Wistar-Kyoto Rat Strain Research Articles

Effects on Atrial Fibrillation in Aged Hypertensive Rats by Ca 2+ -Activated K + Channel Inhibition

We have shown previously that inhibition of small conductance Ca(2+)-activated K(+) (SK) channels is antiarrhythmic in models of acutely induced atrial fibrillation (AF). These models, however, do not take into account that AF derives from a wide range of predisposing factors, the most prevalent being hypertension. In this study we assessed the effects of two different SK channel inhibitors, NS8593 and UCL1684, in aging, spontaneously hypertensive rats to examine their antiarrhythmic properties in a setting of hypertension-induced atrial remodeling. Male spontaneously hypertensive rats and the normotensive Wistar-Kyoto rat strain were divided in 2×3 groups of animals aged 3, 8, and 11 months, respectively. The animals were randomly assigned to treatment with NS8593, UCL1684, or vehicle, and open chest in vivo experiments including burst pacing-induced AF were performed. The aging spontaneously hypertensive rats were more vulnerable to AF induction both by S2 stimulation and burst pacing. Vehicle affected neither the atrial effective refractory period nor AF duration. SK channel inhibition with NS8593 and UCL1684 significantly increased the atrial effective refractory period and decreased AF duration in both the normotensive and hypertensive strains with no decline in efficacy as age increased. In conclusion, SK channel inhibition with NS8593 and UCL1684 possesses antiarrhythmic properties in a rat in vivo model of paroxysmal AF with hypertension-induced atrial remodeling. The present results support the notion that SK channels may offer a promising new therapeutic target in the treatment of AF.

Hepatic expression of spermatogenic genes and their transiently remarkable downregulations in Wistar-Kyoto rats in response to lead-nitrate administration: strain-difference in the gene expression patterns

Administration of lead ion (Pb) to rats and mice affects hepatic functions such as the induction of hepatic cell proliferation and upregulation of cholesterol biosynthesis. To identify the genes for which expression changes in response to Pb-administration, we analyzed hepatic gene expression patterns in stroke-prone spontaneously hypertensive rat (SHRSP), its normotensive control, Wistar-Kyoto rat (WKY), and Spraque-Dawley (SD) rat strains, 3, 6, and 12 hr later after single i.v. injection of lead nitrate (LN) at a dose of 100 µmol using a DNA microarray technique. The data analysis demonstrated that the expression of a great number of genes was transiently and remarkably downregulated 3 hr after LN-injection, and then recovered to control levels only in LN-injected WKY. These normal hepatic expression levels in WKY and SHRSP were much higher than those in SD rats. Furthermore, most of these genes were ones thought to be expressed specifically in the spermatids and/or testes; i.e. genes encoding protamin 1, transition protein 1, and transition protein 2. These findings suggest that the regulation system common to expression of all of these genes could be a target site of Pb-toxic action, at least, in the liver of WKY, and that this system might be similar to the system essential for spermatogenesis, especially spermiogenesis, in the testis. In addition, it appears that clarifying the cause of the difference between the systems of WKY and SHRSP might aid in identifying the pathologic genes in SHRSP. Finally, it will be an important to clarify how the products of the genes related to spermatogenesis, including spermiogenesis, are functional in the livers of WKY and SHRSP.

Central monoamine levels differ between rat strains used in studies of depressive behavior

Previous studies have shown that the Wistar-Kyoto (WKY) rat strain may be a genetic model of depression when their behaviors are compared to Sprague-Dawley (SD) or Wistar (WIS) rats. Significant differences in dopamine (DA), serotonin (5-HT), and norepinephrine (NE) transporter site densities have been reported when comparing WKY to both SD and WIS rats. Susceptibility of WKY rats to anxiety and depressive behavior may be related to underlying differences in monoamine levels in various regions of the brain. Levels of monoamines (DA, 5-HT and NE) and their metabolites were measured in monoaminergic cell body, cortical and limbic brain regions using HPLC with electrochemical detection and compared between WKY, WIS and SD rats. In regions where strain differences in monoamine levels were observed (the basolateral amygdala, subregions of the hippocampus and the nucleus accumbens shell), WKY rats consistently had lower levels than SD rats. Similarly, WKY rats had lower monoamine levels compared to WIS, although these differences were observed in a more restricted number of brain regions. Interestingly, WIS rats showed reduced levels of the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) in several regions including the prefrontal cortex, subregions of the hippocampus and subregions of the hypothalamus, suggesting decreased 5-HT turnover when compared to both WKY and SD rats. Overall, these results imply that decreased monoamine levels, combined with alterations in transporter sites, may be related to the predisposition of WKY rats towards depressive behavior.

