grouping, which requires global analysis of neural representations of stimulus elements. Rats were trained to discriminate solid lines as well as patterns of dots that could be perceptually grouped into vertical or horizontal stripes. Psychophysical measures determined thresholds of perceptual grouping capacities. Rats receiving maximum subanesthetic doses of Ketamine discriminated solid patterns normally, but were impaired on dot pattern discrimination when greater demands were placed on perceptual grouping. These results demonstrate a selective disruption by Ketamine of visual discrimination that requires perceptual grouping of stimulus patterns. These results also provide evidence associating NMDA receptor-dependent neural mechanisms with context-dependent perceptual function. [Copyright &y& Elsevier]

Abstract: It has been demonstrated that, on abrupt withdrawal, patients with chronic exposure can experience a number of symptoms indicative of a dependent state. In clinical patients, the earliest to arise and most persistent signal of withdrawal from chronic benzodiazepine (Bzp) treatment is anxiety. In laboratory animals, anxiety-like effects following abrupt interruption of chronic Bzp treatment can also be reproduced. In fact, signs that oscillate from irritability to extreme fear behaviours and seizures have been described already. As anxiety remains one of the most important symptoms of Bzp withdrawal, in this study we evaluated the anxiety levels of rats withdrawn from diazepam. Also studied were the effects on the motor performance and preattentive sensory gating process of rats under diazepam chronic treatment and upon 48-h withdrawal on three animal models of anxiety, the elevated plus-maze (EPM), ultrasonic vocalizations (USV) and startle+prepulse inhibition tests. Data obtained showed an anxiolytic- and anxiogenic-like profile of the chronic intake of and withdrawal from diazepam regimen in the EPM test, 22-KHz USV and startle reflex. Diazepam chronic effects or its withdrawal were ineffective in promoting any alteration in the prepulse inhibition (PPI). However, an increase of PPI was achieved in both sucrose and diazepam pretreated rats on 48-h withdrawal, suggesting a procedural rather than a specific effect of withdrawal on sensory gating processes. It is also possible that the prepulse can function as a conditioned stimulus to informing the delivery of an aversive event, as the auditory startling-eliciting stimulus. All these findings are indicative of a sensitization of the neural substrates of aversion in diazepam-withdrawn animals without concomitant changes on the processing of sensory information. [Copyright &y& Elsevier]

Abstract: Glutaric acidemia type I (GA I) is an autosomal recessive metabolic disorder caused by glutaryl-CoA dehydrogenase deficiency leading to predominant accumulation of glutaric acid (GA), and to a lesser extent of 3-hydroxyglutaric acid (3HG) in body fluids and tissues. The clinical manifestations of GA I are predominantly neurological. Although the pathophysiological mechanisms responsible for the brain damage of this disease are virtually unknown, they are thought to be due to the neurotoxic actions of GA and 3HG. Therefore, in the present work we investigated whether chronic exposure of GA (5μmolg of body weight−1, twice per day), the major metabolite accumulating in GA I, during early development (from the 5th to the 28th day of life) could alter the cognitive performance of adult rats in the Morris water maze, open field and elevated plus maze tasks. Control rats were treated with saline in the same volumes. GA administration provoked an impairment of spatial performance in the water maze since adult rats pretreated with GA were not able to remember the previous location of the platform spending significantly less time in the training quadrant. In contrast, GA chronic administration did not affect rat performance in the open field and elevated plus maze tasks, indicating that motor activity and anxiety was not changed by GA. The results provide evidence that early chronic GA treatment induces long-lasting spatial behavioral deficit. [Copyright &y& Elsevier]

Objective: To study the effect of vasocation intestinal peptide (VIP) on immune privilege of the rat testis. Methods: The UU infected SD rats and Leydig cells were intervened by VIP, the secretion of TGF-β and the expression of FasL in rat Leydig cells were compared between VIP-intervened group and control group to test the effect of VIP on immune privilege of the rat testis in vitro and in vivo. Results: In vitro, the secretion of TGF-β in Leydig cells could be increased by low dosage of VIP while inhibitited by high dosage of VIP; expression of FasL mRNA in Leydig cells could be decreased by VIP. In vivo, increased expression of TGF-β mRNA and decreased FasL mRNA were observed in VIP group in 2–3 weeks after infected by UU. In addition, the apoptosis of Jurkat cells mediated by Leydig cells could be prevented by VIP. Conclusion: When Leydig cells or testis infected by UU, VIP could regulate the immune function of rat Leydig cells and participate in the regulation of immune privilege of testis through the regulation of TGF-β secretion and FasL expression pattern of Leydig cells. [Copyright &y& Elsevier]

