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Phenotypes Associated with This Genotype
Genotype
MGI:2675764
Allelic
Composition
Drd2tm1Ebo/Drd2tm1Ebo
Genetic
Background
involves: 129S2/SvPas * C57BL/6
Find Mice Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Drd2tm1Ebo mutation (0 available); any Drd2 mutation (52 available)
phenotype observed in females
phenotype observed in males
N normal phenotype
behavior/neurological
N
• homozygotes exhibit a normal exploratory response in a stressful (highly illuminated) open field with unknown objects relative to wild-type controls
• in response to morphine administration (2 and 6 mg/kg body weight), homozygous mutant and wild-type mice show a similar increase in horizontal locomotor activity under non-stressful conditions
• in response to endogenous opioid administration (RB 101, 100 mg/kg body weight), homozygous mutant and wild-type mice show a similar increase in horizontal locomotor activity relative to saline-treated controls, indicating normal opioid-induced hyperlocomotion
• following chronic administration of increasing doses of morphine , homozygotes show no differences in the incidence of naloxone-precipitated somatic signs of morphine withdrawal relative to similarly treated wild-type controls
• in a non-selective attention test, mice exhibit higher scanning times (measured by duration of individual rearing episodes) during the second part of the test compared with wild-type mice
• at 10 mg/kg kainic acid (i.p.), homozygotes display preconvulsive behaviors (rigid posture, tail stiffening, and forelimb extension) whereas wild-type and heterozygotes remain immobile
• at 20 mg/kg kainic acid, homozygotes exhibit obvious symptoms of limbic epileptic activity (repeated episodes of rearing with forelimb clonus, alternating with rigid posture and head bobbing), whereas wild-type and heterozygous controls display only preconvulsive signs
• however, at 35 mg/kg kainic acid, homozygotes exhibit repeated limbic seizures of the same severity as those observed in wild-type and heterozygous controls
• in response to s.c. morphine administration (3 mg/kg body weight), homozygotes, unlike wild-type controls, fail to display a significant increase in the time spent in the morphine-associated compartment during the testing phase of a conditioned place preference paradigm, indicating that opioid rewarding properties are suppressed
• in response to a higher morphine dose (9 mg/kg body weight), drug-naive homozygotes also fail to show place preference in the same place-conditioning paradigm, indicating lack of a developed tolerance to endogenous opioids
• however, morphine-treated homozygotes display a behavior similar to that of wild-type controls during the preconditioning phase of the place-conditioning paradigm, and retain a normal exploratory activity and locomotor response to morphine treatment
• homozygotes show a normal conditioned place preference when palatable food is used as reward, indicating that the motivational deficit affects morphine rewarding properties but not natural rewards
• homozygotes display a 10-15% reduction in water intake relative to wild-type mice
• homozygotes display a 10-15% reduction in food intake relative to wild-type mice
• homozygotes spend significantly less time on the rotarod than heterozygous or wild-type mice
• homozygotes display an abnormal posture, with fore- and hindpaws flattened to the ground
• homozygotes exhibit no vertical activity (rearing) in the open-field test (J:29045)
• homozygotes show normal reflexes but exhibit slower movements relative to wild-type littermates
• homozygotes show a significant reduction in locomotion (74%) and backward movements in the open-field test (J:29045)
• when allowed to walk on a flat surface, homozygotes display an abnormal gait, with sprawled hind legs
• homozygotes display a cataleptic-like behavior as quantified in the ring test

