Patterns of behavioral development in spontaneously hypertensive rats and Wistar-Kyoto normotensive controls

We have examined the behavior of spontaneously hypertensive (SHR) rats and stroke-prone hypertensive (SP-SHR) male rats during the development and maintenance of elevated blood pressure and compared this pattern with age- and gender-matched normotensive (WKY) rats of the same Wistar-Kyoto strain as controls. Rats of each strain (n = 10/age group) were isolated in individual cages and observed for 60 min at 3,4,6,8,10, or 20 weeks of age using a scan sampling technique. At all ages SHR rats were significantly more active than WKY rats whereas SP-SHR rats were intermediate in level of activity. In a 2nd series, activity of male rats of each strain was monitored continuously for 24 hr in the home cage. No strain differences in amount or pattern of total daily activity were evident at either 4-6 or 16-18 weeks of age. These results indicate that SHR rats are more reactive to environmental change, but the intermediate level of activity of SP-SPHR rats suggests that this response is not related to the degree of blood pressure elevation,     

Aging effects on elevated plus maze behavior in spontaneously hypertensive, Wistar-Kyoto and Sprague-Dawley male and female rats

Male and female spontaneously hypertensive (SHR), Wistar-Kyoto (WKY), and Sprague-Dawley (SD) rats were assessed at one of two ages (postnatal day 74 or 346) for open field locomotor activity and anxiety-related behavior in the elevated plus maze (EPM). In general, the SHR displayed the least anxiety-related behavior, an effect that was magnified with age. At 11 months of age, the SHR more frequently entered and remained longer in the open arms than either the SD or the WKY strains. EPM behavior of the WKY strain was much less affected by age than that of the SD strain which displayed increased anxiety-related behavior with age. At the younger age, the typical sex effects were apparent; specifically, females exhibited a shorter duration in the closed arms. While the SHR were the most active strain in the EPM at both ages, they were more active in the open field only at the older age. In general, age-related changes in open field activity mirrored those of the EPM. These results provide a more comprehensive illustration of aging-related behavioral changes in male and female SHR, WKY and SD rats.     

The SHR Y-Chromosome Increases Testosterone and Aggression, but Decreases Serotonin as Compared to the WKY Y-Chromosome in the Rat Model

The Spontaneously Hypertensive Rat (SHR) model was used to test the hypothesis that a locus on the SHR Y-chromosome is responsible for increased aggression resulting from increased serum testosterone and decreased amygdala serotonin content compared to the WKY Y-chromosome. To examine the Y-chromosome in SHR and WKY males, consomic Y-chromosome strains were used (WKY.SHR-Y and SHR.WKY-Y). Novel resident intruder tests and intra-colony scarring behavioral paradigms were used to measure aggression in a colony environment. Both resident intruder test attack number and wounding, along with intra-colony scarring scores showed the colony males with the SHR Y-chromosome (SHR and WKY.SHR-Y strains) were more aggressive than the colony males with the WKY Y-chromosome (WKY and SHR.WKY-Y strains). The SHR Y-chromosome colony male animals also had significantly higher serum testosterone, as well as overall lower amygdala serotonin content than the WKY Y-chromosome colony male animals. The results suggest that these behavioral and physiological differences between the SHR and WKY strains are a result of a mutation in the non-pseudoautosomal region unique to the Y-chromosome.     

Early behavioral development in the spontaneously hypertensive rat: a comparison with the Wistar-Kyoto and Sprague-Dawley strains

The spontaneously hypertensive rat (SHR) is often used as a model for childhood attention-deficit/hyperactivity disorder (ADHD). To investigate behavioral maturation in SHR, body weight, age at eye opening, and performance in several behavioral tasks in male and female SHR, Wistar-Kyoto (WKY), and Sprague-Dawley rats were compared. SHRs were slower in performing the righting reflex on PND 4 and negative geotaxis compared with WKY and Sprague-Dawley. Both SHR and WKY were delayed relative to Sprague-Dawley in eye opening and beam walking. Rotarod performance was comparable in the 3 strains. Males were faster to right themselves than females, but there were no other significant sex differences nor Sex X Strain interactions. Delayed development in SHR may be related to a maturational delay observed in children with ADHD. Research assessing early behaviors in SHR, WKY, and other strains will help determine the most appropriate model for childhood ADHD and may help predict later behavioral dysfunction.     

Behavior of hypertensive and hyperactive rat strains: hyperactivity is not unitarily determined.