Abstract: Seasonal changes are often gone with mood and behaviour changes which are probably linked to change in day length or photoperiod. The experiments developed in this work are based on the hypothesis that changes in photoperiod affect emotionality in rats. To check this hypothesis, female rats were exposed to four different photoperiods (LP: 16L/8D; MP: 12L/12D; SP: 8L/16D; SP-F: 8L/16D with a light pulse in midpoint of the dark phase). Eight or 14 weeks later, rats were subjected to two behavioural tests to quantify anxiety level. Independently of duration, rats exposed to SP exhibited higher levels of anxious-like behaviour than rats raised in LP and SP-F, in an open field test (OFT) and in elevated plus maze (EPM). Significant differences in EPM are obtained only after 14 weeks of treatment. Moreover rats treated more long time showed greater suprarenal gland mass. Compared to all other groups, females exposed to SP had greater suprarenal gland. Our results indicate that changes in day length are associated with different levels of anxious-like behaviours consistent with the conjecture that short days may have an anxiogenic effect in female rats. [Copyright &y& Elsevier]

Abstract: Behavioral disinhibition, a component of impulsivity, has been associated with cocaine abuse and dependence. To examine the relationship between behavioral disinhibition and vulnerability to cocaine use disorders, we employed the high responder (HR)/low responder (LR) rodent model, in which rats that exhibit high levels of activity in response to a novel environment are more sensitive to the effects of psychostimulants. In Experiment 1, performance under a differential reinforcement of low-rate (DRL) schedule was used as a measure of behavioral disinhibition in HR and LR rats. The HR rats displayed more behavioral disinhibition relative to LR rats on the DRL 20- and 35-s schedules. In Experiment 2, rats were divided into groups with high disinhibition (HD) and low disinhibition (LD) based on DRL 20-s performance, then challenged with cocaine. Rats characterized as HD and LD had similar DRL 20-s performance to rats characterized as HR and LR (Experiment 1), respectively, but did not differ in their response to cocaine. The results of this study suggest that the HR phenotype may also be characterized by greater behavioral disinhibition, and that the DRL task is a suitable animal model to investigate the role of behavioral disinhibition in vulnerability to the behavioral effects of cocaine. [Copyright &y& Elsevier]

Abstract: Cav1.2 L-type calcium channels are essential in heart and smooth muscle contraction. Rat Cav1.2 gene contains 11 alternatively spliced exons (1a, 1, 8a, 8, 9⁎, 21, 22, 31, 32, 32-6nt and 33) which can be assorted to generate a large number of functionally distinct splice variants. Until now, it is unknown whether the utilization of these alternatively spliced exons is altered in the hypertrophied hearts of hypertensive rats. By comparing the assortments of these 11 exons in full-length Cav1.2 transcripts derived from Spontaneously Hypertensive Rats (SHRs) and Wistar Kyoto Rats (WKYs) hearts, we found that the inclusion of Cav1.2 alternative exons was significantly different between the two rats both at individual loci and in combinatorial arrangements. Functional characterizations of three Cav1.2 channel splice variants that were identified to be significantly altered in SHR hypertrophied cardiomyocytes demonstrated distinct whole-cell electrophysiological properties when expressed in HEK 293 cells. Interestingly, aberrant splice variants which included or excluded both mutually exclusive exons 21/22 or exons 31/32 were found to be increased in hypertensive rats. Two aberrant splice variants that included both exons 21 and 22 were found to be unable to conduct currents even though they expressed proteins with the predicted molecular mass. Characterization of one of the aberrant splice variants showed that it exerted a dominant negative effect on the functional Cav1.2 channels when co-expressed in HEK293 cells. The altered combinatorial splicing profiles of Cav1.2 transcripts identified in SHR hearts provide a different and new perspective in understanding the possible role of molecular remodeling of Cav1.2 channels in cardiac hypertrophy as a consequence of hypertension. [Copyright &y& Elsevier]

