Potential Animal Model Research Articles

Neurochemical Bases of Locomotion and Ethanol Stimulant Effects

The locomotor stimulant effect produced by alcohol (ethanol) is one of a large number of measurable ethanol effects. Ethanol-induced euphoria in humans and locomotor stimulation in rodents, a potential animal model of human euphoria, have long been recognized and the latter has been extensively characterized. Since the euphoria produced by ethanol may influence the development of uncontrolled or excessive alcohol use, a solid understanding of the neurochemical substrates underlying such effects is important. Such an understanding for spontaneous locomotion and for ethanol's stimulant effects is beginning to emerge. Herein we review what is known about three neurochemical substrates of locomotion and of ethanol's locomotor stimulant effects. Several lines of research have implicated dopaminergic, GABAergic, and glutamatergic neurotransmitter systems in determining these behaviors. A large collection of work is cited, which strongly implicates the above-mentioned neurotransmitter substances in the control of spontaneous locomotion. A smaller, but persuasive, body of evidence suggests that central nervous system processes utilizing these transmitters are involved in determining the effects of ethanol on locomotion. Particular emphasis has been placed on the mesolimbic ventral tegmental area to nucleus accumbens dopaminergic pathway, and on the ventral pallidum/substantia innominata, where GABA and glutamate have been found to play a role in altering the activity of this dopaminergic pathway. Research on ethanol and drug locomotor sensitization, increased responsiveness to the substance with repeated administration, is also reviewed as a process that may be important in the development of drug addiction.

Random Samples

Random Samples

Potential Animal Model For AIDS

Potential Animal Model For AIDS

Mechanisms for the pleiotropic effects of the agouti gene.

The agouti locus is one of several classic genetic loci that affect the coat color of mice. The wild-type agouti phenotype, exemplified by dorsal coat hairs that are black with a single subapical band of yellow and lighter-colored ventral hairs, is found in many mammals including animals of the genera Mus (mice), Oryctolagus (rabbits), Sciurus (squirrels), and Canis (wolves) (reviewed in ref. 1). Much interest has focused on the agouti gene because several dominant mutations result in mice that exhibit adult onset obesity, hyperinsulinemia, and' noninsulindependent diabetes. In addition, mice carrying dominant agouti mutations show an increased susceptibility to a variety of spontaneous and/or induced solid tumors. These mutations provide potential animal models of human disease, and the mouse provides an organism amenable to molecular genetic, biochemical, physiological, and pharmacological manipulations to investigate the causes and treatments of these diseases. The mechanism of action of the agouti gene in all of these phenotypes is under intense investigation. Several recent papers including two in this issue by Klebig et al (2) and Zemel et al (3) now shed light on some modes of action of the agouti protein as well as provide models for in vivo and in vitro tests of agouti function.

Potential animal models of Helicobacter pylori infection in immunological and vaccine research.

Presence of Helicobacter pylori in the human gastric mucosa is associated with chronic gastritis and promotes the formation of peptic ulceration. Furthermore, long-term gastritis caused by the bacteria represents an increased risk of developing gastric cancer. Much controversy remains about the pathogenic mechanisms by which H. pylori can induce disease because of the limitations of animal models and the relevance of in vitro observations to the in vivo disease process. Studies of putative pathogenic factors such as induction of inflammatory mediators and immune evasion are required to understand how to design a vaccine against the infection. Vaccine adjuvants, delivery systems and therapeutic vaccination are likely to be the areas of major progress in the future. Data related to immunological aspects and vaccine development in potential animal models are reviewed.

Potential animal models of Helicobacter pylori infection in immunological and vaccine research

Presence of Helicobacter pylori in the human gastric mucosa is associated with chronic gastritis and promotes the formation of peptic ulceration. Furthermore, long-term gastritis caused by the bacteria represents an increased risk of developing gastric cancer. Much controversy remains about the pathogenic mechanisms by which H. pylori can induce disease because of the limitations of animal models and the relevance of in vitro observations to the in vivo disease process. Studies of putative pathogenic factors such as induction of inflammatory mediators and immune evasion are required to understand how to design a vaccine against the infection. Vaccine adjuvants, delivery systems and therapeutic vaccination are likely to be the areas of major progress in the future. Data related to immunological aspects and vaccine development in potential animal models are reviewed.

The SCID mouse as a model for multiple myeloma.

The SCID mouse was investigated as a potential animal model for human multiple myeloma (MM). Duplicate samples of bone marrow mononuclear cells (BMMC) and/or peripheral blood mononuclear cells (PBMC) of six MM patients in different clinical phases and one patient with monoclonal gammapathy of undetermined significance (MGUS) were injected intraperitoneally into SCID mice. Human immunoglobulins (Ig) in the SCID sera were quantified with a light-chain isotype-specific ELISA, and their monoclonality biochemically characterized, using a sensitive immunoblotting technique after agar gel electrophoresis. Successful transplantation of bone marrow derived-tumour cells in SCID mice was obtained with BMCC of two MM patients with progressive disease. Human plasma cells were detected in the mesenteric fat tissue around the pancreas and the spleen. This model in SCID mice may facilitate studies on processes involved in tumour progression and provides a new tool for therapeutic approaches in MM.