Differential patterns of alcohol consumption and dopamine-2 receptor binding in Wistar-Kyoto and Wistar rats.

The Wistar-Kyoto (WKY) rat strain has been described as an animal model of depressive behavior that consumes significantly greater amounts of alcohol compared to the Wistar (WIS) rat strain. Since the mesolimbic dopamine (DA) type-2 (D2) receptors mediate reward-related behaviors, the present study measured the binding of [(125)I]-Iodosulpiride to D2 receptors in the brains of WKY versus WIS rats following 24 days of voluntary alcohol or water consumption. Alcohol consuming WKY rats showed a significant increase in D2 receptor binding in several regions of the mesolimbic and nigrostriatal systems. In contrast, alcohol consuming WIS rats showed a reduction in D2 receptor binding in DA cell body areas. The differential regulation of D2 receptors by voluntary alcohol consumption in the two rat strains suggests that D2 receptor mediated neurotransmission may be playing a role in the increased alcohol drinking behavior reported in WKY rats.

N-methyl- d-aspartic acid receptors are altered by stress and alcohol in Wistar–Kyoto rat brain

Previous studies have shown that the Wistar–Kyoto (WKY) rat strain is more sensitive to stressors and consumes significant quantities of alcohol under basal as well as stressful conditions when compared to other strains. Given that the glutamate neurotransmitter system has been implicated in depression and addiction, the goals of the present study were to investigate the effects of stress and stress-alcohol interactions on N-methyl- d-aspartate (NMDA) receptors in the rat brain. Thus this study measured the binding of [ 3H] MK-801 to NMDA receptors in the prefrontal cortex (PFC), caudate putamen (CPu), nucleus accumbens (NAc), hippocampus (HIP) and basolateral amygdala (BLA) in WKY rats in comparison to the Wistar (WIS) rat strain. Our results suggested that while voluntary alcohol consumption did not alter NMDA receptors in the PFC, CPu or NAc in either rat strain, it increased NMDA receptors in the HIP and BLA in both strains. In contrast, chronic stress increased NMDA receptors in the PFC, CPu, NAc in WKY rats but not in WIS rats. Chronic stress also decreased NMDA receptors in the HIP and increased NMDA receptors in the BLA in both strains. Alcohol co-treatment with stress increased NMDA receptors in the PFC, CPu and NAc in WKY rats but not in WIS rats. Interestingly, while alcohol co-treatment did not reverse stress induced decreases in NMDA receptors in the HIP, it reduced the binding of NMDA receptors in the BLA to control levels in both strains. Thus it appears that NMDA receptors in the PFC, CPu and NAc may be more sensitive to the effects of stress and could be implicated in the stress-induced alcohol consumption behavior seen in WKY rats. In contrast, NMDA receptors in the HIP and BLA may reflect an adaptive response and may not be responsible for the stress susceptible phenotype of the WKY rat strain.

Cytisine and diarylpropionitrile may not modulate depressive behaviors in female WKY rats