Abstract: Footshock stress induces both endocannabinoid mobilization and antinociception. The present studies investigated behavioral plasticity in cannabinoid antinociceptive mechanisms following repeated activation using the tail-flick test. A secondary objective was to ascertain whether blockade of stress antinociception by the CB1 antagonist rimonabant could be attributed to changes in locomotor activity. The cannabinoid agonist WIN55,212-2 induced hypoactivity in the open field relative to vehicle-treated controls. By contrast, rimonabant, administered at a dose that virtually eliminated endocannabinoid-mediated stress antinociception, failed to alter locomotor behavior (i.e. time resting, ambulatory counts, distance traveled) in rats subjected to the same stressor. Rats exposed acutely to footshock were hypersensitive to the antinociceptive effects of WIN55,212-2 and Δ9-tetrahydrocannabinol (Δ9-THC). The converse was also true; acute Δ9-THC and WIN55,212-2 administration potentiated stress antinociception, suggesting a bidirectional sensitization between endocannabinoid-mediated stress antinociception and exogenous cannabinoid antinociception. Stress antinociception was also attenuated following chronic relative to acute treatment with WIN55,212-2 or Δ9-THC. Repeated exposure to footshock (3min/day for 15days), however, failed to attenuate antinociception induced by either footshock stress or WIN55,212-2. Our results demonstrate that endocannabinoid-mediated stress antinociception cannot be attributed to motor suppression. Our results further identify a functional plasticity of the cannabinoid system in response to repeated activation. The existence of cross-sensitization between endocannabinoid-mediated stress antinociception and exogenous cannabinoid antinociception suggests that these phenomena are mediated by a common mechanism. The observation of stress-induced hypersensitivity to effects of exogenous cannabinoids may have clinical implications for understanding marijuana abuse liability in humans. [Copyright &y& Elsevier]

Abstract: Three experiments examined appetitive trace and delay conditioning of the licking response (LR). In Experiment 1, normal rats were trained in trace conditioning using different trace intervals (2, 4, or 8s) and in delay conditioning (i.e., with a 0-s trace) in order to determine an appropriate trace interval for the following lesion experiments. Only the rats trained with a 2-s trace interval ultimately reached the same level of learning as rats trained in delay conditioning. In Experiments 2A and 2B, the performance of rats with dorsal, ventral, and complete excitotoxic hippocampal lesions was compared to that of sham-operated rats in LR conditioning with a 2-s trace. In Experiment 2B, the performance of rats in trace LR conditioning was also compared to that of rats tested in the delay paradigm. In both experiments, acquisition did not differ in lesioned and sham-operated rats and, in Experiment 2B, it was faster in the delay than in the trace paradigm. These results contrast with those showing that aversive trace conditioning is impaired after hippocampal damage. Experiment 3 examined whether the differential effects of hippocampal lesions on aversive and appetitive trace conditioning could be related to a parametric difference, that is, the relative durations of the conditional stimulus and of the trace interval. Again, hippocampal damage failed to produce a learning impairment. It is suggested that the procedure of aversive, but not of appetitive, trace conditioning is context-specific and that an intact hippocampus is required only in these situations. [Copyright &y& Elsevier]

Abstract: Objective: To investigate the distribution of the motilin receptor in the amygdala of rats and its role in regulating the duodenal migrating myoelectric complex (MMC). Methods: The distribution of motilin receptor in the amygdala in adult SD rats was detected by immunohistochemistry methods, and the duodenal interdigestive MMC was recorded via the electrodes implanted in the duodenum and analyzed using a multichannel recorder. Results: Motilin receptor was observed in the amygdala of rats. The great amount of motilin receptor was found in the medial amygdaloid nucleus, which was also abundant in the basolateral nucleus but less abundant in the basomedial amygdaloid nucleus, the central amygdaloid nucleus and the lateral amygdaloid nucleus. The shortening of the duodenal MMC cycle duration and the increase of the amplitude and the frequency of phase III were recorded after motilin receptors being bound with exogenous motilin in the amygdala. The effects could be completely blocked by the subdiaphragmatic vagotomy but not by the intravenous injections of atropine, phentolamine or propranolol. Anti-motilin serum could partially block these effects, and the destruction of the basolateral nucleus of the amygdala had no significant effects on the duodenal MMC. Conclusion: Motilin receptor is present in all the subnuclei of the amygdala, with the greatest amount of motilin receptor present in the medial amygdaloid nucleus. Microinjections of motilin in the amygdala can shorten the duodenal MMC cycle duration and increase the amplitude and the frequency of phase III. These effects might be accomplished via the amygdala-hypothalamus-brainstem-vagus pathway, indicating the important role of the amygdala motilin receptor in the duodenal MMC regulation. [Copyright &y& Elsevier]

