Genetic deletion of MT1 and MT2 melatonin receptors differentially abrogates the development and expression of methamphetamine‐induced locomotor sensitization during the day and the night in C3H/HeN mice

Abstract: This study explored the role of the melatonin receptors in methamphetamine (METH)‐induced locomotor sensitization during the light and dark phases in C3H/HeN mice with genetic deletion of the MT₁ and/or MT₂ melatonin receptors. Six daily treatments with METH (1.2 mg/kg, i.p.) in a novel environment during the light phase led to the development of locomotor sensitization in wild‐type (WT), MT₁KO and MT₂KO mice. Following four full days of abstinence, METH challenge (1.2 mg/kg, i.p.) triggered the expression of locomotor sensitization in METH‐pretreated but not in vehicle (VEH)‐pretreated mice. In MT₁/MT₂KO mice, the development of sensitization during the light phase was significantly reduced and the expression of sensitization was completely abrogated upon METH challenge. During the dark phase the development of locomotor sensitization in METH‐pretreated WT, MT₁KO and MT₂KO mice was statistically different from VEH‐treated controls. However, WT and MT₂KO, but not MT₁KO mice receiving repeated VEH pretreatments during the dark phase expressed a sensitized response to METH challenge that is of an identical magnitude to that observed upon 6 days of METH pretreatment. We conclude that exposure to a novel environment during the dark phase, but not during the light phase, facilitated the expression of sensitization to a METH challenge in a manner dependent on MT₁ melatonin receptor activation by endogenous melatonin. We suggest that MT₁ and MT₂ melatonin receptors are potential targets for pharmacotherapeutic intervention in METH abusers.     

A single major gene controls most of the difference in susceptibility to streptozotocin-induced diabetes between C57BL/6J and C3H/HeJ mice

Summary To assess genetic factors determining sensitivity to streptozotocin-induced diabetes in inbred strains of mice, a genetic analysis of streptozotocin-sensitive C57BL/6J and streptozotocin-resistant C3H/HeJ mice was performed. One week after a single dose of streptozotocin (200 mg/kg body weight), differences in plasma glucose concentration were marked between male mice of the C57BL/6J and C3H/HeJ strains (p<0.001). To determine the number of genes responsible for the difference, F₁ male progeny of a cross between parental strains were produced, and found to be streptozotocin resistant like C3H/HeJ parents. F₁ mice were, therefore, backcrossed with streptozotocin-sensitive C57BL/6J mice (Backcross: F₁ X C57BL/6J ). The plasma glucoses of backcrossed male mice (n=41) following streptozotocin treatment appeared to segregate into two populations, half like the C57BL/6J parent, and half like the F₁ parent. Statistical analysis of the data revealed that the data fit a model with two distributions better than one with a single distribution, suggesting a single major gene responsible for the difference in streptozotocin susceptibility. This hypothesis was also supported by the observation that streptozotocin sensitivity in 12 recombinant inbred strains of C57BL/6J and C3H/HeJ mice appeared to segregate into two classes. Resistance to streptozotocin induced diabetes in F₁ mice suggested that the expression of this gene is recessive, although X-chromosome linked inheritance could not be excluded.Efforts to map the streptozotocin-sensitivity gene revealed lack of right linkage to several loci including the H-2 locus. If inherited differences in the ability to resist a B-cell toxin play a role in genetic susceptibility to diabetes in man, then mapping the streptozotocin-susceptibility gene in mice may provide a means to evaluate the role of a putative homologous locus in the aetiology of diabetes in man.     

The influence of the site of parasite inoculation on the development of Th1 and Th2 type immune responses in (BALB/c × C57BL/6) F1 mice infected with Leishmania major

Although inbred strains of mice are classified as genetically resistant or susceptible to Leishmania major based upon their ability to control infection, other factors such as the strain, dose, and site of parasite inoculation can also affect the outcome of the disease. Here we used the Fl progeny of BALB/c (susceptible) and C57BL/6 (resistant) mice (designated CB6F1) to investigate whether mice or intermediate susceptibility to infection differed from the parental strains in their ability to control infections at different cutaneous sites. CB6F1 mice developed progressive disease when inoculated in the dorsal skin, but healed infections in the footpad. Consistent with these observations, mice inoculated in the footpad ultimately developed Th1 responses, known to be required for healing, while Th2 responses developed in mice inoculated in the dorsal skin. However, IL-4 and IFN-γ production during the first few weeks of infection was similar in CB6F1 mice inoculated at either site, suggesting that factors in addition to the relative levels of these cytokines produced early in infection may influence the nature of the antileishmanial immune response, and the eventual disease outcome. Infection in CB6F1 mice provides a model for the study of immunity to L. major in genetically identical animals, in which a prolonged mixed Thl/Th2 cytokine pattern initially develops, but ultimately diverges into more defined Th1 and Thl type responses.     

Changes of the intestinal endocrine cells in the C57BL/6 mouse after implantation of murine lung carcinoma （3LL）： An immunohistochemical quantitative study

AIM: To study the distributions and frequencies of intestinal endocrine cells in the C57BL/6 mouse with immunohistochemical method using seven types of specific antisera against chromogranin A (CGA), serotonin, somatostatin, glucagons, gastrin, cholecystokinin (CCK)-8 and human pancreatic polypeptide (hPP) after abdominal subcutaneous implantation of murine lung carcinoma (3LL). METHODS: The experimental animals were divided into two groups, one is non-implanted Sham and the other is 3LL-implanted group. Samples were collected from six regions of intestinal tract at 28~(th) d after implantation of 3LL cells (1×10~5 cell/mouse). RESULTS: In this study, five types of immunoreactive (IR) cells were identified except for gastrin and hPP. The regional distributions of the intestinal endocrine cells in the 3LL-implanted group were similar to those of the non-implanted Sham. However, significant decreases of IR cells were detected in 3LL-implanted group compared to those of non-implanted Sham. CGA- and serotonin-IR cells significantly decreased in 3LL-implanted groups compared to that of non-implanted Sham. Somatostatin-IR cells in the jejunum and ileum and CCK-8-IR cells in the jejunum of 3LL-implanted groups significantly decreased compared to that of non-implanted Sham. In addition, glucagon-IR cells were restricted to the ileum and colon of non-implanted Sham. CONCLUSION: Implantation of tumor cell mass (3LL) induced severe quantifiable changes of intestinal endocrine cell density and the abnormality in density of intestinal endocrine cells may contribute to the development of gastrointestinal symptoms such as anorexia and indigestion, frequently encountered in patients with cancer.