Chronic, severe hypertension does not impair spatial learning and memory in Sprague-Dawley rats

This study tested the hypothesis that long-term hypertension impairs spatial learning and memory in rats. In 6-wk-old Sprague-Dawley rats, chronic hypertension was induced by placing one of three sizes of stainless steel clips around the descending aorta (above the renal artery), resulting in a 20–80-mm Hg increase of arterial pressure in all arteries above the clip, that is, the upper trunk and head. Ten months later, the rats were tested for 5 d in a repeated-acquisition water maze task, and on the fifth day, they were tested in a probe trial; that is, there was no escape platform present. At the end of the testing period, the nonsurgical and sham control groups had similar final escape latencies (16±4 sec and 23±9 sec, respectively) that were not significantly different from those of the three hypertensive groups. Rats with mild hypertension (140–160 mm Hg) had a final escape latency of 25±6 sec, whereas severely hypertensive rats (170–199 mm Hg) had a final escape latency of 21±7 sec and extremely hypertensive rats (>200 Hg) had a final escape latency of 19±5 sec. All five groups also displayed a similar preference for the correct quadrant in the probe trial. Together, these data suggest that sustained, severe hypertension for over 10 mo is not sufficient to impair spatial learning and memory deficits in otherwise normal rats.     

Infantile stimulation and its effects on frustration- and fear-motivated behavior in rats

Infant rats that were either removed from the nest each day (handled) or left undisturbed (nonhandled) were, in adulthood, given 72 food-reinforced runway acquisition trials followed by 24 trials of extinction training with or without shock. Handled and nonhandled control animals were given runway training without food reinforcement. Reinforced rats ran faster than nonreinforced rats, and handled rats ran faster than nonhandled rats during the initial trials of runway acquisition irrespective of the reinforcement condition. Nonhadled rats stopped running sooner than handled rats when shock was introduced in the goalbox, but differences between handled and nonhandled rats given extinction training without shock were small. Results of a second experiment showed no differences between handled and non-handled rats in the magnitude of the depression effect after an incentive shift. It was concluded that infantile handling had little effect on frustration-motivated behavior, but did affect fear-motivated behavior.     

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.     

The borderline hypertensive rat (BHR): A new model for the study of environmental factors in the development of hypertension

While many studies have attempted to produce hypertension through the use of various environmental Stressors, few have succeeded in producing chronic elevations in blood pressure beyond levels considered to be borderline hypertensive (140–160 mm Hg systolic). The problem with most studies stems from the use of genetically normotensive animals and the selection of Stressors to which animals readily adapt. A new approach is suggested, which recognizes the role of genetics in human essential hypertension. Animals with one hypertensive parent do not develop spontaneous hypertension but show a more sensitive cardiovascular response to environmental Stressors than animals with normotensive parents. Preliminary studies revealed that animals with a mixed genetic history of hypertension develop spontaneous borderline hypertension. When subjected to shock-shock conflict, these borderline hypertensive rats (BHR) developed permanent hypertension that failed to abate even after a ten-week, shock-free recovery period. The hypertension was accompanied by elevated heart weight to body weight ratios and by significant cardiac pathology. Subsequent work has demonstrated that these animals also become hypertensive when fed a high-sodium diet. Finally, in a series of exercise studies, we found that BHRs subjected to a shock stressor were protected against stress-induced hypertension if they exercised daily. The potential of this model for studies of the mechanisms by which environmental variables produce permanent hypertension is discussed.     

Handling from weaning to adulthood does not prevent hyperdefensiveness induced by septal, medial accumbens, or medial hypothalamic lesions

Weanling male hooded rats were handled or not handled for 10 min each day, 5 days/week, for 6 weeks. At the end of this time all animals received one of the following: a septal lesion, a medial accumbens lesion, a medial hypothalamic lesion, or a sham lesion. The animals were tested for defensiveness toward the experimenter on Days 3, 7, and 14 postoperatively. All behavioral testing was done blind. Each of the three lesions increased defensiveness toward the experimenter. However, with each lesion, there was no difference in the defensiveness scores of preoperatively handled and nonhandled animals at any of the postoperative test sessions while those of animals with medial hypothalamic lesions did not. These results are consistent with observations that hyperdefensiveness occurs in human subjects following tumors in each of these brain areas in spite of their familiarity with the situation in which they are observed. They contrast with observations that mouse killing induced by septal lesions is readily prevented by preoperative exposure to a mouse.     

High calcium intake does not prevent stress-salt hypertension in dogs

Avoidance conditioning sessions and isotonic saline (1.3 L/day) were administered to dogs for 12 days under conditions of a low (0.1%) or high (1.5%) calcium diet. Twenty-four-hour mean arterial pressure increased comparably during the stress-salt conditioning periods on both the low (systolic: +16 ± 5 mm Hg; diastolic: +6 ± 2 mm Hg) and high (systolic: +17 ± 4 mm Hg; diastolic: +11 ± 4 mm Hg) calcium diets. Urine volume, sodium excretion, and serum calcium levels on the high calcium diet were not significantly different from those on the low calcium diet. In a second experiment, calcium was infused continuously for six days into the arterial circulation of normotensive or stress-salt hypertensive dogs at a rate of 0.12–0.23 mEq/min. Although serum calcium levels increased by up to 50% under these conditions, there were no significant effects on 24-hour levels of arterial pressure. In contrast to the protective effect of augmented potassium intake, these findings indicate that calcium intake does not influence the development of stress-salt hypertension in dogs.     