Abstract: The aim of the present study is to investigate the changes in hippocampal synapses and their relation with learning-memory abilities at different ages, and evaluate the effects of 2,3,5,4′-tetrahydroxystilbene-2-O-β-d-glucoside (TSG), which is one of the major components of a traditional Chinese herb Polygonum multiflorum, on brain aging. Sprague–Dawley rats at the age of 1, 3, 6, 18 and 24 months were used. TSG at doses of 30 and 60 mg/kg/day was intragastrically administered to 21-month-old rats for 3 months, respectively. Learning-memory abilities were determined by Morris water maze and passageway water maze tests. The ultrastructure of synapses in the hippocampal CA1 region was observed by electronic microscopy. The expression of synaptophysin (SYP) in whole hippocampus was measured by using immunohistochemistry. Compared with rats at 6 months of age, both the 1-month-old rats and 24-month-old rats showed longer escape latency and swimming distance in the Morris water maze test, while more errors were detected in the passageway water maze test, with a smaller number of synapses and synaptic vesicles and less expression of SYP in the hippocampus. Treatment with high-dose TSG in rats at 24 months of age had significant improvement in the learning-memory abilities in the water maze tests associated with an increase in the number of synapses and synaptic vesicles, and an elevation of expression of SYP in the hippocampus. In conclusion, hippocampal synapses count and synaptophysin expression decreased in aged rats, which may be one of the mechanisms involved in learning-memory deficit. TSG reversed the above changes in aged rats, suggesting that TSG may be beneficial for the treatment of Alzheimer disease or cognitive impairment in old people. [Copyright &y& Elsevier]

Background & Aims: The neurobiologic basis of pancreatic hyperalgesia in chronic pancreatitis (CP) is understood poorly and there is a need to identify novel therapeutic targets. Our aim was to study the role of the transient receptor potential vanilloid 1 (TRPV1), a key integrator of noxious stimuli, in the pathogenesis of pancreatic pain in a rat model of CP. Methods: CP was induced in rats by intraductal injection of trinitrobenzene sulfonic acid. TRPV1 currents in pancreas-specific DRG neurons were measured using perforated patch-clamp techniques. Reverse-transcription polymerase chain reaction was used to measure mRNA expression of TRPV1 in these neurons after laser capture microdissection. Immunofluorescence and Western blot analysis, using TRPV1-specific antibodies, also were performed. Pancreatic hyperalgesia was assessed by rat’s nocifensive behavior to electrical stimulation of the pancreas. Results: CP was associated with a 4-fold increase in capsaicin-induced current density (P < .02), along with an increase in the proportion of pancreas-specific DRG neurons that responded to capsaicin (52.9% in controls vs 79.0% in CP; P < .05). CP also was associated with a significant increase in TRPV1 expression both at the messenger RNA and protein level in whole thoracic DRGs and pancreas-specific sensory neurons. Systemic administration of the TRPV1 antagonist SB-366791 markedly reduced both visceral pain behavior and referred somatic hyperalgesia in rats with CP, but not in control animals. Conclusions: TRPV1 up-regulation and sensitization is a specific molecular mechanism contributing to hyperalgesia in CP and represents a useful target for treating pancreatic hyperalgesia caused by inflammation. [Copyright &y& Elsevier]