endocrine/exocrine glands
• unlike in wild-type mice, the mutant zonae fasciculata and reticularis are fused in mutant mice
• unlike in wild-type mice, the mutant zonae fasciculata and reticularis are fused in mutant mice
• at 4 months of age, homozygotes exhibit significant adrenocortical hypertrophy with the characteristic fusion of the zona fasciculata and reticularis seen in patients with Cushing's syndrome
• at 4 months of age, homozygotes exhibit significant adrenocortical hyperplasia relative to wild-type controls
• at 4 months of age, prolactin-positive cells appear smaller and more compact than normal
• at 4 months of age, female homozygotes show an increased number of lactotrophs relative to wild-type controls
• aberrant proliferation of lactotrophs gives rise to tumors in aged mice
• at 4 months of age, female homozygotes show a 25% decrease in the number of GH-expressing cellls relative to wild-type controls
• at 4 months of age, female homozygotes show a 2-fold increase in thyrotroph cell number relative to wild-type controls
• however, plasma beta-TSH levels are not significantly increased
• at 4 months of age, the anterior lobe of female mutant pituitaries shows an increase in both cell number and density relative to that in wild-type controls
• at 4 months of age, homozygotes of both sexes display an enlarged pituitary
• however, pituitary enlargement is less pronounced in males
• mutant pituitaries show absence of dopaminergic control (sites) resulting in pituitary cell proliferation
• male homozygotes display less prominent pituitary gland hyperplasia than age-matched female homozygotes
• hyperplasia appears to correlate with a progressive induction of prolactin receptor levels in the pituitary gland as homozygotes become older
• whereas hyperplasia of the intermediate lobe occurs earlier (7-8 weeks of age) and remains contained even in aged animals, hyperplasia of the anterior lobe is delayed (3-4 months) but progressive leading to tumors in aged mice
• at 4 months of age, homozygotes display both increased melanotroph proliferation and altered cellular identity
• at 4 months of age, intermediate lobe hyperplasia is due to increased proliferation of POMC-producing melanotrophs (J:110599)
• at 4 months of age, the intermediate lobe of female mutant pituitaries shows a 40% increase in cell number, but not in cell density, relative to that in wild-type controls (J:41857)
• at 8-14 months of age, all female homozygotes display anterior pituitary tumors with nodular areas and large blood vessel infiltration
• male homozygotes develop anterior pituitary tumors much later than female homozygotes (19 months versus 8 months of age, respectively)
• at 4 months of age, homozygotes display adrenal hypersecretion of corticosterone due to excess circulating ACTH levels
• at 4 months of age, homozygotes show a 2-fold increase in POMC expression that is specifically restricted to pituitary melanotrophs
• mutant melanotrophs lose their cell identity and display aberrant production of ACTH leading to adrenal hyperplasia
• however, expression of the hypothalamic corticotropin releasing hormone (CRF) involved in the regulation of POMC synthesis remains unaffected

growth/size/body
• homozygotes exhibit a 15% reduction in body weight relative to wild-type mice

homeostasis/metabolism
• at 16 hrs after 20 or 35 mg/kg kainic acid administration, homozygotes, but not wild-type controls, display induction of Jun mRNA and the proapoptotic factor BAX, as well as fragmented DNA in CA3 cells and an increased number of TUNEL-positive cells, suggesting hippocampal cell death by apoptosis
• the extension of BAX labeling and tissue damage in the CA3 subfield are larger than that of TUNEL staining, indicating progressive apoptotic hippocampal cell death after kainic acid-induced seizures
• cell loss is detected only in the CA3 subfield but not in other regions of the hippocampus
• an extensive gliosis is observed in the CA3 subfield by GFAP immunohistochemistry
• the extent of CA3 cell damage following treatment with 35 mg/kg kainic acid is greater than that observed with 20 mg/kg, indicating a dose-dependent toxic effect; a higher number of TUNEL-positive cells and a larger extension of reactive gliosis are additionally observed in homozygotes treated with 35 mg/kg
• at 12 hrs after 35 mg/kg kainic acid administration, homozygotes show a stronger Jun induction in the hippocampus and cerebral cortex than wild-type controls, correlating with the occurrence of hippocampal cell death
• female homozygotes show a 70% reduction in serum estrogen levels relative to wild-type females
• male homozygotes display a 20% reduction in serum estrogen levels relative to wild-type males
• interestingly, female and male homozygotes display very similar serum estrogen levels (8 ng/l and 9 ng/ml, respectively)
• at 4 months of age, homozygotes show a 1.5-fold increase in plasma corticosterone levels relative to wild-type controls
• at 4 months of age, plasma GH levels are reduced by 25% and 35% in male and female homozygotes, respectively
• at 4 months of age, homozygotes show a 5.7- and 2.7-fold increase in serum levels of beta-endorphin and alpha-MSH, respectively, relative to wild-type controls
• in the absence of dopaminergic control, adult homozygotes show 10.9- and 5.3-fold higher serum prolactin levels in females and males, respectively, relative to wild-type controls
• female homozygotes show a 6-fold rise in plasma prolactin levels relative to male homozygotes (264 +/- 35.2 ng/ml versus 41.1 +/- 7.2 ng/ml, respectively), whereas wild-type females show only a 3-fold difference in prolactin levels relative to wild-type males
• unexpectedly, 4-month-old homozygotes show a 4-fold increase in serum ACTH levels relative to wild-type controls
• increased ACTH levels are due to aberrant processing of the POMC propeptide in melanotrophs, as shown by a 4- to 5-fold increase in expression of prohormone convertase Pcsk1 (PC1) in the intermediate lobe of mutant mice
• homozygotes exhibit a 0.7 degree C reduction in body temperature relative to wild-type mice

