Open-field behavior of spontaneously hypertensive and Wistar-Kyoto normotensive rats: effects of reciprocal cross-fostering

The influence of the maternal environment on the development of open-field behavior in spontaneously hypertensive (SHR) rats was investigated using the technique of reciprocal cross-fostering. Entire litters of SHR and Wistar-Kyoto (WKY) normotensive rats were either reared by their natural mothers, in-fostered to dams of the same strain, or cross-fostered to dams of the opposite strain on the day after birth. Open-field behavior was assessed in male and female rats from the six groups (2 strains x 3 rearing conditions) at 30, 60, 90, and 120 days of age. Animals were observed in the open-field during a 5-min test period and the number of squares entered and hindlimb rears were recorded. At all ages tested, SHR rats were more active in the open field, entering more squares and rearing more frequently than WKYs. SHR females were more active than age-matched SHR males, while no sex differences were apparent in the WKY strain. At each age, open-field behavior was similar across WKY rearing groups. SHR control and in-fostered animals responded similarly in the open field; however, SHR cross-fostered rats (particularly females) tended to be more active than controls. Although cross-fostering has profound effects on cardiovascular development and functioning in the SHR, it appears that altering the early maternal environment experienced by SHR pups does not grossly affect the development of open-field behavior.     

Passive-avoidance behavior of spontaneously hypertensive rats

Spontaneously hypertensive rate (SHR) generally exhibit higher performance in avoidance tasks than Wistar-Kyoto control rats (WKY) do. The SHR are more active than the WKY after transfer to a novel environment and after electric footshocks. The present study examined the performance, behavior, and plasma corticosterone of young male SHR and WKY in a passive-avoidance task in which high levels of locomotor activity do not facilitate performance. The effects of three levels of discriminability of the safe area were studied. Passive-avoidance performance was statistically significantly lower in the SHR, but the difference was small. There was no difference between the SHR and the WKY in post-test plasma-corticosterone levels, and there was no relationship between ambulation and plasma-corticosterone levels. The behavioral differences between the SHR and the WKY varied as a function of the discriminability of the safe area. Specifically, in the low-discriminability condition, ambulation, but not rearings, was equally suppressed in the SHR as in the WKY and there was no difference in immobility. In the high-discriminability condition the SHR exhibited more ambulation, more rearing, and less immobility than the WKY. These data confirm that the SHR exhibit an increased tendency for facilitation of locomotor activity during activation compared to the WKY. Because the passive-avoidance performance of the SHR was lower than that of the WKY, these data suggest that previous reports of superior avoidance learning in the SHR reflect their elevated level of locomotor activity rather than an improved ability to acquire conditioned responses. Ability to discriminate stimuli seems to be normal in the SHR since ambulation was modified according to stimulus parameters.     

Spontaneously hypertensive Wistar-derived male rats are more aggressive than those of their normotensive progenitor strain

We compared a group of spontaneously hypertensive rats (SHRs) to a group of Wistar-Kyoto (WKY) rats on each of the three most commonly studied forms of aggressive behavior in rats: muricide, intraspecific aggression, and shock-induced fighting (SIF). A significantly higher proportion of SHRs were muricidal; they also fought more at the lowest shock level. A trend for a higher incidence of intraspecific offense behaviors by SHRs was not significant. SHR flinch and jump thresholds were lower than the respective WKY thresholds. Although there were no significant correlations between shock thresholds and any aspects of SIF, the possibility that strain differences in shock sensitivity may contribute to differences in SIF cannot be ruled out. Within strains, there were no correlations among the different forms of aggression. Several different inherited characteristics may be associated with the accentuation of different forms of aggression in SHRs.     

