Decreased hyperthermic effect of MK-801 in selectively bred hypercholinergic rats

The Flinders Sensitive Line (FSL) of rats has been selectively bred to have increased sensitivity to cholinergic agonists. However, these rats exhibit altered responsiveness to a number of noncholinergic agents, such as apomorphine, buspirone and ethanol. This study compared the FSL and control Flinders Resistant Line (FRL) rats in terms of their hyperthermic response to the phencyclidine (PCP) receptor agonist, MK-801 (0.2 mg/kg SC) and their MK-801 binding characteristics. We have found that FSL rats react with a delayed hyperthermia, having a significantly lower hyperthermia for the first 120 min of observation. Thereafter the response does not differ in FSL and FRL rats. Both groups had similar affinities and numbers of [3H]MK-801 binding sites in the hippocampus/cerebral cortex. Pretreatment with scopolamine (1 mg/kg SC) failed to affect MK-801-induced hyperthermia in either line of rats. These findings suggest that selective breeding of FSL rats attenuated the secondary mechanisms involved in the PCP receptor-mediated hyperthermic response. However, by itself cholinergic supersensitivity does not appear to be a major factor in the blunted responsiveness of FSL rats to MK-801.     

Effects of Ethanol, Chlordiazepoxide, and MK-801 on Performance in the Elevated-Plus Maze and on Locomotor Activity

The effects of ethanol, chlordiazepoxide, and MK-801 on performance in the elevated-plus maze and on activity measured in a circular activity monitor were compared in Sprague-Dawley rats to determine whether these effects of ethanol could be explained by its action on either GABA_A or NMDA receptors. Both ethanol and chlordiarepoxide produced an increase in the time spent in the open arms of the elevated-plus maze and in the ratio of open arm to total arm entries, indicative of an anxiolytic action of these drugs. MK-801 did not alter either the time spent in the open arms or the ratio of open to total arm entries. Chlordiazepoxide and MK-801 produced an increase in total arm entries that suggested that these compounds were increasing locomotor activity. Ethanol also increased total arm entries, but the effect was not statistically reliable. Following habituation to an activity monitor, neither ethanol nor chlordiazepoxide increased activity in this task, whereas MK-801 produced a robust increase in locomotion. Additionally, neither ethanol nor chlordiazepoxide blocked the MK-801-induced locomotor stimulation. The latter finding suggests that the effects of ethanol on GABAA receptors was not Mocking an increased activity level produced by its antagonism of NMDA. Additionally, these results indicate that the anxiolytic and locomotor action of ethanol in rats parallel the effects of a benzodiazepine and not those of an NMDA antagonist. Finally, these results suggest that the consequence of ethanol's antagonism of NMDA receptor function is more restricted than that produced by MK-801.     

Behavioral characteristics of rat lines selected for differential hypothermic responses to cholinergic or serotonergic agonists

The present review will describe the formation of two pharmacologically selected lines of rats, their behavioral phenotypes, their responses to select drugs, their possible neurochemical correlates, and their use to detect the therapeutic potential of antidepressant drugs. The Flinders Line rats were established at Flinders University in Australia by selectively breeding for differential responses to an anticholinesterase agent from outbred Sprague-Dawley (SD) rats; the Flinders Sensitive Line (FSL) rats were more sensitive to the hypothermic and behavioral suppressing effects of this agent than the Flinders Resistant Line (FRL) rats. The 8-OH-DPAT line rats were established at the University of North Carolina at Chapel Hill by selectively breeding for differential hypothermic responses to the 5-HT_1A receptor agonist, 8-OH-DPAT; the high DPAT sensitive (HDS) line rats were more sensitive to the hypothermic effects of 8-OH-DPAT than the low DPAT sensitive (LDS) line rats. Studies of these two pairs of lines have indicated that the FSL and HDS rats are both more susceptible to stress-induced behavioral disturbances. Their usefulness in detecting potential antidepressant drugs and the relationship between mood disorders and drug abuse will be discussed.     

Defects in neurofibromatosis 2 protein function can arise at multiple levels

Neurofibromatosis 2 (NF2) is an inherited cancer syndrome resulting from mutations in the NF2 tumor suppressor gene. Analysis of NF2 mutations has revealed some general genotype-phenotype correlations. Severe disease has been associated with mutations that produce a premature termination while more mild disease has been associated with missense mutations. Here, we provide experimental proof for these genotype-phenotype correlations by demonstrating that nonsense mutations fail to produce stable merlin protein while missense mutations result in the generation of merlin proteins defective in negative growth regulation. This inability to suppress cell growth may result from defects in the function of merlin at several levels, including failure to form an intramolecular complex. Based on these findings, we propose a model for merlin growth suppression that provides a framework for analyzing NF2 patient mutations and merlin function.      