reproductive system
• female homozygotes display an abnormal estrous cycle
• female homozygotes display a prolonged diestrus, as shown by the continued presence of lymphocytes in vaginal fluid
• a recognizable estrus is observed only once a month instead of every 4 days
• litters can only be obtained by breeding homozygous mutant mice with their heterozygous counterparts
• female homozygotes display impaired gonadal function due to hyperprolactinemia
• in contrast, male homozygotes exhibit normal spermatogenesis

nervous system
• at 10 mg/kg kainic acid (i.p.), homozygotes display preconvulsive behaviors (rigid posture, tail stiffening, and forelimb extension) whereas wild-type and heterozygotes remain immobile
• at 20 mg/kg kainic acid, homozygotes exhibit obvious symptoms of limbic epileptic activity (repeated episodes of rearing with forelimb clonus, alternating with rigid posture and head bobbing), whereas wild-type and heterozygous controls display only preconvulsive signs
• however, at 35 mg/kg kainic acid, homozygotes exhibit repeated limbic seizures of the same severity as those observed in wild-type and heterozygous controls
• at 4 months of age, prolactin-positive cells appear smaller and more compact than normal
• at 4 months of age, female homozygotes show an increased number of lactotrophs relative to wild-type controls
• aberrant proliferation of lactotrophs gives rise to tumors in aged mice
• at 4 months of age, female homozygotes show a 25% decrease in the number of GH-expressing cellls relative to wild-type controls
• at 4 months of age, female homozygotes show a 2-fold increase in thyrotroph cell number relative to wild-type controls
• however, plasma beta-TSH levels are not significantly increased
• at 4 months of age, the anterior lobe of female mutant pituitaries shows an increase in both cell number and density relative to that in wild-type controls
• at 4 months of age, homozygotes of both sexes display an enlarged pituitary
• however, pituitary enlargement is less pronounced in males
• mutant pituitaries show absence of dopaminergic control (sites) resulting in pituitary cell proliferation
• male homozygotes display less prominent pituitary gland hyperplasia than age-matched female homozygotes
• hyperplasia appears to correlate with a progressive induction of prolactin receptor levels in the pituitary gland as homozygotes become older
• whereas hyperplasia of the intermediate lobe occurs earlier (7-8 weeks of age) and remains contained even in aged animals, hyperplasia of the anterior lobe is delayed (3-4 months) but progressive leading to tumors in aged mice
• at 4 months of age, homozygotes display both increased melanotroph proliferation and altered cellular identity
• at 4 months of age, intermediate lobe hyperplasia is due to increased proliferation of POMC-producing melanotrophs (J:110599)
• at 4 months of age, the intermediate lobe of female mutant pituitaries shows a 40% increase in cell number, but not in cell density, relative to that in wild-type controls (J:41857)
• at 8-14 months of age, all female homozygotes display anterior pituitary tumors with nodular areas and large blood vessel infiltration
• male homozygotes develop anterior pituitary tumors much later than female homozygotes (19 months versus 8 months of age, respectively)
• at 4 months of age, homozygotes show a 2-fold increase in POMC expression that is specifically restricted to pituitary melanotrophs
• mutant melanotrophs lose their cell identity and display aberrant production of ACTH leading to adrenal hyperplasia
• however, expression of the hypothalamic corticotropin releasing hormone (CRF) involved in the regulation of POMC synthesis remains unaffected
• at 3 hrs after kainic acid treatment (20 mg/kg), homozygotes show a strong and widespread Fos expression throughout the entire brain, whereas wild-type controls display a reduced labeling that is primarily restricted to the hippocampus
• at 6 hrs after kainic acid treatment (20 mg/kg), homozygotes exhibit sustained Fos expression in the hippocampus and cerebral cortex, whereas no labeling is detected in wild-type controls
• at 6 hrs after kainic acid treatment (20 mg/kg), homozygotes, but not wild-type controls, exhibit a robust Jun induction in the dentate gyrus, and hippocampal CA1 nd CA3 regions
• at 16 hrs after 20 or 35 mg/kg kainic acid administration, homozygotes, but not wild-type controls, display induction of Jun mRNA and the proapoptotic factor BAX, as well as fragmented DNA in CA3 cells and an increased number of TUNEL-positive cells, suggesting hippocampal cell death by apoptosis
• the extension of BAX labeling and tissue damage in the CA3 subfield are larger than that of TUNEL staining, indicating progressive apoptotic hippocampal cell death after kainic acid-induced seizures
• cell loss is detected only in the CA3 subfield but not in other regions of the hippocampus
• an extensive gliosis is observed in the CA3 subfield by GFAP immunohistochemistry
• the extent of CA3 cell damage following treatment with 35 mg/kg kainic acid is greater than that observed with 20 mg/kg, indicating a dose-dependent toxic effect; a higher number of TUNEL-positive cells and a larger extension of reactive gliosis are additionally observed in homozygotes treated with 35 mg/kg
• at 12 hrs after 35 mg/kg kainic acid administration, homozygotes show a stronger Jun induction in the hippocampus and cerebral cortex than wild-type controls, correlating with the occurrence of hippocampal cell death