Lifelong hyperarousal in the spontaneously hypertensive rat indicated by operant behavior

Instrumental conditioning techniques were used to obtain objective evidence of differences in behavioral arousal between the spontaneously hypertensive rat (SHR) and the normotensive ancestral Wistar Kyoto (WKY) strain. Subjective emotionality ratings previously indicated that the genetically hypertensive rats were more active and aggressive than their normotensive cousins. In a lengthy series of operant conditioning sessions using a small number of adult female SHR and WKY rats, hyperarousal in the SHR was confirmed by their significantly higher response outputs on either response contingent or time contingent schedules of reinforcement. Conditioned emotionality tests during this series of experiments also suggested hyperarousal and aggressiveness in the SHR, since the fear-conditioned stimulus suppressed bar-pressing in the SHR much less than in the WKY. Further experiments with young prehypertensive SHR rats provided the same evidence of hyperresponsivity in the SHR compared to the WKY strain. Furthermore, these young SHR failed to develop hypertension by the end of the study (14 weeks of age), while their nonconditioned SHR cousins had become clearly hypertensive by the same age. This suggests that factors related to the conditioning methods modified the development of high blood pressure in this animal model of essential hypertension.     

Plasma corticosterone and renin activity during two-way active avoidance learning in spontaneously hypertensive and Wistar-Kyoto rats

The spontaneously hypertensive rat (SHR) exhibits increased sympathetic and behavioral responses to several types of environmental stress compared to its normotensive progenitor, the Wistar-Kyoto rat (WKY). The aim of the present study was to investigate response-dampening mechanisms in the SHR. This study examines whether learning to control a stressful environment reduces behavioral and neuroendocrine activation in the SHR. Twelve SHR and 12 WKY were subjected to daily sessions (S) of 20 trials of signaled two-way active avoidance. Another 12 SHR served as maturation controls. Blood samples were collected immediately after S 1, S 5, and S 14 and plasma level of corticosterone (p-CS) and plasma renin activity (PRA) were measured. There was an insignificant tendency for the SHR to exhibit larger increases in p-CS in response to stress than the WKY did. By S 5 both groups had attained the avoidance task. However, the level of p-CS was the same as after S 1, showing that activation is independent of the number of shock pulses received and performance. Postsession p-CS decreased between S 5 and 14, slightly more so in the SHR than in the WKY. The SHR exhibited lower PRA than the WKY, but there were no significant effects of exposure to the avoidance schedule. Behaviorally, the SHR exhibited shorter latency to escape in the first trial than the WKY did. The SHRs were hyperactive compared to the WKY, showing more ambulation and rearing behavior. The maturation control SHR reached the same mean arterial pressure as the SHRs which were tested. After S 14, signal duration was shortened from 10 to 3 s for six additional sessions. Both p-CS and PRA increased, while at the same time ambulation and rearing behavior decreased. These data show that the relationship between behavioral control and adrenocortical activation is normal in the SHR in spite of differences in behavior. The present results also confirm previous data on hyperreactivity to footshocks in two-way active avoidance tasks in the SHR.     

Adult blood pressure reduction in spontaneously hypertensive rats reared by normotensive Sprague-Dawley mothers.

Spontaneously hypertensive (SHR), Wistar-Kyoto (WKY) normotensive, and Sprague-Dawley (SD) normotensive rats were either reared by their natural mothers (controls) or fostered to a mother of one of the other strains. The effects of rearing environment were assessed by measures of body weight at weaning and adult resting mean arterial blood pressure (MAP) and heart rate (HR). At weaning, SHR control rats weighed less than WKY controls which in turn weighed less than SD controls. SHR and WKY rats reared by SD mothers weighed significantly more than their respective controls, whereas SD rats reared by either SHR or WKY mothers weighed less than SD control rats. Manipulation of the maternal environment was attended by a change in adult resting MAP in only one group. SHR rats reared by SD mothers had MAPs which were significantly lower than SHRs reared by their natural mothers. No within-strain adult HR differences were observed between control and cross-fostered groups. These data indicate that the effects of cross-fostering on adult resting MAP previously reported for SHR and WKY animals are generalizable to another normotensive strain. That is, genetically hypertensive (SHR) animals exposed to a normotensive (WKY or SD) maternal environment display a reduction in adult resting MAP, whereas hypertension or an increase in adult MAP is not induced in normotensive rats (WKY or SD) as a consequence of exposure to a hypertensive maternal environment.     