The spontaneously hypertensive rat (SHR) is behaviorally hyperactive relative to the Wistar-Kyoto rat (WKY). By breeding SHR with WKY, followed by inbreeding, two new strains have been developed in which hypertension seems to be separated from hyperactivity to novel stimuli: the WKHT and the WKHA strains. The main purpose of the present study was to determine which behavioral characteristics of SHR have been dissociated from the hypertensive trait in the WKHA strain. Male SHR, WKY, WKHT, and WKHA were subjected to three protocols: 1) Two forced-exploration tests, where the results showed that both the SHR and the WKHA rats were hyperactive. 2) A free-exploration open field, where the SHR was more active than the other strains, showing shorter latencies to leave the home cage, spending more time in the field, ambulating and rearing more. Furthermore, the WKHT behavior was more similar to the SHR behavior than the WKHA behavior. 3) A two-component schedule of reinforcement, where one component (fixed-interval 2 min) was signaled by houselight on and the other (extinction, EXT) by houselight off. In this test, the SHR behavior was markedly different from that of the three other strains: the fixed-interval scallop, the accelerated responding towards the end of the interval, was steeper in SHR than in the other groups. The SHR emitted more responses during the extinction component of the schedule. The SHR hyperactivity was dependent upon the reinforcement value of the water deliveries and was increased even further by sensory-reinforcing respones feedback lights. Thus, the hyperactivity of the WKHA strain seems to be less pervasive than that of the SHR.(ABSTRACT TRUNCATED AT 250 WORDS)     

Baseline serum cardiac troponin I concentrations in Sprague-Dawley, spontaneous hypertensive, Wistar, Wistar-Kyoto, and Fisher rats as determined with an ultrasensitive immunoassay

Cardiac troponins have proved to be reliable blood biomarkers for identifying a variety of myocardial alterations in humans and animals. Recently, an ultrasensitive cTnI assay (Erenna IA) has been used to demonstrate increases in baseline cTnI resulting from drug-induced myocardial injury in rats, dogs, and monkeys, as well as to document baseline cTnI ranges in Sprague-Dawley (SD) rats. The present study was initiated to use the Erenna cTnI assay to further document baseline cTnI concentrations in normal control animals from multiple strains, including SD, Spontaneous Hypertensive (SHR), Wistar, Wistar-Kyoto (WKY), and Fisher strains. Baseline cTnI concentrations were quantified in all rats tested, and males had higher mean cTnI concentrations than females of the same strain. SHR males had the highest mean cTnI concentrations and the largest cTnI variability. Interestingly, cTnI concentrations increased in castrated SHR compared with unaltered male SHR, whereas cTnI concentrations decreased in ovariectomized SHR compared with unaltered female SHR. These results show significant differences in cTnI concentrations between strains, sexes, and noncardiac surgical alterations in control animals, and identify these as potential contributing factors to cTnI baseline variability that should be taken into account when using ultrasensitive cTnI as a biomarker to assess preclinical cardiotoxicity.     

"Behavioral despair" test predicts stress ulcer in WKY rats

Spontaneously hypertensive rats (SHR), Wistar Kyoto (WKY) and Wistar rats were exposed to Porsolt's forced-swimming test of "behavioral despair." In addition to floating time, which was the measure of despair, headshakes, bobbing, diving and struggling time were also recorded. Rats were subsequently exposed to the activity stress (A-S) ulcer procedure. Wistar rats had the highest struggling time scores and the fewest A-S ulcers. WKY rats were judged as more depressed and their ulcer severity scores were significantly greater as compared to SHR and Wistar rats. In addition, a within strains analysis revealed that WKY rats with high despair scores also had the most severe stress-ulcer scores. These data suggested that stress-ulcer disease may be more prevalent in animals which are prone to depression as defined by the Porsolt test. The value of WKY rats as an animal model to study the relationship between depression and stress ulcer is discussed.     

Stress ulcer susceptibility and depression in Wistar Kyoto (WKY) rats

In a series of studies, Wistar Kyoto (WKY) normotensive rats were more susceptible to water-restraint-induced stress ulcer as compared to spontaneously hypertensive rats (SHR) Fisher-344 (F344) and Wistar rats. In these same studies, WKY rats were also deficient in several behavioral tasks. The four strains were observed in the open-field test of emotionality and WKYs were judged more emotional. In a study on "learned helplessness" WKYs were more deficient in the acquisition of a shuttlebox escape response following unavoidable shock the day before. The prevalence of freezing behavior in the shuttlebox task and the low ambulation scores in the open-field test suggested depressive behavior as a WKY behavior characteristic. WKY rats were judged more depressed in the Porsolt forced-swim test as compared to the other strains. A possible depression-ulcer relationship may exist in WKY rats. This strain may represent a good model for studying possible relationships between depression and stress-induced disease.     