Background & Aims: This study examined the possible role of endotoxinemia (from increased gut permeability) as an additional trigger factor for overt pancreatic disease and as a promoter of chronic pancreatic injury in alcoholics by using a rat model of chronic alcohol feeding and in vitro experiments with cultured pancreatic stellate cells (PSCs), the key mediators of pancreatic fibrosis. Methods: In the in vivo model, Sprague-Dawley rats fed isocaloric Lieber-DeCarli liquid diets ± alcohol for 10 weeks were challenged with a single dose or 3 repeated doses of the endotoxin lipopolysaccharide (LPS) and the pancreas was examined. In the in vitro studies, rat PSCs were assessed for activation on exposure to LPS ± ethanol. The expression of LPS receptors TLR4 and CD14 also was assessed in rat and human PSCs. Results: In the in vivo model, single or repeated LPS challenge resulted in significantly greater pancreatic injury in alcohol-fed rats compared with rats fed the control diet without alcohol. Notably, repeated LPS injections caused pancreatic fibrosis in alcohol-fed rats, but not in rats fed the control diet. In the in vitro studies, PSCs were activated by LPS. Alcohol + LPS exerted a synergistic effect on PSC activation. Importantly, both rat and human PSCs expressed TLR4 and CD14. Conclusions: This study describes, for the first time, a clinically relevant animal model of alcohol-related pancreatic injury and provides strong in vivo and in vitro evidence that suggests that LPS is a trigger factor in the initiation and progression of alcoholic pancreatitis. [Copyright &y& Elsevier]

Abstract: The ability of rats to detect the presence of sinusoidal amplitude modulation (AM) of a broadband noise carrier was determined before and after bilateral ablation of auditory cortex. The rats were trained to withdraw from a drinking spout to avoid a shock when they detected a modulation of the sound. Sensitivity was evaluated by testing the rats at progressively smaller depths of modulation. Psychophysical curves were produced to describe the limits of detection at modulation rates of 10, 100 and 1000Hz. Performance scores were based on the probability of withdrawal from the spout during AM (warning periods) relative to withdrawal during the un-modulated noise (safe periods). A threshold was defined as the depth of modulation that produced a score halfway between perfect avoidance and no avoidance (performance score=0.5). Bilateral auditory cortical lesions resulted in significant elevations in threshold for detection of AM at rates of 100 and 1000Hz. No significant shift was found at a modulation rate of 10Hz. The magnitude of the deficit for AM rates of 100 and 1000Hz was positively correlated with the size of the cortical lesion. Substantial deficits were found only in animals with lesions that included secondary as well as primary auditory cortical areas. The results show that the rat’s auditory cortex is important for processing sinusoidal AM and that its contribution is most apparent at high modulation rates. The data suggest that the auditory cortex is a crucial structure for maintaining normal sensitivity to temporal modulation of an auditory stimulus. [Copyright &y& Elsevier]

Abstract: The aim of this research was to study the effects of estrogen deficiency on the receptor activator of nuclear factor kappa B ligand (RANKL) and osteoprotegerin (OPG) synthesis in the periapical lesions that were induced in ovariectomized (OVX) and sham-ovariectomized (Sham) rats. After mandibles were collected, the enzyme histochemical test for tartrate-resistant acid phosphatase and immunohistochemical examination for RANKL and OPG were performed. On days 0, 7, and 28, the numbers of osteoclasts in the periapical areas of the OVX rats were significantly more than those of the Sham group. The data had statistical differences on days 7, 21, and 28 for RANKL-positive cells between the 2 groups. The number of OPG-positive cells of the OVX rats was more than that of the Sham group at the early stage of estrogen deficiency (day 7). Estrogen deficiency–induced severe periapical bone resorption might be mediated by overexpression of RANKL. At the early stage of estrogen deficiency, the osteoblastogenesis was also accelerated, which was shown as a kind of reactive protective response. [Copyright &y& Elsevier]