Combined uridine and choline administration improves cognitive deficits in spontaneously hypertensive rats

Rationale. Hypertension is considered a risk factor for the development of cognitive disorders, because of its negative effects on cerebral vasculature and blood flow. Genetically induced hypertension in rats has been associated with a range of cognitive impairments. Therefore, spontaneously hypertensive rats (SHR) can potentially be used as a model for cognitive deficits in human subjects. Consecutively, it can be determined whether certain food components can improve cognition in these rats. Objective. The present study aimed to determine whether SHR display specific deficits in attention, learning, and memory function. Additionally, effects of chronic uridine and choline administration were studied. Methods. 5-7 months old SHR were compared with normotensive Wistar-Kyoto (WKY) and Sprague-Dawley (SD) rats. (a) The operant delayed non-matching-to-position (DNMTP) test was used to study short-term memory function. (b) The five-choice serial reaction time (5-CSRT) task was used to assess selective visual attention processes. (c) Finally, the Morris water maze (MWM) acquisition was used as a measure for spatial learning and mnemonic capabilities. Results. (1) SHR exhibited significantly impaired performance in the 5-CSRT test in comparison with the two other rat strains. Both the SHR and WKY showed deficits in spatial learning when compared with the SD rats. (2) Uridine and choline supplementation normalized performance of SHR in the 5-CSRT test. (3) In addition, uridine and choline treatment improved MWM acquisition in both WKY and SHR rats. Conclusion. The present results show that the SHR have a deficiency in visual selective attention and spatial learning. Therefore, the SHR may provide an interesting model in the screening of substances with therapeutic potential for treatment of cognitive disorders. A combination of uridine and choline administration improved selective attention and spatial learning in SHR.     

The spontaneously hypertensive rat as an animal model of attention-deficit hyperactivity disorder: effects of methylphenidate on exploratory behavior

Spontaneously hypertensive rats (SHR) show a pervasive hyperactivity in several paradigms. Thus, these rats may be used as an animal model of childhood hyperactivity also called Attention-Deficit Hyperactivity Disorder. This disorder is frequently treated with psychomotor stimulant drugs, but little is known about the effects of such drugs on behavior. The present study investigated the behavioral effects of 1-24 mg/kg methylphenidate (Ritalin) on the exploratory behavior of male SHR and Wistar-Kyoto control rats (WKY) in a two-compartment free-exploration open field. Except following very high doses. SHR spent most of the session time in the field while WKY stayed in the home cage. Low and medium doses were followed by increased activity in the field for SHR and increased activity in the cage for WKY. The response-stimulatory effects of low to medium doses of methylphenidate are less in SHR than in WKY. Starting at medium doses, activity decreased and stereotyped behavior increased progressively by increasing dose. Locomotor activity in the field decreased following lower doses than locomotor activity in the cage, and vertical activity (rearing) was reduced by lower doses than horizontal activity (crossing). The following conclusions were drawn. (i) There is no "paradoxical" inhibition of SHR hyperactivity following methylphenidate. On the contrary, SHR activity is in fact stimulated, albeit to a lesser degree than that of WKY. (ii) The stimulatory effects of low to medium doses are, in general, most pronounced for the kind of exploratory behavior most frequently used by the rat during baseline conditions. (iii) Rearing might be more susceptible to adverse effects of methylphenidate than ambulation.     

Behavioral hyperreactivity in the spontaneously hypertensive rat compared to its normotensive progenitor

The spontaneously hypertensive rat (SHR) is an excellent model of essential hypertensive disease. Hyperreactivity has been postulated as a contributing factor in the development of high blood pressure in the SHR and in man. In the maturing organism recurring hypertensive stress responses may promote permanent vascular changes and result in a fixed hypertension. Simple behavioral activity and emotionality rating scales were used to compare a large number of SHR with equally large groups of closely-related and distantly-related normotensive rats. As predicted, the SHR were clearly more active and emotional than their ancestral Wistar Kyoto (WKY) strain. However, the distantly-related normotensive Wistars did not differ from the SHR in either activity or emotionality. These results indicate that behavior and hypertension are not necessarily related in the rat. Nonetheless, the behavioral differences between the SHR and their closest genetic match, the WKY, suggest that arousal and blood pressure levels may be causally linked in this case of naturally occurring hypertension.     