Mechanism of reproductive deficiency in spontaneously hypertensive rats.

Spontaneously hypertensive rats (SHR) show multiple endocrine disorders. In the present work, specific reproductive modifications were analysed using normotensive Wistar-Kyoto rats (WKY) as controls. SHR showed delayed vaginal opening and first estrus presentation, regular vaginal cycles and released a normal number of ova each cycle. When compared with controls, SHR showed a decrease in the percentage of successful pregnancies (69% vs. 86% in WKY) and in the litter size (7.83 +/- 0.5 vs. 10.41 +/- 0.5). In SHR, progesterone plasma levels were significantly increased during the days 1-14 of pregnancy, and on the 5th day of pregnancy the plasma concentrations of LH but not of FSH were enhanced. Mortality during the first month of life was higher in SH (50%) than in control (24%) strain. When the SH females were mated with Wistar or WKY males, the percentage of pregnancies rose up to 95%. On the contrary, Wistar or WKY females mated with SH males showed a decrease in the percentage of pregnancies (62.5% and 50%, respectively). Besides, the litter sizes were significantly reduced in Wistar females mated with SH males. Newborn SH suckled immediately after birth from a WKY mother showed a significant reduction in the mortality during the first month of life (8% vs. 50%). In conclusion, our results suggest that changes in fertilization and/or implantation processes of SH rats were responsible for the reduced pregnancy rate, whereas the increased neonatal mortality could be due to lactation activity of SH mothers.     

Differential stress effects on responses to noxious stimuli as measured by tail-flick latency and squeak threshold in rats

In the present study tail-flick latency (TFL) and squeak threshold (ST) were investigated in different environmental conditions in normotensive Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). The TFL did not vary significantly during the testing period (120 min). The ST increased gradually and significantly with time when measured in rats restrained in the TFL test tube. Freely moving rats transferred to the TFL test tube showed a marked decrease of the ST. During the stay in the TFL test tube, the ST value increased gradually. Also after transfer from the test tube to the home cage the threshold increased to the same level as freely moving rats. There were no significant differences in these effects between WKY and SHR. Naloxone (1 mg kg-1 i.v.) decreased the ST in both freely moving and restrained animals of either strain. Intravenous injection of morphine (mg kg-1) gave a pronounced threshold increase of ST in both groups. It is suggested that animals restrained in the TFL test tube become hyperalgesic. The adaptation to stress is reflected in the ST but not in the TFL. Squeak threshold appears to be influenced by a tonically active endorphin system.     

Sympathetic-adrenal medullary response to stress in hyperactive and hypertensive rats

Sympathetic-adrenal medullary hyperreactivity to acute stress, measured as an exaggerated elevation of plasma epinephrine and norepinephrine levels in response to footshock, was examined in four genetically related, inbred rat strains, all derived from the Wistar-Kyoto rat (WKY). These four strains are endowed with the traits of hypertension and behavioral hyperactivity, expressed either together (in SHR), or separately in two new strains (Wistar-Kyoto hyperactive rats, WK-HA, and Wistar-Kyoto hypertensive rats, WK-HT), or not at all (in WKY). Male rats of the SHR, WKY, WK-HA and WK-HT strains were subjected to acute footshock stress in order to determine whether the previously reported hyperreactivity of the SHR is attributable to the hypertensive trait, or to the behavioral hyperactivity trait, both of which are characteristic of the SHR. Plasma catecholamine levels were determined prior to, immediately following, and 5 min following acute footshock stress. We report here that the WK-HA strain (hyperactive but not hypertensive) exhibited the hyperreactivity characteristic of SHRs, and not the WK-HT strain (hypertensive but not hyperactive). We conclude that the exaggerated sympathetic-adrenal medullary response to acute stress is associated with the hyperactivity trait and not with hypertension among these congenic rat strains.     