Event Abstract Back to Event Cytisine and diarylpropionitrile may not modulate depressive behaviors in female WKY rats Praveen Kandi1, Joseph Tanga1 and Renee L. Hayslett1* 1 Mercer University, College of Pharmacy and Health Sciences, United States Nicotine and estrogen may regulate mood and influence depressive behaviors. Results from rodent studies suggest the potential involvement of nicotinic cholinergic receptors and estrogen receptors in antidepressant-like behavior. Specifically, blockade of nicotinic receptors containing the β2 subunit may be responsible for antidepressant effects [1]. Furthermore, selective estrogen receptor β (ERβ) agonists have been shown to reduce depressive behaviors in female ovariectomized rats [2]. In this study, we evaluated potential anti-anxiety and anti-depressant effects of a nicotinic agent, cytisine, and a selective estrogen receptor modulator, diarylpropionitrile (DPN), in an animal model of depression in female rats. Cytisine is a partial agonist at α4β2 receptors and a full agonist at α3β4 and α7 receptors. DPN is a selective ERβ agonist. The Wistar Kyoto (WKY) rat strain is a putative model of endogenous depression. Compared to their control, the Wistar rat, WKY rats demonstrate hormonal, behavioral and physiological parameters that are similar to symptoms found in depressed patients [3]. WKY rats appear to be resistant to standard SSRI antidepressants. Interestingly, a subset of depressed patients does not respond to SSRI drugs. Therefore, this model could be useful in identifying novel agents for antidepressant therapy. Female WKY and Wistar rats (n=6-8/group) received subcutaneous injections of cytisine (0.5, 1, 1.5 mg/kg), DPN (10 μg, 0.5 mg/kg, 1 mg/kg) or vehicle prior to being tested in the elevated plus maze (EPM), locomotor activity chamber (LCA) and forced swim test (FST). Dosages and latencies for drug administration were chosen based on previous reports and data from preliminary studies. Our results show that WKY rats displayed significantly more depressive behaviors compared to Wistar rats. WKY rats had significantly more immobility counts and also significantly less locomotor activity compared to Wistar rats. No differences were detected in the EPM with cytisine or DPN in either strain. In addition, none of the doses of DPN produced significant effects on behavior in the other tested paradigms. Because the rats had intact reproductive systems, their behavior could be influenced by the estrous cycle. At the tested doses of cytisine, the 1.5 mg/kg dose significantly increased immobility in the FST in Wistar and WKY rats. There was a trend for WKY rats treated with 1.5 mg/kg of cytisine to exhibit reduced locomotor activity; however, this did not reach statistical significance. At this dose of cytisine there appears to be an exaggeration of depressive behaviors. This observation could be due to activation of nicotinic receptors in the peripheral ganglia, which may cause autonomic dysregulation and account for the decrease of locomotor activity and increase in immobility in the FST. In conclusion, cytisine and DPN do not appear to have anti-anxiety or anti-depressant effects in the female WKY rat. Additional experiments that test a wider range of doses, combination of drugs, and consider the phase of estrous cycle are necessary.

Antidepressant-Like Effects of κ-Opioid Receptor Antagonists in Wistar Kyoto Rats

The Wistar Kyoto (WKY) rat strain is a putative genetic model of comorbid depression and anxiety. Previous research showing increased kappa-opioid receptor (KOR) gene expression in the brains of WKY rats, combined with studies implicating the KOR in animal models of depression and anxiety, suggests that alterations in the KOR system could have a role in the WKY behavioral phenotype. Here, the effects of KOR antagonists in the forced swim test (FST) were compared with the WKY and the Sprague-Dawley (SD) rat strains. As previously reported, WKY rats showed more immobility behavior than SD rats. The KOR antagonists selectively produced antidepressant-like effects in the WKY rats. By contrast, the antidepressant desipramine reduced immobility in both strains. Brain regions potentially underlying the strain-specific effects of KOR antagonists in the FST were identified using c-fos expression as a marker of neuronal activity. The KOR antagonist nor-binaltorphimine produced differential effects on the number of c-fos-positive profiles in the piriform cortex and nucleus accumbens shell between SD and WKY rats. The piriform cortex and nucleus accumbens also contained higher levels of KOR protein and dynorphin A peptide, respectively, in the WKY strain. In addition, local administration of nor-binaltorphimine directly into the piriform cortex produced antidepressant-like effects in WKY rats further implicating this region in the antidepressant-like response to KOR antagonists. These results support the use of the WKY rat as a model of affective disorders potentially involving KOR overactivity and provide more evidence that KOR antagonists could potentially be used as novel antidepressants.

Strain differences in the distribution of N-methyl- d-aspartate and gamma (γ)–aminobutyric acid-A receptors in rat brain

Aims Previous studies have shown that the Wistar–Kyoto (WKY) rat strain exhibits depressive symptoms such as anhedonia, psychomotor retardation, ambivalence and negative memory bias following exposure to stress. Given the involvement of excitatory glutamate and inhibitory gamma (γ)-aminobutyric acid (GABA) signaling pathways in influencing depressive behavior, the present study investigated strain differences in the distribution of central N-methyl- d-aspartate (NMDA) and GABA A receptor sites in WKY compared to their inbred counterpart, Wistar (WIS) rats. Main methods Quantitative autoradiographic analysis was used to map the binding and distribution of NMDA and GABA A receptors in various brain regions in WKY and WIS rats. Key findings Results indicated a significant difference between the two strains. Lower NMDA receptor binding was found in the anterior cingulate cortex, caudate putmen, nucleus accumbens, CA1 region of the hippocampus and the substantia nigra pars reticulata in WKY compared to WIS rats. Conversely, higher GABA A receptor binding was found in the amygdala, caudate putmen, dentate gyrus, CA2 and CA3 fields of the hippocampus, periaqueductal grey and substantia nigra pars reticulata in WKY compared to WIS rats. Significance Given that these two rat strains differ in their behavioural, endocrine and neurochemical profile, the observed strain differences in NMDA and GABA A receptor binding suggest that these two neurotransmitter systems may be involved in the depressive and stress-sensitive phenotype of the WKY rat strain.