Secondary amyloidosis and gastrointestinal stromal tumors. A case report and discussion of pathogenesis

A 69-year-old man presented with a malignant gastrointestinal stromal tumor associated with secondary amyloidosis. The tumor had classic features of a malignant gastrointestinal stromal tumor with interlacing fascicles and whorls of spindled cells, numerous and conspicuous mitotic figures, and extensive coagulative necrosis. The cells stained diffusely for CD117 (c-Kit), confirming the diagnosis of gastrointestinal stromal tumor. The spleen, 1 adrenal gland, and part of the pancreas were removed en block with the stomach. By microscopy, the spleen and adrenal gland were partially replaced with amyloid deposits confirmed by Congo red staining, electron microscopy, and immunohistochemistry. In contrast, neither the tumor nor the surrounding vasculature showed amyloid deposition. To our knowledge, this represents only the second case of systemic amyloidosis associated with a gastrointestinal stromal tumor. This case is unique in that extensive, diffuse amyloid deposits were observed in the spleen, adrenal gland, and liver.     

Reduced primary antibody responses in a genetic animal model of depression

OBJECTIVE: Clinical depression is associated with multiple abnormalities of immune function, including reduced virus-specific responses. This study tested the hypothesis that the Flinders Sensitive Line (FSL) rat, a promising genetic animal model of depression, would exhibit reductions in antigen-specific primary antibody responses to immunization. METHODS: FSL (N = 13) and control Flinders Resistant Line (FRL; N = 14) rats were immunized with the protein antigen keyhole limpet hemocyanin (KLH; 300 microg/kg), and KLH-specific immunoglobulin (Ig)M, IgG, IgG1, and IgG2a responses were measured before and 3, 5, 7, 11, and 14 days after immunization. In separate experiments, production of interferon-gamma (IFN-gamma) by cells from naive and KLH-immunized animals was measured in vitro to determine whether strain differences in antibody production might be associated with differential production of this regulatory cytokine. RESULTS: KLH-specific production of IgM (p <.01) and IgG2a (p <.05) was significantly reduced in the FSL rats compared with the FRL controls. There were no strain differences in IgG or IgG1 production. Although IFN-gamma production between the two strains was similar in naive animals, cells from KLH-immunized FSL rats produced significantly less IFN-gamma when stimulated with KLH in vitro than cells from KLH-immunized FRL controls (p =.01). CONCLUSIONS: This study extends previous reports of altered immune function in the FSL rats to include reduced in vivo antigen-specific antibody responses. Moreover, diminished production of IFN-gamma by KLH-primed lymphocytes may contribute to lower antibody production in these animals. Collectively, these data suggest deficiencies in type 1 T-helper cell-mediated immunity in the FSL rats.     

Enduring effects of prenatal cocaine administration on emotional behavior in rats

The present studies sought to determine whether prenatal cocaine administration (15 mg/kg b.i.d. between gestational ages 1-20) had enduring effects on emotional behavior of rats. Rats prenatally treated with cocaine interacted less with other rats in the social interaction test of anxiety at both 30 and 120 days of age. However, there were no differences in the elevated plus maze test of anxiety. Rats prenatally treated with cocaine were significantly more immobile in the forced-swim test at 60 and 120 days of age. In addition, animals exposed to prenatal cocaine were more sensitive to the enhancing effect of phencyclidine (2.0 mg/kg) on startle responses to an acoustic stimulus. The cocaine-treated animals tested at 50 to 60 days of age showed higher levels of prepulse inhibition, in comparison to the saline group, after vehicle pretreatment, but not after phencyclidine. Although there were gender differences in the expression of some of these behavioral tasks, there were no gender differences in the effects of cocaine. These findings indicate that when emotional behavior is altered by prenatal cocaine administration, the effects are enduring.     

Breast cancer detection: one versus two views

Mammographic examinations of 169 patients with 172 biopsy-proved carcinomas, and of 194 healthy subjects, were interpreted independently and retrospectively by three experienced mammographers, initially as single-view oblique examinations and 6 months later as two-view oblique-cephalocaudal examinations. For the single-view examinations of the cancer patients, 67% of the cancers were correctly recommended for biopsy, additional views were requested for 23%, and a "negative" interpretation was made for 10%. For the single-view examinations of healthy subjects, biopsy was recommended for 7% and additional views were recommended for 32%. For the two-view examinations of women with cancer, 80% of the cancers were correctly recommended for biopsy, additional views were requested for 4%, and a "negative" interpretation was made for 16%. For two-view examinations of healthy subjects, biopsy was recommended for 7% and additional views were requested for only 5%. The authors conclude that single-view screening should not be performed, because it would lead to an excessive number of "call-back" examinations of healthy patients, producing additional cost and anxiety that would outweigh any theoretical benefit.