The emergence test: effects of psychotropic drugs on neophobic disposition in Wistar Kyoto (WKY) and Sprague Dawley rats.

1. The Emergence Test (ET), a variation of the open field test in which the rat is not handled, and is purported to measure neophobia, was applied to Wistar Kyoto (WKY) and Sprague Dawley (S-D) rats. 2. While no-stress control WKY rats were less active in the ET, pre-treatment with shock stress exacerbated strain differences. WKY rats, previously exposed to shock, did not emerge from the home cage start box during repeated testing, whereas previously stressed S-D rats vacated the home cage quickly and revealed increasing behavioral agitation. 3. Diazepam reduced emergence latency only in S-D rats, whereas nomifensine significantly increased head poke responses in WKY rats. 4. WKY rats responded to the ET with characteristically depressive behavior, whereas S-D rats responded to the same ET with behavioral agitation and anxiety. The implications of these behavior patterns for discriminating between anxiety and depressive behavior are presented.

Paradoxical hormonal and behavioral responses to hypothyroid and hyperthyroid states in the Wistar-Kyoto rat.

Wistar-Kyoto (WKY) rats show endogenous depressive behavior that can be reversed by antidepressants. Given that WKYs exhibit decreased sensitivity to some antidepressants and treatment-resistant depressed patients often show hypothalamic-pituitary-thyroid (HPT) dysregulation, we examined the behavioral and HPT hormonal responses of WKYs to altered thyroid status. "Euthyroid" WKYs had elevated basal plasma TSH and T(3) levels as compared to Wistars. Hypothyroidism increased TSH levels more in WKYs than in Wistars and increased response latency in the open field test (OFT) of WKYs only. Administration of T(4) and T(3) suppressed plasma TSH equally in both strains. Wistars responded to increased T(3) levels with decreased response latency and increased activity in the OFT, but increased immobility in the forced swim test. In contrast, WKYs responded only to the high T(3) levels with decreased response latency in the OFT. These results suggest the existence of a decreased central nervous system sensitivity to thyroid hormones in WKYs that could be related to their depressive behavior.

Negative affect and voluntary alcohol consumption in Wistar-Kyoto (WKY) and Sprague-Dawley rats.

Based on the assumption that the Wistar-Kyoto (WKY) rat strain represents an animal model for depressive behavior, the purported relationship between depression and alcohol consumption was investigated in three experiments. WKY rats consumed more alcohol than Sprague-Dawley (S-D) rats when offered a choice between a 7% alcohol solution and tap water. Subsequently, the severity of stress-induced stomach ulcers was significantly less in WKY rats that had access to alcohol. In Experiment 2, WKY and S-D rats were assigned to either an alcohol access treatment or to a water-only treatment for 27 days and subsequently observed in the open-field test (OFT) and the elevated plus-maze (EPM). Access to alcohol reduced response latency in the OFT, and increased the percent time in the open arm and the total number of arm entries in the EPM for WKY rats. In Experiment 3, the antidepressant, imipramine, reduced alcohol consumption in both strains and significantly increased percent time in the open arms of the EPM for WKY rats. These studies support the assumption that depression and alcohol consumption may be related.

Gender differences in acute and chronic stress in Wistar Kyoto (WKY) rats.

While females are considered more susceptible to depressive behavior, this assertion is not strongly supported by the experimental literature. Since stress contributes to depressive behavior, male and female Wistar Kyoto (WKY) rats were exposed to either one session (acute stress) or 5 sessions (chronic stress) of restraint plus cold in order to study depressive behavior in male and female rats. After their respective treatment exposure, rats were tested in the open field test (OFT) and for retention of a passive-avoidance (P-A) task. One stress session resulted in significant immobility in the OFT for males, whereas 5 sessions were required to produce similar immobility in female rats. Acute stress interfered with the retention of the P-A response for males, while both acute and chronic stress produced poor P-A responses in female rats. Food consumption decreased progressively, as a function of stress sessions, in female rats, whereas feeding in males returned to control levels after five stress days. Both acute and chronic stress exacerbated the stress ulcer response in male rats, but not in female rats. Chronic, but not acute, stress resulted in an increase in serotonin transporter mRNA levels in the dorsal raphe nucleus of both male and female rats. The general consensus from these data suggested that female rats were more vulnerable to chronic stress and consequently supported the notion that females may be more susceptible to stress-induced behavioral depression. Key Words: WKY rats, acute and chronic stress, gender, passive avoidance, open field behavior, stress-ulcer, adrenal weight, serotonin, dorsal raphe nucleus

Differences in the stress response of Wistar-Kyoto (WKY) rats from different vendors.

