scholarly journals Genetic Modulation of Initial Sensitivity to Δ9-Tetrahydrocannabinol (THC) Among the BXD Family of Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Cory Parks ◽  
Chris M. Rogers ◽  
Pjotr Prins ◽  
Robert W. Williams ◽  
Hao Chen ◽  
...  
Keyword(s):  
Single Dose ◽  
Drugs Of Abuse ◽  
Cannabinoid Receptor ◽  
Inbred Mice ◽  
Strain Differences ◽  
Inbred Strains ◽  
Thermal Stimulus ◽  
Motor Impairments ◽  
Initial Sensitivity ◽  
Acute Responses

Cannabinoid receptor 1 activation by the major psychoactive component in cannabis, Δ9-tetrahydrocannabinol (THC), produces motor impairments, hypothermia, and analgesia upon acute exposure. In previous work, we demonstrated significant sex and strain differences in acute responses to THC following administration of a single dose (10 mg/kg, i.p.) in C57BL/6J (B6) and DBA/2J (D2) inbred mice. To determine the extent to which these differences are heritable, we quantified acute responses to a single dose of THC (10 mg/kg, i.p.) in males and females from 20 members of the BXD family of inbred strains derived by crossing and inbreeding B6 and D2 mice. Acute THC responses (initial sensitivity) were quantified as changes from baseline for: 1. spontaneous activity in the open field (mobility), 2. body temperature (hypothermia), and 3. tail withdrawal latency to a thermal stimulus (antinociception). Initial sensitivity to the immobilizing, hypothermic, and antinociceptive effects of THC varied substantially across the BXD family. Heritability was highest for mobility and hypothermia traits, indicating that segregating genetic variants modulate initial sensitivity to THC. We identified genomic loci and candidate genes, including Ndufs2, Scp2, Rps6kb1 or P70S6K, Pde4d, and Pten, that may control variation in THC initial sensitivity. We also detected strong correlations between initial responses to THC and legacy phenotypes related to intake or response to other drugs of abuse (cocaine, ethanol, and morphine). Our study demonstrates the feasibility of mapping genes and variants modulating THC responses in the BXDs to systematically define biological processes and liabilities associated with drug use and abuse.

scholarly journals Genetic modulation of initial sensitivity to Δ9-tetrahydrocannabinol (THC) among the BXD family of mice

2021 ◽  
Author(s):  
Cory Parks ◽  
Chris M Rogers ◽  
J. Pjotr Prins ◽  
Robert W. Williams ◽  
Hao Chen ◽  
...  
Keyword(s):  
Single Dose ◽  
Drugs Of Abuse ◽  
Cannabinoid Receptor ◽  
Inbred Mice ◽  
Strain Differences ◽  
Inbred Strains ◽  
Thermal Stimulus ◽  
Motor Impairments ◽  
Initial Sensitivity ◽  
Acute Responses

Cannabinoid receptor 1 activation by the major psychoactive component in cannabis, Δ9-tetrahydrocannabinol (THC), produces motor impairments, hypothermia, and analgesia upon acute exposure. In previous work, we demonstrated significant sex and strain differences in acute responses to THC following administration of a single dose (10 mg/kg, i.p.) in C57BL/6J (B6) and DBA/2J (D2) inbred mice. To determine the extent to which these differences are heritable, we quantified acute responses to a single dose of THC (10 mg/kg, i.p.) in males and females from 20 members of the BXD family of inbred strains derived by crossing and inbreeding B6 and D2 mice. Acute THC responses (initial sensitivity) were quantified as changes from baseline for: 1. spontaneous activity in the open field (mobility), 2. body temperature (hypothermia), and 3. tail withdrawal latency to a thermal stimulus (analgesia/antinociception). Initial sensitivity to the immobilizing, hypothermic, and antinociceptive effects of THC varied substantially across the BXD family. Heritability was highest for mobility and hypothermia traits, indicating that segregating genetic variants modulate initial sensitivity to THC. We identified genomic loci and candidate genes, including Ndufs2, Scp2, Rps6kb1 or P70S6K, Pde4d, and Pten, that may control variation in THC initial sensitivity. We also detected strong correlations between initial responses to THC and legacy phenotypes related to intake or response to other drugs of abuse (cocaine, ethanol, and morphine). Our study demonstrates the feasibility of mapping genes and variants modulating THC responses in the BXDs to systematically define biological processes and liabilities associated with drug use and abuse.