P.2.09 The source of resting and physiologically-evoked L-glutamate levels in prefrontal cortex in awake rats

the central regulation of stress and anxiety. Wistar Kyoto (WKY) rats are a genetically selected strain which has a marked elevation in anxiety. Previous studies have shown that WKY rats exhibit depressive-like behaviour in a wide range of behavioural paradigms and show reduced responsiveness to some antidepressants when compared to other, less anxious strains (reviewed in [3]). WKY rats also show dysregulation of the HPA axis, with increased basal levels of ACTH and CORT when compared to other rat strains. Whilst it is clear that cortical regions play a role in the integration of the stress response, the relative contribution of various divisions within the cortex to the altered stress responsivity of MS or WKY rats remain unknown. The immediate early gene, c-fos, is rapidly expressed in several brain regions in response to various stressors and is therefore a reliable indicator of activated cell populations in the central nervous system. Following acute exposure to open field (10 min), animals were sacrificed at 2 hours, a time-point which allows for the peak expression of c-fos to be detected. Using c-fos protein immunoreactivity we have compared the response of MS and non-MS Sprague Dawley rats following exposure to an acute psychological (open field) stressor, to analyse their adult behaviour. Defecation rates and behavioural analysis in the openfield were also quantified. The effect of the open field stressor on the WKY rat strain was also assessed to allow a comparison of an environmental and genetic model of depression to be made. Several cortical-limbic structures were analysed for the presence of c-fos positive immunoreactivity including the prelimbic cortex, infralimbic cortex and the rostral and caudal anterior cingulate cortices. These regions of interest were chosen as dysfunctional cortical-limbic structures have been implicated in depression. Our data demonstrate distinct activation patterns within these cortical regions following stress, with significant (p< 0.05) increases in the number of c-fos positive cells found in all regions analysed. These findings suggest an altered cortical activity in these animals that is consistent with that seen in human depressed patients, further supporting their use as animal models of depression. The identification of this neuronal activation pattern may in turn provide further insight into the neurochemical pathways through which therapeutic strategies for depression could be derived.

Genetic Mapping Found Major QTLs for Antibody-Induced Glomerulonephritis in WKY Rats

Genetic bases of glomerulonephritis, a major cause of kidney dysfunction in humans and one of the most characteristic complications of autoimmune disorders such as Goodpasture syndrome, are complex. The Wistar-Kyoto (WKY) rat strain is well characterized for its susceptibility to autoantibodies against glomerular basement membrane (GBM), however the molecular mechanisms underlining the phenotype are largely unknown. Here we performed a whole genome scan using a backcross (BC) F(1) (WKY x DA) x WKY population, for which the DA rat is a nonsusceptible control strain. We found two significant QTLs on chromosomes 1 and 12, which were involved in elevated levels of proteinuria and kidney weight index, respectively. The relevance of these QTLs with the genetic factors involved in autoimmunity and renal disease is discussed.

Region specific decrease in glial fibrillary acidic protein immunoreactivity in the brain of a rat model of depression

A growing body of evidence from human postmortem and animal studies suggests that deficits in glial cell (particularly astrocytes) density and function, in limbic regions of the brain contribute to the etiology of depressive disorders. Despite the widespread use of Wistar-Kyoto (WKY) rat strain as a model of depression and stress susceptibility, there is a paucity of data examining whether alterations in brain astrocytic population are present in the model. In the present study, we investigated the expression of the astrocytic markers glial fibrillary acidic protein (GFAP) in various brain regions in WKY rats in comparison to Sprague–Dawley rats. A significant deficit in GFAP-immunoreactive cells was found in the prefrontal cortex region (infralimbic, prelimbic and anterior cingulate cortex), in the basolateral amygdala as well as in the hippocampus (CA3 and dentate gyrus) in WKY rat brain. No statistical difference was found in the other brain regions analyzed (insular cortex, somatosensory cortex, CA1 and callosal white matter). No difference was found in the total density of astrocytes (assessed by s-100β immunoreactivity), neurons (determined by NeuN expression) or in the total number of cells in the regions of interest. A slight increase in the intensity of s-100β immunoreactivity was observed. The lower expression of GFAP in WKY rats was further confirmed by Western-blot analysis. These results suggest that specific astrocytic deficits in GFAP expression in corticolimbic circuits may be a general correlate of depressive-like behavior in animal models in addition to human major depression. Moreover, they suggest that glial physiology may become a therapeutic target in depression and other stress-related conditions.