Beneficial effects of docosahexaenoic acid on active avoidance performance in 1K-1C hypertensive rats

The present study evaluated the role of chronic docosahexaenoic acid (DHA) supplementation on active avoidance learning task performance in experimental hypertension. Male Wistar rats were randomly divided into five experimental groups as follows: control, sham, DHA treated, 1K-1C hypertensive, and 1K-1C hypertensive+DHA treated. Hypertension was induced in 1K-1C rats via placing a silver clip (0.20-mm ID) around the left renal artery following a right uninephrectomy. DHA (36 mg/kg/day) was given to the treatment groups for 60 days by gastric gavage. Arterial blood pressure was measured by using the tail-cuff method. Active avoidance responses were determined by an automated shuttle-box. In brain (cerebrum) and hippocampus tissues, thiobarbituric acid reactive substances (TBARS) and nitrite levels were measured by fluorometric methods. DHA supplementation decreased blood pressure in hypertensive rats. Data from active avoidance training indicated that performance of active avoidance learning tasks were significantly impaired in 1K-1C hypertensive rats, but was completely restored by DHA supplementation. Increased cerebrum TBARS levels in 1K-1C rats were abolished by DHA administration. Cerebrum nitrite levels were lower in the DHA, 1K-1C and 1K-1C+DHA treated groups compared to controls. Hippocampus nitrite levels were lower in DHA treated and 1K-1C hypertensive rats compared to controls and higher in 1K-1C+DHA treated rats compared to the 1K-1C group. Our data indicates that DHA supplementation improves the performance of active avoidance learning tasks which is impaired in experimental hypertension. These affirmative changes might be due to a DHA-induced decrease in lipid peroxidation which may in turn limit the consumption of nitric oxide (NO) which promotes active avoidance learning.     

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.     

Effects of neonatal handling on play behavior and fear towards a predator odor in juvenile rats (Rattus norvegicus)

The effects of brief daily separation, also known as "handling," during the first 2 weeks of life on play behavior and fearfulness toward a predatory odor were assessed in juvenile rats. Handled rats were more playful than nonhandled control rats, and while handling had no effect on the direct response of these rats toward a predatory odor, handled rats did not exhibit a conditioned suppression of play when tested later in the same context where they had been exposed to the predatory odor. Handled rats were still wary of the environment in that they continued to show a heightened level of risk assessment behavior. These data suggest that early postnatal experiences may play a significant role in determining how an animal deals with predatory threats later in life.     

The effect of different hypertension models on active avoidance learning

This study tested the effects of different hypertension models on active avoidance learning in rats. Three-month-old male Wistar rats were divided randomly into six groups as follows: control (C), sham operated (sham), two kidney-one clip (2K-1C), one kidney-one clip (1K-1C), deoxycorticosterone-salt (DOCA), and N-omega-nitro-L-arginine-methyl ester (L-NAME) groups. Mean arterial blood pressures were significantly higher in four hypertensive groups compared with control and sham groups. The active avoidance training results indicated that hypertension state is associated with learning impairment. Thiobarbituric acid-reactive substances (TBARS) were determined as an indicator of lipid peroxidation in brain and hippocampus. Additionally, brain and hippocampus nitrite levels were studied.     

Early stimulation and patterned responding in rats

This experiment was designed to determine the extent to which performance differences on learning tasks arising from infantile handling reflect learning or emotionality differences. Handled and nonhandled rats were trained and tested in a controlled operant situation where a response on every other trial yielded reinforcement. A key light was turned on for 10 sec during each trial and was off during the 10-sec intertrial interval. The reinforced (S+) trials alternated in a regular sequence with nonreinforced (S–) trials. The pattern of S+ and S– trials recycled continuously throughout the session of 160 trials. The handled rats emitted more responses during both S+ and S– trials than did the nonhandled rats. However, when they were compared on the percentage of emitted responses that were reinforced, there was no significant differences between the two groups. These results were interpreted to suggest that infantile handling does not directly facilitate associative learning in rats.This research was aided by a grant from the National Research Council of Canada, 67-0247. I thank Linda Easton and Beverly Clark for their help in collecting and analyzing the data.     