Chemotherapy-induced hemolytic uremic syndrome: Description of a potential animal model

Hemolytic uremic syndrome (HUS) is an uncommon complication of chemotherapy that contributes to the morbidity of oncology and bone marrow transplant patients. The pathogenesis is not well understood and no established clinical animal model exists. We studied four rhesus monkeys (RM) that developed fatal HUS following high-dose chemotherapy. Microangiopathic hemolytic anemia (pre-Hct 40% and day 5-8 Hct 31% (P < .05), increased BUN (168 mg/dl), creatinine (8.2 mg/dl), and lactate dehydrogenase (1458 IU/L) (mean day 5-8 measurements) were observed. Platelets counts decreased to 39 +/- 15 x 10(9)/l from a mean of 397 +/- 31 x 10(9)/L (P < .0001). vWF, ATIII, thrombin:anti-thrombin complex (T:AT) and prothrombin fragment F1.2 levels were not different from a control group (N = 2). The data presented describe chemotherapy-induced HUS with typical clinical and laboratory features which may provide an animal model for the study of this important syndrome.

The Sry-related gene Sox9 is expressed during chondrogenesis in mouse embryos.

Mutations in the human SRY-related gene, SOX9, located on chromosome 17, have recently been associated with the sex reversal and skeletal dysmorphology syndrome, campomelic dysplasia. In order to clarify the role of this gene in skeletal development, we have studied the expression of mouse Sox9 during embryogenesis. Sox9 is expressed predominantly in mesenchymal condensations throughout the embryo before and during the deposition of cartilage, consistent with a primary role in skeletal formation. Interspecific backcross mapping has localized mouse Sox9 to distal chromosome 11. The expression pattern and chromosomal location of Sox9 suggest that it may be the gene defective in the mouse skeletal mutant Tail-short, a potential animal model for campomelic dysplasia.

Correction of lethal intestinal defect in a mouse model of cystic fibrosis by human CFTR.

Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). A potential animal model of CF, the CFTR-/- mouse, has had limited utility because most mice die from intestinal obstruction during the first month of life. Human CFTR (hCFTR) was expressed in CFTR-/- mice under the control of the rat intestinal fatty acid-binding protein gene promoter. The mice survived and showed functional correction of ileal goblet cell and crypt cell hyperplasia and cyclic adenosine monophosphate-stimulated chloride secretion. These results support the concept that transfer of the hCFTR gene may be a useful strategy for correcting physiologic defects in patients with CF.

Effects of chronic mild stress on performance in behavioural tests relevant to anxiety and depression

Chronic exposure to mild unpredictable stress (CMS) has previously been found to depress the consumption of a weak (1%) sucrose solution by rats. This effect was confirmed in each of three experiments in the present study, following which behaviour was examined in other tests relevant to either depression or anxiety. CMS did not significantly affect behaviour in the social interaction test and caused an anxiolytic-like profile in the elevated plus-maze. CMS increased submissive behaviour in the resident-intruder test, and decreased male sexual behaviour. The latter effect was more pronounced in animals reared in isolation from the time of weaning; isolation rearing did not influence sexual behaviour in nonstressed animals. Isolation rearing also potentiated the effect of CMS on sucrose drinking, in both male and female rats. These results support the relevance of the CMS procedure as a potential animal model of depression.

Development of immediate-type hypersensitivity in the chronic phase of contact dermatitis in mice: A potential animal model for atopic dermatitis

Development of immediate-type hypersensitivity in the chronic phase of contact dermatitis in mice: A potential animal model for atopic dermatitis

In vitro susceptibility of Macaca nemestrina to human herpesvirus 6: a potential animal model of coinfection with primate immunodeficiency viruses.

Human herpesvirus 6 (HHV-6), a lymphotropic herpesvirus, has been suggested as a potential cofactor in the acquired immunodeficiency syndrome (AIDS). Previous studies indicate that HHV-6 has a restricted range of susceptible species. In this study, we tested the in vitro susceptibility to HHV-6 of Macaca nemestrina (pig-tailed macaque), a species that has been found to be infectable by human immunodeficiency virus type I in vivo and that develops an AIDS-like syndrome following simian immunodeficiency virus (SIV) infection. Two different HHV-6 isolates (HHV-6GS and HHV-6BA), belonging to the two major HHV-6 variants (A and B, respectively), were employed. Both viruses induced a productive and cytopathic infection in phytohemagglutinin-stimulated peripheral blood T lymphocytes from M. nemestrina. In contrast, only HHV-6BA (variant B) was able to replicate in lymphocytes from Macaca mulatta (rhesus macaque). Moreover, HHV-6GS and SIVsmE660 productively coinfected individual M. nemestrina lymphocytes, resulting in increased levels of SIV replication. Genetic sequences of HHV-6 were not amplified by polymerase chain reaction from peripheral blood mononuclear cells of several adult M. nemestrina, suggesting that these animals, unlike humans, are not commonly infected by HHV-6, or a related virus. Thus, M. nemestrina may represent an optimal animal model system to investigate the in vivo interactions between HHV-6 and the primate immunodeficiency viruses.