Methylphenidate does not increase ethanol consumption in a rat model for attention-deficit hyperactivity disorder—the spontaneously hypertensive rat

Attention-deficit hyperactivity disorder (ADHD) is a behavioural disorder that has been suggested to result from disturbances in the dopaminergic system of the brain. The most effective drugs used to treat ADHD are the psychostimulants, methylphenidate and amphetamine. They block dopamine transporters and increase dopamine release, thereby increasing the extracellular concentration of dopamine and altering dopamine signaling. Drugs of abuse, such as cocaine, also block dopamine transporters, which raises the concern that treatment of children with ADHD with psychostimulants might increase their susceptibility to drug addiction. The present study was aimed at investigating whether treatment with methylphenidate at an early stage of development increased preference for ethanol in a widely used rat model for ADHD, the spontaneously hypertensive rat (SHR). SHR display the three major characteristics of ADHD (hyperactivity, impulsivity, poor sustained attention) compared to their progenitor Wistar-Kyoto (WKY) rat strain. Ethanol increased locomotor activity of SHR slightly more than WKY when injected intraperitoneally (0.6 g/kg). SHR also spent more time in the inner zone of the open field than WKY, consistent with SHR being less anxious than WKY. When given free access to ethanol-containing solutions of increasing concentration, SHR consumed less ethanol than WKY. Treatment with methylphenidate at an early age (P21 to P35) did not alter ethanol consumption in adult SHR or WKY, suggesting that it does not increase susceptibility to ethanol addiction in these rats. In vitro superfusion studies further demonstrated that preadolescent methylphenidate treatment did not have long-term effects on dopamine release in adult SHR and WKY striatum. A major finding of this study is the fact that methylphenidate treatment did not increase alcohol use in SHR.

Testosterone influences renal electrolyte excretion in SHR/y and WKY males

BackgroundThe Y-chromosome (Yc) and testosterone (T) increase blood pressure and may also influence renal electrolyte excretion. Therefore, the goal of this study was to determine if the Yc combined with T manipulation could influence renal Na and K excretion.MethodsTo investigate the role of the Yc and T, consomic borderline hypertensive (SHR/y) and normotensive Wistar-Kyoto (WKY) rat strains were used (15 weeks) in three T treatment groups: castrate, castrate with T implant and gonadally intact males. Urine was collected (24 hrs at 15 weeks of age) for Na and K measurements by flame photometry. RT-PCR was used to demonstrate the presence of renal androgen receptor (AR) transcripts. Plasma T and aldosterone were measured by RIA. In another experiment the androgen receptor was blocked using flutamide in the diet.ResultsNa and K excretion were decreased by T in SHR/y and WKY. AR transcripts were identified in SHR/y and WKY kidneys. Plasma aldosterone was decreased in the presence of T. Blockade of the AR resulted in a significant increase in Na excretion but not in K excretion in both SHR/y and WKY males.ConclusionT influences electrolyte excretion through an androgen receptor dependent mechanism. There was not a differential Yc involvement in electrolyte excretion between WKY and SHR/y males.