A longitudinal study of short- and long-term activity levels in male and female spontaneously hypertensive,Wistar-Kyoto,and Sprague-Dawley rats

The pattern of locomotor activity across development was assessed in male and female spontaneously hypertensive (SHR), Wistar-Kyoto (WKY), and Sprague-Dawley (SD) rats. Open field activity did not indicate hyperactivity in the SHR. Instead, the SD strain was generally more active. Strains and sexes did not differ in open-field locomotor response to drug challenges. When short-term (10-12 min) activity in different apparatuses was compared, the SD were most active in the open field, the SHR in the residential figure-eight maze, and the WKY in the running wheel. Long-term tests indicated hyperactivity in the SHR in the residential figure-eight maze and hypoactivity in the SD in the running wheels. Until such strain differences in activity are thoroughly defined, the use of the SHR as a model of attention-deficit/ hyperactivity disorder is limited.     

Age-related decline in water maze learning and memory in rats: strain differences

Rats display an age-related impairment in learning and memory; however, few studies have systematically examined this relationship in multiple strains. The present study used a repeated acquisition water maze task to test the hypothesis that age-related decreases in learning and memory occur at different rates in three strains of rats, i.e. Sprague-Dawley (SD), spontaneously hypertensive (SHR), and Wistar Kyoto (WKY) rats. All three strains of rats displayed age-related decreases in spatial learning and memory; however, the rate of decline differed between the strains. Compared to young rats of the same strain, only SHR were significantly impaired at 12 months of age. All three strains displayed moderate impairment in learning the task at 18 months of age, and at 24 months of age all three strains of rats were severely impaired in the task, but SD performed best at 18 and 24 months of age. Further, SD and SHR displayed a probe trial bias at 3 months of age, but only SD had a bias at 12 months of age and none of the rats showed the bias at later ages. Thus, in these three strains, age-related impairment of spatial memory proceeds at different rates.     

Influence of neonatal handling on blood pressure,locomotor activity,and preweanling heart rate in spontaneously hypertensive and Wistar Kyoto rats

This experiment tested the hypothesis that increased stimulation early in development would (a) alter developmental changes in heart rate and behavioral reactivity and (b) affect the level at which blood pressure was regulated in adulthood. For this purpose, the effects of daily handling and maternal separation (3 min per day) on both behavioral and cardiovascular measures were examined in spontaneously hypertensive (SHR) and normotensive control Wistar Kyoto (WKY) rats. Prior to weaning, elevated heart rates in pups handled during the first postnatal week were most pronounced among 4-week-old prehypertensive SHR pups. Early handling affected behavior observed during openfield testing similarly in young adult rats of the SHR and WKY strains (e.g., increased locomotor activity on the first day of testing). In female rats of the WKY strain, early handling resulted in a lower baseline blood pressure; the blood pressure; the blood pressure of SHR rats was not affected by increased stimulation in infancy. Examination of longitudinal data yielded no support for a direct association between behavioral reactivity or preweaning heart rate and high blood pressure. These findings demonstrate the influence of both early environmental conditions and genetic factors on maturation within the cardiovascular system and suggest that genetic models of pathological conditions may provide a productive means of examining environmentally shaped aspects of individual differences in physiological regulation.     

Behavioral reactivity in spontaneously hypertensive rats

Spontaneously hypertensive rats of the Okamoto strain (SHR) were compared with inbred normotensive rats of the Wistar-Kyoto strain (WKY) and with normally bred Wistar rats (NT) in tests on the audiogenic immobility reaction (freezing), open-field behavior in a dark and an enlightened arena respectively, auditory startle response and male sexual behavior. Compared to the WKYs the SHRs showed increased locomotion and rearing in the open-field situations, reduced startle response and shortened immobility reaction. The SHRs differed in the same way from the NT rats with the exception for motor activity in the dark arena, where no differences were observed. The WKY rats showed less motor activity than the NT animals. Both SH and WKY rats showed shorter latency time for ejaculation than the NT rats. The characteristics of the behavior patterns displayed by the SH rats were interpreted as indicating a reduced propensity for fear reactions in this strain of rats compared to the WKY and NT strains used in the present study.     