Open-field behavior in two models of genetic hypertension and the behavioral effects of salt excess

In order to assess the relationship of behavior to blood pressure and salt intake, open-field behavior was studied in 123 rats of the spontaneously hypertensive (SHR), Wistar-Kyoto (WKY), Sprague-Dawley (SD), and Dahl resistant (DR) and sensitive (DS) strains. DS rats become hypertensive upon exposure to either high dietary salt or psychogenic stress, while DR rats remain normotensive. A circular photobeam open field was used under full room illumination. Three 5-min trials were given on consecutive days. Rats were tested with or without 5 days of an 8% NaCl diet. We found that DS rats were less active than DR rats, regardless of diet. In contrast, SHR rats were more active than WKY rats. However, DS and SHR rats were equally active. Thus, behavioral differences between these two models of hypertension are expressed by the normotensive control strains. The relative ranking of activity levels between strains was DR = SD greater than SHR = DS greater than WKY. High-salt-enhanced intertrial habituation, defined as the decrease in activity across trials (DS, 100%; SD, 82%; SHR, 90%; WKY, 1350%; but DR, -50%) as well as intratrial habituation, defined as the decrease from the first to the second half of the trial (14%, all subjects). Defecation was increased with high salt (DS, 975%; SD, 59%; SHR, 267%; WKY, 89%; but DR, 40%). These effects of high salt may reflect an increase in an emotionality factor. DR rats were largely resistant to the behavioral effects of salt. Total activity was positively correlated with blood pressure in hypertensive rats, r(42) = 0.33, p less than .01, but negatively correlated in normotensive rats, r(81) = -0.34, p less than .01. The proportion of total activity occurring in the first half of the trial for the initial test day was correlated with blood pressure in normotensive rats r(81) = 0.44, p less than .01. Dietary salt excess has behavioral as well as cardiovascular consequences.     

Auditory startle in normotensive and hypertensive rats

In the present experiment auditory startle was examined in male and female rats of the spontaneously hypertensive (SHR) and Wistar-Kyoto normotensive (WKY) strains and borderline hypertensive rats (BHR) derived from cross-breeding SHR females with WKY males. The magnitude of auditory startle declined over trials and was significantly higher in WKYs than in both SHRs and BHRs which did not differ from each other. These data add to an increasing body of literature concerning behavioral differences between hypertensive and normotensive rats and are discussed as they relate to the possible strain differences in either behavioral reactivity or tonic fear.     

Stress ulcer and open-field behavior of spontaneously hypertensive,normotensive, and Wistar rats

Spontaneously hypertensive rats (SHRs) and the normotensive Wistar/Kyoto (WKY) rat were observed, along with Wistar rats (which represent the parent strain), on various open-field behaviors. All three strains were subsequently exposed to the activity-stress (A-S) ulcerogenic procedure. SHR and Wistar rats were very active in most open-field measures as compared with WKY rats, but only SHRs were active during the A-S treatment. WKY rats were very ulcer prone and had significantly more ulcers than SHRs, which in turn had more ulcers than Wistar rats. It was anticipated that Wistar rats would resemble the WKY rats, but in most measures the Wistars resembled the SHRs. The study suggests that although WKY rats function as an appropriate control for hypertension studies, these rats may be inappropriate as controls for other physiological and behavioral studies.     

Inbreeding of Wistar-Kyoto rat strain with hyperactivity but without hypertension

A genetic inbreeding program using Wistar-Kyoto rat strains as progenitors was used to combine the hyperactivity trait of the spontaneously hypertensive rat (SHR) with the normotensive trait of the WKY genetic control strain. From an SHR X WKY cross we produced a gene-assorting F2 population from which selected brother-sister matings were carried out through seven successive inbred populations. This program produced a new strain of hyperactive rats with normotensive mean systolic blood pressure levels, and we have designated the new strain as the Wistar-Kyoto hyperactive (WK/HA) rat. Another behavioral characteristic of the SHR rat, poor habituation in a nonreinforcing novel environment, did not appear as a characteristic trait of the new strain of WK/HA rats, suggesting a separate underlying genetic basis for the two traits that had been apparently fortuitously fixed in the SHR genotype as a result of intensive inbreeding of that strain. The new WK/HA strain, together with the WKY control strain, is considered as more suitable for subjects in studying hyperactivity in rats than the original SHR strain with its concomitant hypertension and poor habituation traits.     