Increased mRNA for corticotrophin releasing hormone in the amygdala of fawn-hooded rats: a potential animal model of anxiety.

Compared to the outbred Wistar rat strain, the Fawn-hooded rat strain has several characteristics which suggest that the Fawn-hooded strain is hyperaroused. Fawn-hooded rats exhibit more freezing behavior in response to stress, have an increased preference for alcohol, develop adult onset hypertension, and have elevated urinary catecholamine levels. We used quantitative in situ hybridization to investigate central components of the corticotropin releasing hormone (CRH), arginine vasopressin (AVP) and noradrenergic stress response and arousal systems in these rats. We also measured basal corticosterone levels and adrenal weights to assess tonic hypothalamic-pituitary-adrenal axis activity. Compared to Wistar rats, Fawn-hooded rats had significantly increased CRH mRNA in the central nucleus of the amygdala and reduced CRH mRNA in the paraventricular nucleus of the hypothalamus. Fawn-hooded rats also bad reduced AVP mRNA expression in the parvocellular cells of the hypothalamic paraventricular nucleus. There were no differences between strains in glucocorticoid receptor mRNA in the hippocampus or the paraventricular nucleus or in mineralocorticoid receptor mRNA in the hippocampus. There was also no difference between strains in tyrosine hydroxylase mRNA in the locus ceruleus. Finally, adrenal weights were significantly reduced in the Fawn-hooded rats while basal corticosterone levels were similar in the two strains, which suggests central hypoactivity of the hypothalamic-pituitary-adrenal axis in Fawn-hooded rats compared to Wistar rats. Increased CRH mRNA in the central nucleus of the amygdala and reduced tonic hypothalamic-pituitary-adrenal axis activity may play a role in the unique behavioral and physiological characteristics of Fawn-hooded rats.

Decreased skin blood flow early in the course of streptozotocin-induced diabetes mellitus in the rat.

We have previously used laser Doppler technology to demonstrate that skin blood flow is reduced in Type 1 (insulin-dependent) diabetic patients. The possibility of using the skin as an extremely accessible indicator of diabetic microvascular disease is attractive. The streptozotocin diabetic rat is an appealing potential animal model. We performed measurements of skin blood flow in two rat species, nine Sprague Dawley (SD) rats and nine Wistar Kyoto (WKY) rats, observing early changes following the inception of diabetes. Four of the SD rats and five of the WKY rats were made diabetic, the rest serving as controls. There were no significant differences in skin blood flow between the two rat strains. As in man, there appear to be rat skin sites with primarily nutritive capillary supply and those with arteriovenous anastomotic predominance. The back and base of tail, both hair-covered areas, demonstrated low flow characteristics, consistent with nutritive perfusion. In contrast, the plantar surface of the paw behaved similarly to the finger or toe pulps in man, sites of arteriovenous perfusion, with high basal flow and a marked increment with thermal stimulation. In diabetic rats of both species, there was significantly lower flow at the back and base of tail than in non-diabetic animals. The differences were of the order of 30-40%. As a function of time, the decrease in blood flow at the base of tail parallelled the increase in glycohaemoglobin levels in the diabetic rats. In contrast, blood flow at the plantar surface of the paw was unchanged throughout the 3-month post-streptozotocin observation period.(ABSTRACT TRUNCATED AT 250 WORDS)

Postpubertal emergence of hyperresponsiveness to stress and to amphetamine after neonatal excitotoxic hippocampal damage: a potential animal model of schizophrenia.