In vivo basal and amphetamine-induced striatal dopamine and metabolite levels are similar in the spontaneously hypertensive, Wistar-Kyoto and Sprague-Dawley male rats

Nigrostriatal alterations are proposed to partially underlie the hypertension and hyperactivity exhibited by the spontaneously hypertensive rat (SHR). Here, in vivo microdialysis was used to measure baseline and d-amphetamine (AMPH)-stimulated striatal dopamine (DA) and metabolite levels in adult male SHR, Wistar-Kyoto (WKY), and Sprague-Dawley (SD) rats. At approximately 19 weeks of age, baseline levels of DA, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) were measured after which time, each rat was injected intraperitoneally with 2 mg/kg AMPH and samples were collected for the subsequent 200 min. There were no significant strain differences in baseline levels of DA, HVA, and 5-HIAA. The baseline level of DOPAC was decreased in the WKY relative to the SD. AMPH treatment altered DA, DOPAC, HVA, and 5-HIAA to a similar extent in all strains; thus, there were no significant strain differences, nor did the area under the curve (AUC) for DA levels differ between strains. AUC for DOPAC was significantly smaller for the WKY relative to the SD strain, likely due to the lower baseline level. At the single dose of amphetamine used here, the results indicate that in vivo DA levels in the SHR are similar to the WKY and SD strains.     

Factors affecting the acute pressor response to bolus cadmium injections

Cadmium chloride solutions were given at dosages of 1 or 2 mg/kg intraperitoneally, intravenously, subcutaneously or orally to conscious or anesthetized female rats. A rapid and persistent pressor response was usually obtained from parenteral, but not from oral administration. Blood pressure elevation was quantitatively equivalent at 15 and 30 min after injection, except on subcutaneous administration, in conscious and anesthetized rats, although anesthesia depressed the initial pressures. Within a minute or so of administration, all animals given cadmium intraperitoneally exhibited body, limb and tail movements typically displayed during parturition, and did so for up to two hours thereafter. When 5-week-old males of Sprague-Dawley, Fischer 344, SHR and WKY strains were given 2 mg/kg of CdCl₂ intraperitoneally, a pressor response did not usually occur. At 6–10 weeks of age a pressor response commonly occurred in conscious or unconscious Sprague-Dawley and Fischer 344, but only in unconscious SHR or WKY rats. Conscious males exhibited the same contortions as females following intraperitoneal cadmium injections.     

Myocardial cell growth and blood pressure development in neonatal spontaneously hypertensive rats

We evaluated the changing morphologic features of cardiac muscle cells (myocytes) and nuclei from neonatal spontaneously hypertensive rats (SHR) and their parent, normotensive strain Wistar Kyoto rats (WKY) and compared these with increasing heart weight and blood pressure development to determine if alterations in cell growth were present at this early stage of development. Femoral artery blood pressures were obtained from rats at 2 to 5-day intervals from birth to 21 days of age by using a micropipette servo-null pressure recording system. Tritiated thymidine autoradiography was used to study myocyte nuclear development, and isolated myocytes were prepared to evaluate cell-size changes by using a Coulter Counter system (Coulter Electronics, Hialeah, Florida). Heart weight and blood pressure were elevated in SHR when compared to WKY at birth. Myocytes were all mononucleated at birth in both strains and were of equal size, demonstrating that the larger heart mass in SHR was due to an increased number of cells. Heart weight relative to body weight remained greater in SHR when compared to WKY throughout the 28-day study period, but cell numbers became equal in the two strains by the 2nd week. A this time (6 to 9 days postpartum) blood pressure was also similar in both strains, but increased significantly again in SHR by 15 and 21 days of age. Cell maturation occurred earlier in SHR than in WKY as indicated by an earlier development of binucleate myocytes and there was an earlier initiation of hypertrophic myocyte growth in SHR. Increase in SHR cell size occurred at a time when blood pressures were not different, suggesting that greater cell size in SHR than in WKY was not due to differences in blood pressure. Therefore, when compared to the WKY, the SHR had three phases of altered cell growth: a first phase of accelerated hyperplastic growth during the fetal period, and a second phase (6 to 12 days of age) of earlier initiation of hypertrophic cell growth and increased myocyte size. The SHR myocyte changes in the second phase occurred while the SHR and the WKY blood pressures were not significantly different. Finally, in a third phase (at 15 days of age and over), SHR had a sustained increase in myocyte size as well as elevated blood pressure.     

Grooming behavior of spontaneously hypertensive rats

In an open field spontaneously hypertensive rats (SHR) exhibited lower scores for grooming when compared to their normotensive controls, the Wistar-Kyoto rats (WKY). After i.c.v. injection of 1 microgram ACTH cumulative 50-min grooming scores were lower in SHR. Analysis of subscores indicated that the lesser effect of ACTH in SHR was especially prominent for headwashing and anogenital grooming. Moreover, a time course study revealed that the difference between SHR and WKY occurred in the first 6 observation periods of 5 min and thereafter disappeared. The results are discussed in the light of behavioral and central neurochemical differences between SHR and WKY.