Neophobia in spontaneous hypertensive (SHR) and normotensive control (WKY) rats

Latency of approaching a novel object (white-colored cube) placed in an unfamiliar open field, duration of object exploration, ambulation, rearing, grooming, and defecation were investigated in spontaneous hypertensive rats (SHR), their genetic normotensive controls (WKY), and standard Laboratory rats of Wistar origin (Tif:RAIf). The parameters measured were taken as indices of fear due to novelty (neophobia). Remarkable differences in behavior of all three strains were observed. By comparison to RAIf and WKY rats, SHR showed decreased neophobia as reflected in the significantly shorter latency of approaching the object and enhanced ambulation and rearing activity in the open field. By comparison to RAIf rats SHR also showed reduced grooming and defecation. WKY rats distinguished themselves from both SHR and RAIf by almost total absence of all responses in this test situation. This behavioral suppression was antagonized by 7.5 mg/kg ip of chlordiazepoxide. The results of this study further support the notion that, by comparison to standard laboratory rats, both SHR and WKY rats show possible genetically determined, altered behaviors which are diametrically opposite to each other.     

Maternal behavior of spontaneously hypertensive and Wistar-Kyoto normotensive rats: effects of reciprocal cross-fostering of litters

Maternal behavior of spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) normotensive dams rearing either their natural pups or pups of the opposite strain was assessed when pups were 4-6 days of age. Consistent with previous reports, SHR dams caring for their natural pups were observed nursing and licking their pups more often than WKY dams and were away from their pups less often. The behavior of dams rearing cross-fostered pups demonstrated that this strain difference in patterns of maternal behavior is dependent on pup type. Mothers of both strains shifted their behavior in the direction of the opposite strain's maternal behavior pattern when caring for cross-fostered pups. This shift was most pronounced in SHR dams caring for WKY pups. These data suggest that alterations in patterns of maternal behavior produced by cross-fostering may play an important role in cross-fostering effects on the physiological development of SHRs previously reported.     

Residential-maze behavior of spontaneously hypertensive rats

Spontaneously hypertensive rats (SHR) exhibit elevated levels of ambulation after transfer to a novel environment compared to the Wistar-Kyoto rat (NR). The present experiment compared long-term activity of SHR and NR in a residential maze to determine whether the SHR exhibit elevated levels of locomotor activity under undisturbed, baseline conditions in addition to enhanced reactivity to stimuli. The SHR were much more active visiting more arms of the maze than the NR during the initial hours following transfer to the maze, and during hours around dark onset and light onset. However, the SHR also exhibited higher levels of activity than the NR under baseline conditions. While the NR visited the arm containing food more frequently than other arms, the SHR exhibited no such preference. These data show that both stimulus-induced and basal levels of ambulation are increased in the SHR compared to its normotensive genetical counterpart.     

The spontaneously hypertensive rat (SHR) as an animal model of childhood hyperactivity (ADHD): changed reactivity to reinforcers and to psychomotor stimulants.

Childhood hyperactivity (attention-deficit hyperactivity disorder, ADHD) is a behavior disorder affecting 2-6% of grade-school children. The main symptoms are attention problems and hyperkinesis. The disorder is commonly treated with psychomotor stimulants, usually methylphenidate hydrochloride (ritalin) or d-amphetamine. Neither the cause of the disorder nor the basis of the effectiveness of the drug treatment is well understood. Differences in reinforcement processes have been implicated as part of the underlying problem. The main purpose of the present research was to investigate reinforcement processes and motor characteristics with and without stimulant medication in SHR, as an animal model of ADHD, and WKY controls, its normoactive progenitor strain. SHR behavior turned out to be more sensitive to immediate reinforcement and proportionately less sensitive to delayed reinforcement when compared to the behavior of WKY, as demonstrated by systematic changes in rates of responding throughout fixed-interval schedules of reinforcement of bar-presses by water. The psychomotor stimulants weakened the control by immediate reinforcers and strengthened the control by delayed reinforcers, with the effect of the drugs being more pronounced in WKY than in SHR. The results are consistent with clinical observations that ADHD children are less willing than others to accept "delayed gratification" and that methylphenidate increases the control of delayed reward over their behavior.     