Evidence for aggression-modulating pheromones in prepuberal pigs

A series of behavioral bioassays were conducted to determine the aggression-influencing properties of urine and other fluids. Subjects were prepuberal castrated male and female domestic pigs from commercial stocks. In the behavior assay, pigs were painted with a test fluid and grouped for a videotaped 90 min observation period. Experiment 1 validated use of videotape recording by showing that duration of aggressive behavior registered live was correlated with that obtained from video records (R = .98). In experiment 2, urine and plasma collected from actively aggressive pigs reduced the durations of aggressive behavior of test pigs compared with the effects of urine and plasma collected from socially stable, handled pigs. In Experiment 3, a new set of test pigs confirmed that urine from fighting pigs reduced the duration of attack by test pigs compared with urine from nonfighting, handled pigs. In addition, the suggested reproductive pheromone, 5 alpha-androst-16-en-3-one, substantially reduced the duration of attack. The effects of gender and aggressive state of urine-donor pigs on test pigs was determined in Experiment 4. Again, urine from castrated male and female aggressive pigs reduced attack by test pigs compared with the level of attack shown by test pigs coated with urine from handled castrated males and females. Urine from fighting and nonfighting intact males had similar effects on test pig aggression. In Experiment 5, urine was obtained from nonhandled, socially stable pigs in their home pens and again from the same pigs after they had been regrouped (aggressive). These urine types had no significant influence on test pigs' aggression over the entire 90-min observation. However, during the first 30 min nonhandled, nonfighting pigs' urine induced less aggression in test pigs than did urine from fighting pigs. Results indicate that urine and blood plasma from aggressive pigs reduces aggression by test pigs compared with the effects of urine from handled pigs. Handling may increase the aggression-promoting properties of urine, and aggression may inhibit this aggression-promoting property.     

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.     

CLASSICAL CONDITIONING OF DECREASES IN HUMAN SYSTOLIC BLOOD PRESSURE1

Decrease in human systolic blood pressure of 4.35 mm Hg (range: 0 to 12 mm Hg) were classically conditioned in normal and hypertensive subjects using a delayed conditioning paradigm in which a 30-sec auditory stimulus (the conditioned stimulus) was followed immediately by tilting the subject 15° head-down to elicit small decreases in blood pressure. Conditioning occurred within five trials. A control group demonstrated that sensitization of the reflex by repeated tilting could not account for the blood-pressure decreases associated with the conditioned stimulus in experimental subjects.     

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.     

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.     

Contrasting effects of social stress and foot-shock on acute cardiovascular response in salt-sensitive rats

Repeated defeat by an aggressive resident attacker rat produces a large decrement in systolic blood pressure (SBP) in male S/JR rats. The present experiments compared the cardiovascular (CV) response of male S/JR rats exposed either to repeated defeat, or to a common laboratory stressor, electric foot-shock. Using the tail-cuff method of determining SBP, the results of Experiment 1 replicated the previous finding that on the second and subsequent exposures, repeated defeat is followed by an acute decrement in SBP (30-40 mm Hg in magnitude). In contrast, repeated exposures to foot-shock were followed by acute increases in SBP (20-40 mm Hg) and in heart rate (HR). In Experiment 2, mean arterial blood pressure (MAP) and HR were measured directly from chronically cannulated male S/JR rats after defeat or exposure to foot-shock: again, defeated males exhibited an acute decrease in MAP, whereas the MAP of rats exposed to foot-shock tended to increase. In Experiment 3 we varied the parameters of shock intensity and the social context of shock exposure. Male S/JR rats exposed to more intense foot-shock than in the previous experiments or to foot-shock while paired with one of the resident attacker rats all exhibited acute increases in SBP. The results of these experiments indicate that CV response to defeat may be qualitatively different from CV response to foot-shock.     

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 effects of pre- and postweaning rearing conditions on latent inhibition and partial reinforcement extinction effect in male rats

Male rats were either handled daily or left undisturbed (nonhandled) during the first 21 days of life. At weaning (Day 22) animals in each early treatment condition were assigned to two housing conditions, isolated or grouped, creating four early/late treatment conditions: Handled-Grouped (HG), Handled-Isolated (HI), Nonhandled-Grouped (NHG), and Nonhandled-Isolated (NHI). At maturity, all animals were tested in the latent inhibition (LI, Experiment 1) and the partial reinforcement extinction effect (PREE, Experiment 2) paradigms. In LI, animals receiving prior nonreinforced preexposure to a stimulus (PE) show subsequently retarded conditioning to that stimulus as compared to nonpreexposed (NPE) controls. In the PREE, partially reinforced (PRF) animals exhibit higher resistance to extinction as compared to continuously reinforced (CRF) controls. LI and PREE were obtained in the HG condition, but were impaired in NHG and HI animals. The pattern of impairment was different in the two conditions. The absence of LI in NHG males was due to increased suppression in the PE group, whereas in HI males, was due to decreased suppression in the NPE group. Likewise, the attenuation of the PREE in NHG males stemmed primarily from decreased resistance to extinction in the PRF group, whereas in HI males, it resulted from increased resistance to extinction in the CRF group. The combination of nonhandling and isolation led to the reinstatement of both LI and PREE: normal LI and PREE were obtained in the NHI animals. These results demonstrate that early rearing experience interacts with later experience differentially depending upon the later experience.     

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.