DIFFERENCES BETWEEN MOUSE STRAINS IN TESTICULAR CHOLESTEROL LEVELS AND ANDROGEN TARGET ORGANS

1972 ◽  
Vol 55 (1) ◽  
pp. 173-184 ◽  
Author(s):  
A. BARTKE ◽  
J. G. M. SHIRE
Keyword(s):  
Inbred Mice ◽  
Strain Differences ◽  
Inbred Strains ◽  
Seminal Vesicles ◽  
Cholesterol Concentration ◽  
Mouse Strains ◽  
Cholesterol Levels ◽  
Target Organs ◽  
Testicular Weight ◽  
Androgenic Steroids

SUMMARY The concentrations of esterified and free cholesterol in the testes, and the weights of the testes, seminal vesicles, kidneys and submandibular glands, were determined in mice of the C57BL/10J and DBA/2J inbred strains. Measurements were also made on reciprocal F1 hybrids. Cholesterol concentration and the weights of the testes and seminal vesicles were also studied in C57BL/6J and AKR/J inbred mice and in mice from two random-bred stocks. Considerable strain differences were found both in the concentration of esterified cholesterol and in gonadal weight. Since all the animals were maintained under the same environmental conditions the differences must have been genetic in origin. The decrease in absolute testicular weight which occurred in the C57BL/10 mice after the age of 8 weeks was accompanied by an increase in the percentage of total cholesterol present as ester. Groups of C57BL/10 males were treated with luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin-secreting pituitary isografts, pregnant mare serum gonadotrophin (PMS), testosterone propionate or pregnenolone. The concentration of esterified cholesterol was slightly decreased by LH and increased by pituitary grafts, confirming earlier studies in other strains. Treatment with PMS caused a drastic depletion of the high levels of esterified cholesterol usually found in the testes of these mice, and also caused marked growth of the seminal vesicles. Testosterone increased the weight of seminal vesicles while pregnenolone had no effect. None of the treatments stimulated spermatogenesis. A marked sex difference in the weight of the kidneys was absent in the C57BL/10 strain but was present in the DBA/2 strain. The kidneys of C57BL/10 males were significantly smaller than those of DBA/2 males. These findings, together with other studies on C57BL/10 mice, suggest that males of this strain are relatively androgen deficient. This could be due to inadequate production of FSH and LH, perhaps accompanied by a deficiency in the conversion of pregnenolone to androgenic steroids. The effect of the C57BL/10 genotype on spermatogenesis either is not hormone mediated or else is irreversible after the age of 6 weeks.

Differential lung mechanics are genetically determined in inbred murine strains

1999 ◽  
Vol 86 (6) ◽  
pp. 1764-1769 ◽  
Author(s):  
Clarke G. Tankersley ◽  
Richard Rabold ◽  
Wayne Mitzner
Keyword(s):  
Mechanical Properties ◽  
Lung Volume ◽  
Recombinant Inbred ◽  
Breathing Pattern ◽  
Inbred Mice ◽  
Strain Differences ◽  
Inbred Strains ◽  
Genomic Region ◽  
Lung Mechanics ◽  
Recombinant Inbred Strains