The constellation of major phenomena associated with schizophrenia (e.g., postpubertal onset, congenital hippocampal area damage, cortical functional deficits, limbic dopamine (DA) dysregulation, and vulnerability to stress) have been difficult to explain with a unitary animal model. Although it has been shown that rats develop increased mesolimbic DA transmission and reduced cortical DA turnover following adult excitotoxic lesions of the ventral hippocampus (VH), the implications of early developmental VH lesions are not known. To determine the developmental sequelae of such changes, we produced ibotenic acid lesions of the ventral hippocampal formation in rats on the 7th day after birth (PD7). Motor activity in a novel environment, after saline injection and after d-amphetamine administration were similar in control and lesioned rats at PD35. However, in early adulthood, at PD56, animals with the hippocampal lesion were hyperactive in each of these conditions. The emergence of the hyperactivity at PD56 could be prevented by pretreatment with haloperidol. Moreover, rats lesioned as neonates, in contrast to a similar lesion induced in adult animals, were also hyperresponsive to stress evaluated with a swim test. This latter effect is analogous to that seen after adult lesions of the medial prefrontal cortex, rather than after adult lesions of VH, suggesting that the neonatal VH lesion may affect functional development of the medial prefrontal cortex. These results demonstrate that in rats with neonatally induced excitotoxic VH lesions, behavioral indices consistent with increased mesolimbic DA responsivity to stressful and to pharmacologic stimuli emerge only in early adulthood. Homologous mechanisms may underlie certain aspects of the pathophysiology of schizophrenia.

Frequent reward eliminates differences in activity between hyperkinetic rats and controls

The spontaneously hypertensive rat (SHR) is a strain that is a potential animal model of attention-deficit hyperactivity disorder (ADHD)/childhood hyperkinesis/disturbance of activity and attention, as SHR exhibit both hyperactivity and attention problems. Altered reinforcement (reward) processes have been suggested as the mechanism for the development of hyperactivity in SHR and ADHD. The purpose of the present study was to analyze basic reinforcement and response processes in the hyperactive SHR and in the progenitor Wistar-Kyoto (WKY) control strain. The results show that differences between the strains emerge in response rates maintained by infrequent reinforcers rather than in asymptotic rates of responding maintained by higher rates of reinforcement. The SHR strain required fewer reinforcers per minute to maintain high rates of responding, but when reinforcer rates were high enough to maintain asymptotic response rates in both strains, the rates were similar. Thus, the increased response rates for hyperactive rats at low reinforcement rates may reflect not only barpresses for water, but possibly also barpresses for other stimuli the animal produces by pressing the lever switch. Extrapolating to hyperactive children (ADHD), the results suggest that ADHD behavior might be made more similar to non-ADHD if reinforcers were scheduled more frequently.

Potential animal model of increased etoh intake in schizophrenia: Prenatal d-amphetamine exposure vs. pair-feeding control conditions

Potential animal model of increased etoh intake in schizophrenia: Prenatal d-amphetamine exposure vs. pair-feeding control conditions

Acute methanol toxicity in minipigs

The pig has been proposed as a potential animal model for methanol-induced neuro-ocular toxicosis in humans because of its low liver tetrahydrofolate levels and slower rate of formate metabolism compared to those of humans. To examine the validity of this animal model, 12 4-month-old female minipigs (minipig YU) were given a single oral dose of water or methanol at 1.0, 2.5, or 5.0 g/kg body wt by gavage (n = 3 pigs/dose). Dose-dependent signs of acute methanol intoxication, which included mild CNS depression, tremors, ataxia, and recumbency, developed within 0.5 to 2.0 hr, and resolved by 52 hr. Average maximum methanol concentrations in plasma, of 3100 +/- 700 (SD), 6200 +/- 2300, and 15,200 +/- 900 micrograms/ml were reached within 0.5 to 4 hr following methanol administration in animals given 1.0, 2.5, or 5.0 g methanol/kg, respectively. The mean initial elimination half-lives of methanol were 9.0 +/- 1.6, 22.4 +/- 6.1, and 18.9 +/- 4.3 hr, for 1, 2.5, and 5.0 g/kg doses, respectively. In 3 minipigs, a transient increase in plasma formate concentration (1.74-3.40 mEq/liter vs control = 0.5 +/- 0.3 mEq/liter) occurred 4 to 30 hr following methanol administration. Methanol- and formate-dosed pigs did not develop optic nerve lesions, toxicologically significant formate accumulation, or metabolic acidosis. Based on results following a single dose, female minipigs do not appear to be overtly sensitive to methanol and thus may not be a suitable animal model for acute methanol-induced neuro-ocular toxicosis.

Criteria for rationally evaluating animal models of postraumatic stress disorder

Animal models of stress have the potential to provide information about the course and etiology of posttraumatic stress disorder (PTSD). To date, however, there have been no systematic approaches for evaluating the relevance of animal models of stress to PTSD. It has been established in the animal literature that different types of stress paradigms lead to different biobehavioral consequences and that many different factors contribute to differential responsivity to stress. It becomes important therefore to differentiate between factors that are essential to the induction of PTSD-like symptoms and those that influence their manifestations. In the present commentary, we present five criteria that must be fulfilled by animal models of stress for them to be useful to understanding the induction of PTSD. We then evaluate two potential animal models of stress—inescapable shock-learned helplessness and time-dependent sensitization—to illustrate how to more successfully pair animal models of stress with the specific clinical syndrome of PTSD.