neoplasm
• at 8-14 months of age, all female homozygotes display anterior pituitary tumors with nodular areas and large blood vessel infiltration
• male homozygotes develop anterior pituitary tumors much later than female homozygotes (19 months versus 8 months of age, respectively)

pigmentation
• at 4 months of age, homozygotes display coat hyperpigmentation due to increased alpha-MSH and ACTH levels

cellular
• at 16 hrs after 20 or 35 mg/kg kainic acid administration, homozygotes, but not wild-type controls, display induction of Jun mRNA and the proapoptotic factor BAX, as well as fragmented DNA in CA3 cells and an increased number of TUNEL-positive cells, suggesting hippocampal cell death by apoptosis
• the extension of BAX labeling and tissue damage in the CA3 subfield are larger than that of TUNEL staining, indicating progressive apoptotic hippocampal cell death after kainic acid-induced seizures
• cell loss is detected only in the CA3 subfield but not in other regions of the hippocampus
• an extensive gliosis is observed in the CA3 subfield by GFAP immunohistochemistry
• the extent of CA3 cell damage following treatment with 35 mg/kg kainic acid is greater than that observed with 20 mg/kg, indicating a dose-dependent toxic effect; a higher number of TUNEL-positive cells and a larger extension of reactive gliosis are additionally observed in homozygotes treated with 35 mg/kg
• at 12 hrs after 35 mg/kg kainic acid administration, homozygotes show a stronger Jun induction in the hippocampus and cerebral cortex than wild-type controls, correlating with the occurrence of hippocampal cell death


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Mouse Genome Database (MGD), Gene Expression Database (GXD), Mouse Tumor Biology (MTB), Gene Ontology (GO), MouseCyc
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last database update
11/07/2017
MGI 6.11
The Jackson Laboratory