Abstract: In the present study, involvement of the N-methyl-d-aspartate (NMDA) receptors of the CA1 region of dorsal hippocampus (intra-CA1) in the acquisition or expression of morphine-induced conditioned place preference in rats was studied. Male Wistar rats were used in these experiments. NMDA-receptor agonist (NMDA) and antagonist (MK-801) were injected into the CA1 region of the dorsal hippocampus (intra-CA1) and morphine was injected subcutaneously. An unbiased conditioned place preference paradigm was used to study the effect of these agents. In the first set of experiments, the drugs were used during the development of conditioned place preference by morphine or they were used alone in order to see if they induce conditioned place preference or conditioned place aversion. Our data showed that subcutaneous (s.c.) injection of morphine sulphate (2.5–10 mg/kg) induced conditioned place preference in rat. NMDA (0.1–1 μg/rat) or MK-801 (1–4 μg/rat) did not induce conditioned place preference or conditioned place aversion. Intra-CA1 administration of different doses of NMDA (0.1–1 μg/rat) increased, while MK-801 (1–4 μg/rat) decreased morphine-induced place preference. MK-801 reversed the effect of NMDA on morphine response. In the second set of experiments, when the drugs were used before testing on Day 5, in order to test their effects on the expression of morphine (7.5 mg/kg)-induced place preference, intra-CA1 administration of NMDA or MK-801 did not alter the morphine response. None of the drugs influenced locomotion. It is concluded that NMDA receptor of the CA1 region of hippocampus are involved in the acquisition but not expression of morphine-induced place preference. [Copyright &y& Elsevier]

Abstract: A novel series of 2-(4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-3-yl)-ethylamine derivatives were designed and synthesized as GnRH receptor antagonists. SAR studies led to a series of highly active molecules against both the rat and human receptors. Furthermore, one potent compound, 17j, demonstrated dose-dependent LH suppression in castrated rats. [Copyright &y& Elsevier]

Objective: Smooth muscle cell proliferation (SMC) is a pivotal factor in the development of intimal hyperplasia after vascular injury. A number of growth factors, including insulin-like growth factor-1 (IGF-1), have been shown to be involved in SMC proliferation. We evaluated the effect of picropodophyllin (PPP), a new IGF-1 receptor inhibitor, in the prevention of SMC proliferation and development of intimal hyperplasia after vascular injury. Methods: The effects of systemic administration of PPP on intimal hyperplasia were studied in a balloon rat carotid injury model. Lesions were quantified by morphometry and SMC proliferation and apoptosis was studied by immunohistochemical staining for proliferating cell nuclear antigen (PCNA) and activated caspase 3, respectively. The effect of PPP on rat aortic SMC proliferation and apoptosis was studied in vitro by using cell counting, 3[H]-thymidine incorporation, and a flow cytometry assay for annexin V. Phosphorylation of the IGF-1 receptor, protein kinase B (Akt), and extracellular signal-regulated kinase 1/2 (ERK1/2) in vitro and in vivo were analyzed by using Western blotting. Results: PPP inhibited IGF-1–mediated SMC proliferation in vitro but no significant increase in apoptosis was detected. In rats treated with PPP, a more than a twofold reduction in carotid intima area was observed 2 weeks after balloon injury, a significant decrease in PCNA staining was demonstrated in early lesions, but activated caspase 3 was not detected. In addition, PPP attenuated phosphorylation of the IGF-1 receptor, Akt, and ERK1/2 in IGF-1–stimulated SMCs in vitro, and a reduced phosphorylation of the IGF-1 receptor and Akt was found in balloon-injured carotid arteries in rats treated with PPP. Conclusion: These results show that PPP potently blocks IGF-1–mediated phosphorylation of the IGF-1 receptor in SMCs, decreases downstream Akt and ERK1/2 activation, inhibits SMC replication, and subsequently attenuates intimal hyperplasia after balloon injury of rat carotid arteries. [Copyright &y& Elsevier]