Genetic determinants of lung structure and function have been demonstrated by differential phenotypes among inbred mice strains. For example, previous studies have reported phenotypic variation in baseline ventilatory measurements of standard inbred murine strains as well as segregant and nonsegregant offspring of C3H/HeJ (C3) and C57BL/6J (B6) progenitors. One purpose of the present study is to test the hypothesis that a genetic basis for differential baseline breathing pattern is due to variation in lung mechanical properties. Quasi-static pressure-volume curves were performed on standard and recombinant inbred strains to explore the interactive role of lung mechanics in determination of functional baseline ventilatory outcomes. At airway pressures between 0 and 30 cmH2O, lung volumes are significantly ( P < 0.01) greater in C3 mice relative to the B6 and A/J strains. In addition, the B6C3F1/J offspring demonstrate lung mechanical properties significantly ( P < 0.01) different from the C3 progenitor but not distinguishable from the B6 progenitor. With the use of recombinant inbred strains derived from C3 and B6 progenitors, cosegregation analysis between inspiratory timing and measurements of lung volume and compliance indicate that strain differences in baseline breathing pattern and pressure-volume relationships are not genetically associated. Although strain differences in lung volume and compliance between C3 and B6 mice are inheritable, this study supports a dissociation between differential inspiratory time at baseline, a trait linked to a putative genomic region on mouse chromosome 3, and differential lung mechanics among C3 and B6 progenitors and their progeny.

Strain Differences in the Liver Autoantibody Response of Inbred Mice

1969 ◽  
Vol 131 (1) ◽  
pp. 121-124 ◽  
Author(s):  
H.- D. Flad ◽  
J. H. L. Playfair ◽  
A. Ghaffar ◽  
P. A. Miescher
Keyword(s):  
Inbred Mice ◽  
Strain Differences ◽  
Autoantibody Response

scholarly journals Induction of a ragweed-specific allergic state in Ir-gene-restricted nonresponder mice.

1977 ◽  
Vol 146 (1) ◽  
pp. 302-307 ◽  
Author(s):  
N Chiorazzi ◽  
A S Tung ◽  
D H Katz
Keyword(s):  
Inbred Mice ◽  
Inbred Strains ◽  
Antibody Responses ◽  
Pollen Extract ◽  
Antibody Synthesis ◽  
Ige Antibody ◽  
Gene Concept ◽  
X Irradiation ◽  
Suppressive Mechanism ◽  
Ir Genes

Mice of the inbred strains, C57BL/6 and C57BL/10 (H-2b), are genetically incapable of developing IgE antibody responses to ragweed pollen extract (RE) or its dinitrophenylated derivative, DNP-RE. This nonresponsiveness has previously been thought to reflect the absence of a relevant H-2-linked Ir genes controlling responses of inbred mice to these antigens. However, pretreatment of H-2b mice with either low doses of ionizing X irradiation or cyclophosphamide abrogates the nonresponder status of such animals, apparently by removal of a suppressive mechanism normally inhibiting development of IgE responses to these antigens. The implications of these findings for mechanisms of genetic control of IgE antibody synthesis and the Ir-gene concept are discussed.

scholarly journals Impact of Cannabinoid Receptor Ligands on Sensitisation to Methamphetamine Effects on Rat Locomotor Behaviour

2008 ◽  
Vol 77 (2) ◽  
pp. 183-191 ◽  
Author(s):  
L. Landa ◽  
K. Šlais ◽  
A. Šulcová
Keyword(s):  
Receptor Agonist ◽  
Drugs Of Abuse ◽  
Cannabinoid Receptor ◽  
Behavioural Change ◽  
Repeated Administration ◽  
Receptor Ligands ◽  
Locomotor Behaviour ◽  
Behavioural Sensitisation ◽  
Stereotypic Behaviour ◽  
Pre Treatment