Wistar-Kyoto (WKY) rats are hyperresponsive to stress and prone to stress ulcer. However, some variability in these general findings has been reported. This variability may reflect differences in the rat stock from different WKY rat vendors. WKY rats from Taconic (WKY-T), Harlan Sprague-Dawley (WKY-H), and Charles River (WKY-CR) were observed in the open-field test (OFT) and the forced-swim test (FST), and subsequently exposed to ulcerogenic water-restraint stress. There were no differences between vendor stocks in the FST, but WKY-CR rats were significantly more immobile in the OFT as compared to WKY-T and a Wistar control group. WKY-CR and WKY-H rats revealed significantly more ulcers as compared to WKY-T and Wistar rats. The WKY inbreeding programs at Charles River and Harlan, as compared to the outbreeding practice at Taconic may contribute to these vendor differences. These data indicate that WKY rat sublines from different vendors represent an important source of variability when comparing studies of stress reactivity using WKY rats.

Developmental factors modify stress ulcer incidence in a stress-susceptible rat strain.

Our multifactor theory of stress ulcer assumes that environmental factors that operate during early growth stages influence the elaboration of stress ulcer in adult rats. The theory would predict that rats exposed to either neonatal handling, or raised in a stimulus enriched environment, would reveal differences in stress ulcer susceptibility. In study 1, some Wistar rats and ulcer-susceptible Wistar Kyoto (WKY) rats were handled daily from birth to day 21, whereas other rats from each strain were not disturbed. In study 2, Wistar and WKY rats were raised (3 months) in a large stimulus-dense enriched environment, whereas other rats from each strain were raised in standard rat cages where visual and auditory stimuli were minimized. At 3 months all rats were observed in the open field test (OFT), a test of emotionality, as well as the Porsolt forced swim test (FST), a test of behavioral depression, and subsequently exposed to the ulcerogenic water restraint procedure. Neonatal handling produced results suggesting increased wall climbing activity in the FST, reduced response latency in the OFT, increased body weight and reduced ulcer severity, but these differences were not significant. Rearing in an enriched environment produced similar results but these difference were more pronounced and significant in the Wistar rats as compared to the WKY rats. Thus early environmental manipulations can influence adult behavior and the elaboration of stress ulcer disease, but the impact of these manipulations is less salient in an organism with an endogenous susceptibility to the disease.

Strain differences in hypothalamic-pituitary-adrenal activity and stress ulcer.

Strain differences in stress responsiveness have been previously described, but specific components of the hypothalamic-pituitary-adrenal (HPA) axis responsible for stress hypo- or hyperactivity have not yet been characterized. This study proposed to analyze the effect of restraint stress on different measures of HPA function and stress ulcer in stress-ulcer prone Wistar-Kyoto (WKY) and Fisher 344 (F-344) rats and in the ulcer-resistant Wistar strain. Adult male rats of these strains were sham adrenalectomized, adrenalectomized, and adrenalectomized-replaced with corticosterone pellet. Ten days after surgery, animals were subjected to the 2-h ulcerogenic water-restraint stress and killed 2 h later. Intact WKY rats had dramatically more ulcers and higher anterior pituitary adrenocorticotropic hormone (ACTH) and proopiomelanocortin mRNA levels than the other two strains. In WKY rats, adrenalectomy increased ulcer incidence but did not affect thymus weight, ACTH content, or hypothalamic corticotropin-releasing factor mRNA levels, in contrast to the profound effects of adrenalectomy on these parameters in the other strains. Furthermore, corticosterone replacement was either without effect or enhanced the effect of adrenalectomy on these parameters in WKY rats, while it reversed the effects of adrenalectomy in the other strains. These data imply that WKY rats respond to stress with enhanced and prolonged changes in peripheral functions that are regulated by glucocorticoids, suggesting the presence of impaired efficacy of the glucocorticoid negative feedback on HPA function.

Reduced incidence of stress ulcer in germ-free Sprague Dawley rats.

Recent findings with respect to the role of spiral gram-negative bacteria in peptic ulcer disease have stimulated interest in discerning the role of these agents in stress ulcer disease. We tested the hypothesis that a standard restraint-cold ulcerogenic procedure would fail to produce ulcers in axenic rats. Axenic, as well as normal Sprague Dawley rats, were exposed to a cold-restraint procedure. The germ-free condition was maintained throughout the study in the axenic rats. Axenic rats had significantly fewer ulcers as compared to normal rats exposed to the standard cold-restraint procedure, as well as handling control rats. The data represent the first report suggesting a microbiologic component in the development of stress ulcer using the rat model.