Abstract: When rats are exposed to heat, they adapt themselves to the stressor with a wide inter-individual variability. Such differences in heat tolerance may be related to particularities in the hypothalamo–pituitary–adrenocortical (HPA) axis activation. To further this hypothesis, 80 rats instrumented with a telemetric device for abdominal temperature (Tabd) measurement were separated into two groups. Sixty-eight rats were exposed during 90 min at an ambient temperature of 40 °C, and 12 rats to an ambient temperature of 22 °C. Heat-exposed rats were then divided into three groups using the a posteriori k-means clustering method according to their Tabd level at the end of heat exposure. Heat tolerant rats (Tol, n=30) exhibiting the lowest Tabd showed a slight dehydration, a moderate triglyceride mobilization, but the highest plasma adrenocorticotropic-hormone (ACTH) and corticosterone levels. Conversely, heat exhausted rats (HE, n=14) presented the highest Tabd, a higher degree of dehydration, a greater metabolic imbalance with the lowest plasma triglyceride level and the highest lactate concentration, as well as a lowest plasma corticosterone and ACTH levels. The fact that the proopiomelanocortin (POMC) mRNA content within the pituitary was low despite of a high c-fos mRNA level is also relevant. Current inflammatory processes in HE rats were underlined by lower inhibitory factor κBα (IκBα) mRNA and higher tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) mRNA. In conclusion, data show that intolerance to heat exposure is associated to an HPA axis impairment, possibly related to changes occurring in the IκBα and TNF-α mRNA levels. [Copyright &y& Elsevier]

Abstract: The present study examined whether N-methyl-d-aspartate receptor (NMDAR), 5-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunits and group I metabotropic glutamate receptors (mGluRs) are constitutively expressed in trigeminal ganglia (TG) using Western blot analysis in male Sprague-Dawley rats. We then investigated whether experimental induction of masseter inflammation influences glutamate receptor expressions by comparing the protein levels from naïve rats to those from complete Freund''s adjuvant (CFA) inflamed rats. Our results showed that NMDAR1 (NR1), NMDAR2A (NR2A), NMDAR2B (NR2B), AMPAR1 (GluR1) and AMPAR2 (GluR2) subunits, and group I metabotropic glutamate receptor, mGluR5, are constitutively expressed in TG. Masseter inflammation significantly down-regulated NR1 subunit expression that persisted to 7 days post-CFA inflammation. NR2A and NR2B expressions were not significantly changed. GluR1 receptor subunit expression was slightly increased in TG 3 days after CFA-induced inflammation, but the change was not statistically significant. GluR2 protein level was not affected by CFA inflammation. The level of mGluR5 protein was significantly up-regulated in TG 3 days after CFA-induced masseter inflammation. There were no inflammation-induced changes in any of the proteins we analyzed in the contralateral, non-inflamed TG. These results suggested that muscle inflammation differentially modulates glutamate receptor subunits at the primary afferent level in male rats and that these inflammation-induced transcriptional changes may contribute to functionally different aspects of craniofacial muscle pain. [Copyright &y& Elsevier]

Abstract: Rats were used to examine the effects of inescapable swim stress on latent inhibition using a conditioned taste aversion procedure. Subjects were subjected to inescapable swim after each of three saccharin taste preexposures and saccharin was later paired with LiCl. The ability of swim to influence latent inhibition was assessed on subsequent saccharin test trials. Swim stress significantly attenuated latent inhibition. The implications of these results regarding the effects of swim stress on conditioned taste aversion are discussed. [Copyright &y& Elsevier]

Abstract: Free radicals play a central role in the development of liver ischemia/reperfusion (I/R) injury. Reduced glutathione (GSH) is the main hepatic free radical scavenger. Brain-dead patients exhibit abnormalities of endocrine status. Many clinicians administer thyroid hormones to improve the transplantation outcomes. We previously reported that thyroxine (T4) pretreatment decreased rat liver tissue GSH, which was associated with increased liver I/R-induced damage. In this study, we investigated whether the reduction in GSH by T4 pretreatment affected cell viability during anoxia or oxidative stress in suspensions of isolated hepatocytes. Furthermore, we evaluated the levels of GSH in isolated livers from hypothyroid rats preserved at 0−1°C and reperfused. Thyroid hormone modulation was obtained by T4 or 6-propylthiouracil (PTU) treatment. Isolated hepatocytes from T4-pretreated rats that underwent anoxia and oxidative stress, which was induced by tert-butylhydroperoxide, displayed progressive, time-dependent loss of cell viability, which was greater than that in hepatocytes in non–T4-pretreated rats. A significant decrease in GSH levels was observed in isolated hepatocytes obtained from hyperthyroid rats compared with those from euthyroid rats. In contrast, administration of the antithyroid drug PTU increased liver concentrations of GSH at the end of reperfusion thereby improving liver function after cold storage. These results may yield new protective strategies in the management of brain-dead organ donors. [Copyright &y& Elsevier]