Behavioral variability in SHR and WKY rats as a function of rearing environment and reinforcement contingency.

The spontaneously hypertensive rat (SHR) may model aspects of human attention deficit hyperactivity disorder (ADHD). For example, just as responses by children with ADHD tend to be variable, so too SHRs often respond more variably than do Wistar-Kyoto (WKY) control rats. The present study asked whether behavioral variability in the SHR strain is influenced by rearing environment, a question related to hypotheses concerning the etiology of human ADHD. Some rats from each strain were reared in an enriched environment (housed socially), and others were reared in an impoverished environment (housed in isolation). Four groups--enriched SHR, impoverished SHR, enriched WKY, and impoverished WKY--were studied under two reinforcement contingencies, one in which reinforcement was independent of response variability and the other in which reinforcement depended upon high variability. The main finding was that rearing environment did not influence response variability (enriched and impoverished subjects responded similarly throughout). However, rearing environment affected body weight (enriched subjects weighted more than impoverished subjects) and response rate (impoverished subjects generally responded faster than enriched subjects). In addition, SHRs tended to respond variably throughout the experiment, whereas WKYs were more sensitive to the variability contingencies. Thus, behavioral variability was affected by genetic strain and by reinforcement contingency but not by the environment in which the subjects were reared.     

Water deprivation associated with operant conditioning inhibits hypertensive disease in young spontaneously hypertensive rats

The development of high blood pressure in young spontaneously hypertensive rats (SHR) is inhibited by operant conditioning motivated by chronic water deprivation. The present study showed that the inhibition of hypertension was not due to the operant conditioning,per se, but was a result of chronic water deprivation (23.5 hr schedule) imposed on the rats from five through 12 weeks of age. Blood pressures were measured directly using a carotid artery cannula and light enflurane anesthesia. The behaviorally conditioned SHR and the water-deprived SHR controls had equal blood pressures and were significantly less hypertensive than untreated or enriched environment SHR groups. The antihypertensive action of water deprivation was not detected by weekly indirect blood pressure measurements made in the awake state. Nonetheless, the chronicity of the deprivation-induced inhibition of hypertension was confirmed by a lesser degree of left ventricular hypertrophy in the deprived SHR relative to the nondeprived SHR. Our behavioral results again demonstrated hyperreactivity in the SHR relative to the Wistar Kyoto (WKY). This behavioral hyperreactivity in the SHR may explain the exaggerated increase in drinking in the deprived SHR groups when returned toad lib conditions. The data of this study and our previous work suggest that arousal differences between SHR and WKY strains are more reliably differentiated by fixed interval schedules of reinforcement than by a fixed ratio schedule. Hyperarousal may precede hypertension in the SHR, but it is undetermined whether hypertension can be found in the absence of hyperarousal in these rats.     

Independence of blood pressure and locomotor hyperactivity in normotensive and genetically hypertensive rat

The spontaneously hypertensive rat (SHR) exhibits locomotor hyperactivity in comparison to its normotensive progenitor Wistar-Kyoto (WKY) strain. We asked whether the hyperactive behavior was a direct consequence of elevated blood pressure in the hypertensive rat. Three experimental protocols were used to chronically alter blood pressure. In the first protocol, a group of adult SHRs was given hydralazine (20 mg/kg/day) in their drinking water to lower blood pressure. These animals exhibited a significant decrease in blood pressure, but no change in locomotor activity. In the second protocol, young SHRs (4 weeks of age) were treated with the same dosage of hydralazine until 16 weeks of age. Blood pressure was significantly decreased in these animals with no change in locomotor activity. In the third protocol, normotensive WKY and Sprague-Dawley (SD) rats were made hypertensive with unilateral renal clips. The resulting increase in blood pressure in these animals did not alter locomotor activity. These results suggest that locomotor hyperactivity is an inherent property of the SHR and is independent of blood pressure.