Lung Transplantation in the Fischer 344→Wistar Kyoto Rat Strain Combination is Not Suitable to Study Bronchiolitis Obliterans

To elucidate the pathogenesis of bronchiolitis obliterans (BO) a reliable animal model is needed. According to the literature, lung transplantation from Fischer 344 (F344) to Wistar Kyoto (WKY) rats is the only model that reliably results in BO without a further stimulus. We performed orthotopic left lung transplantation in F344 to WKY rats and in both isogeneic rat strain combinations. Suture and cuff techniques for anastomosis were compared. The time course of rejection and the morphology of the bronchial anastomoses were documented by repeated flat-panel volumetric computed tomography (fpVCT) in the living animal. Graft histopathology was analyzed 3 months post-transplant. According to the graft outcome, as revealed by fpVCT, grafts were sub-divided into two groups: In Group 1, infiltrates due to acute rejection occurred early after transplantation and resolved thereafter. Graft histopathology showed minor changes but no BO. In Group 2, acute rejection caused total atelectasis that never resolved. After 3 months, grafts were shrunken and exhibited tissue remodeling with some similarities to BO. No correlation between graft outcome and anastomotic technique was apparent. Modeling lung transplantation using the F344-to-WKY combination is without clinical relevance because BO does not develop in grafts with life-sustaining function. Consecutive fpVCT is useful to monitor pathologic changes in rat pulmonary grafts.

Differences in striatal spiny neuron action potentials between the spontaneously hypertensive and Wistar-Kyoto rat strains

The spontaneously hypertensive rat (SHR) and the Wistar-Kyoto (WKY) inbred rat strains display behavioral differences characterized by relative increases and decreases in levels of activity. Both strains have subsequently been utilized as animal models of hyperactive and hypoactive behavioral traits. The etiology of these behavioral characteristics is poorly understood, but may stem from alterations in the physiology of selected neural circuits or catecholamine systems. This study investigated the cellular properties of neurons from three genetically related strains: the SHR; WKY; and Wistar (WI). In vivo intracellular recordings were made under urethane anesthesia from spiny projection neurons in the striatum, a brain area involved in behavioral activation. Results obtained from 71 spiny projection neurons indicate that most cellular properties of these neurons were very similar across the three strains. However, the amplitude and half-duration of both spontaneously occurring and current-evoked action potentials were found to be significantly different between the SHR and WKY strains with neurons from the SHR firing action potentials of relatively greater amplitude and shorter duration. Action potential parameters measured from the WI rats were intermediate between the two other strains. These differences in action potentials between two behaviorally distinct strains may reflect altered functioning of particular membrane conductances.

ACE and ACE2: their role to balance the expression of angiotensin II and angiotensin-(1–7)

The discovery of angiotensin-converting enzyme 2 (ACE-2) has revealed a far more complex enzymatic cascade that may influence the renin-angiotensin system within the kidney, specifically the expression of the functional products angiotensin II (Ang II) and Ang-(1-7). The regulation of this critical system involved in blood pressure control must now encompass the integral relationship of ACE and ACE-2 activities.

Sequence analysis of Drd2, Drd4, and Dat1 in SHR and WKY rat strains

BackgroundThe Spontaneously Hypertensive Rat (SHR) shows a number of behaviours that closely parallel those seen in children with attention-deficit hyperactivity disorder. These include motor hyperactivity, excessive responses under a fixed-interval/extinction schedule, difficulty in acquiring operant tasks and increased sensitivity to immediate behavioural reinforcement. As in children with ADHD, the behavioural and cognitive deficits in the SHR are responsive to stimulants, including d-amphetamine and d,l-methylphenidate. The non-hyperactive Wistar Kyoto (WKY) rat strain is often used as a control in behavioural studies of the SHR, and WKY itself has been suggested to be a useful animal model of depression. Numerous studies have shown that dopaminergic neurotransmission is altered between the two strains. Human genetic studies have found associations between several dopaminergic genes and both ADHD and depression.MethodsWe sequenced three candidate dopaminergic genes (Drd2, Drd4, and Dat1) in the SHR and WKY to identify between-strain sequence differences.ResultsNo between-strain sequence differences were found in either Drd2 or Drd4, but several variations were found in the Dat1 gene that encodes the dopamine transporter.ConclusionIt is plausible that DNA sequence changes in the Dat1 gene account for some of the behavioural differences observed between the SHR and WKY strains. Future work will focus on elucidating the functional effects of the observed polymorphisms.

Cardiomyocyte function associated with hyperactivity and/or hypertension in genetic models of LV hypertrophy

We examined cardiomyocyte intracellular calcium ([Ca2+]i) dynamics and sarcomere shortening dynamics in genetic rat models of left ventricular (LV) hypertrophy associated with or without hypertension (HT) and with or without hyperactive (HA) behavior. Previous selective breeding of the spontaneously hypertensive rat (SHR) strain, which is HA and HT, with the Wistar-Kyoto (WKY) rat strain, which is not hyperactive (NA) and not hypertensive (NT), has led to two unique strains: the WKHA strain, selected for HA and NT, and the WKHT strain, selected for NA and HT. Cardiomyocytes were isolated from young adult males and females of each strain, paced at 2, 3, and 4 Hz in 1.2 mM external Ca2+ concentration at 37 degrees C, and cardiomyocyte [Ca2+]i and sarcomere dynamics were recorded simultaneously. Under these conditions, LV cardiomyocyte systolic and diastolic [Ca2+]i dynamics and diastolic sarcomere dynamics in the WKHT were significantly enhanced compared with WKY controls, suggesting an underlying LV hypertrophic response that successfully compensated for HT in the absence of HA. LV cardiomyocyte [Ca2+]i dynamics in the WKHA and SHR were strikingly similar to each other and only slightly reduced compared with WKY. LV cardiomyocyte systolic and diastolic sarcomere dynamics, on the other hand, were significantly reduced in the SHR compare with WKHA and more so in male than in female SHR. We conclude from these data that HT alone is an insufficient descriptor of the cause of LV hypertrophy and diminished LV cardiomyocyte function in the SHR rat. These data further suggest that HA (augmented by male sex) in the SHR may interact with the HT state to initiate impaired cardiomyocyte function and thereby inhibit or undermine an otherwise compensatory response that may occur with HT in the absence of HA.

Antidepressant drug induced alterations in binding to central dopamine transporter sites in the Wistar Kyoto rat strain

The Wistar Kyoto (WKY) rat has been proposed as an animal model of depressive behavior. Exposing WKY rats to stress stimulation produces symptoms such as anhedonia, psychomotor retardation, ambivalence and negative memory bias. Given the role of the mesolimbic dopamine (DA) system in cognitive, emotional and motivational behaviors, we previously examined the distribution of DA transporter (DAT) sites in the brains of WKY compared to Wistar (WIS) and Sprague–Dawley (S-D) rats. WKY rats exhibited significant differences in DAT binding sites in the cell body as well as mesolimbic areas compared to the other strains. It was reasoned that these differences may lead to altered synaptic levels of DA in specific brain regions thus contributing to the behavioral differences observed in this rat strain. Thus, the present study examined whether repeated treatment with antidepressant drugs that block the uptake of DA (nomifensine and bupropion) would modify [ 3H]-GBR12935 binding to DAT sites in WKY rats compared to WIS and S-D rats. The results indicate that while nomifensine and bupropion increased the binding of [ 3H]-GBR12935 to DAT sites in the mesocorticolimbic regions in WKY rats, these drugs increased the binding of [ 3H]-GBR12935 to DAT sites in the cell body areas in WIS rats but not in S-D and WKY rats. The data from this study suggest that antidepressant induced alterations in DAT sites in the mesocorticolimbic brain regions may play a role in the behavioral improvement seen in WKY rats, as measured by the Open Field Test (OFT) and the Porsolt Forced Swim Test (FST).

Quantitative Trait Loci Associated with Elevated Thyroid-Stimulating Hormone in the Wistar-Kyoto Rat

Thyroid hormones are essential for the regulation of developmental and physiological processes. The genetic factors underlying naturally occurring variability in mammalian thyroid function are, however, only partially understood. Genetic control of thyroid function can be studied with animal models such as the inbred Wistar-Kyoto (WKY) rat strain. Previous studies established that WKY rats have elevated TSH, slightly elevated total T3, and normal total T4 levels compared with Wistar controls. The present study confirmed a persistent 24-h elevation of TSH in WKY rats compared with the Fisher 344 (F344) rat, another inbred strain. Acute T3 challenge (25 microg/100 g body weight ip) suppressed serum TSH and T4 levels in both strains. Quantitative trait locus analysis of elevated TSH in a reciprocally bred WKY x F344 F2 population identified one highly significant locus on chromosome 6 (LOD=11.7, TSH-1) and one suggestive locus on chromosome 5 (LOD=2.3, TSH-2). The confidence interval of TSH-1 contains the TSH receptor and type 2 deiodinase genes, and TSH-2 contains the type 1 deiodinase gene. The WKY alleles of each gene contain sequence alterations, but additional studies are indicated to identify the specific gene or genes responsible for altered regulation of the thyroid axis. These findings suggest that one or more genetic alterations within the TSH-1 locus significantly contribute to the altered thyroid function tests of the WKY rat.