The repeated administration of various drugs of abuse may lead to a gradually increased behavioural response to these substances, particularly an increase in locomotion and stereotypies may occur. This phenomenon is well known and described as behavioural sensitisation. An increased response to the drug tested, elicited by previous repeated administration of another drug is recognised as cross-sensitisation. Based on our earlier experiences with studies on mice, which confirmed sensitisation to methamphetamine and described cross-sensitisation to methamphetamine after pre-treatment with cannabinoid CB1 receptor agonist, we focused the present study on the use of another typical laboratory animal - the rat. A biological validity of the sensitisation phenomenon was expected to be enhanced if the results of both mouse and rat studies were conformable. Similar investigation in rats brought very similar results to those described earlier in mice. However, at least some interspecies differences were noted in the rat susceptibility to the development of sensitisation to methamphetamine effects. Comparing to mice, it was more demanding to titrate a dose of methamphetamine producing behavioural sensitisation. Furthermore, we were not able to provoke cross-sensitisation by repeated administration of cannabinoid CB1 receptor agonist methanandamide and similarly, we did not demonstrate the suppression of cross-sensitisation in rats that were repeatedly given combined pre-treatment with cannabinoid CB1 receptor antagonist AM 251 and methamphetamine. Finally, unlike mice, an alternative behavioural change was registered after repeated methamphetamine treatment instead: the occurrence of stereotypic behaviour (nose rubbing).

Hepatic transcriptional profile reveals the role of diet and genetic backgrounds on metabolic traits in female progenitor strains of the Collaborative Cross

2021 ◽  
Author(s):  
Myungsuk Kim ◽  
M Nazmul Huda ◽  
Annalouise O'Connor ◽  
Jody Albright ◽  
Blythe P. Durbin-Johnson ◽  
...  
Keyword(s):  
Metabolic Diseases ◽  
Strong Association ◽  
Strain Differences ◽  
Inbred Strains ◽  
Atherogenic Diet ◽  
Collaborative Cross ◽  
Liver Triglyceride ◽  
Metabolic Traits ◽  
Nadph Oxidase 4 ◽  
Triglyceride Content

Mice have provided critical mechanistic understandings of clinical traits underlying Metabolic Syndrome (MetSyn) and susceptibility to MetSyn in mice is known to vary among inbred strains. We investigated the diet- and strain-dependent effects on metabolic traits in the eight Collaborative Cross (CC) founder strains (A/J, C57BL/6J, 129S1/SvImJ, NOD/ShiLtJ, NZO/HILtJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ). Liver transcriptomics analysis showed that both atherogenic diet and host genetics have profound effects on the liver transcriptome, which may be related to differences in metabolic traits observed between strains. We found strain differences in circulating trimethylamine N-Oxide (TMAO) concentration and liver triglyceride content, both of which are traits associated with metabolic diseases. Using a network approach, we identified a module of transcripts associated with TMAO and liver triglyceride content which was enriched in functional pathways. Interrogation of the module related to metabolic traits identified NADPH oxidase 4 (Nox4), a gene for a key enzyme in the production of reactive oxygen species, which showed a strong association with plasma TMAO and liver triglyceride. Interestingly, Nox4 was identified as the highest expressed in the C57BL/6J and NZO/HILtJ strains and the lowest expressed in the CAST/EiJ strain. Based on these results, we suggest that there may be genetic variation in the contribution of Nox4 to the regulation of plasma TMAO and liver triglyceride content. In summary, we show that liver transcriptomic analysis identified diet- or strain-specific pathways for metabolic traits in the Collaborative Cross (CC) founder strains.

Examining basal chloride transport using the nasal potential difference response in a murine model

2001 ◽  
Vol 281 (5) ◽  
pp. L1173-L1179 ◽  
Author(s):  
Kristine G. Brady ◽  
Thomas J. Kelley ◽  
Mitchell L. Drumm
Keyword(s):  
Cystic Fibrosis ◽  
Chloride Transport ◽  
Inbred Mice ◽  
Inbred Strains ◽  
Potential Difference ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Inbred Strains Of Mice ◽  
Cystic Fibrosis Transmembrane

Epithelia of humans and mice with cystic fibrosis are unable to secrete chloride in response to a chloride gradient or to cAMP-elevating agents. Bioelectrical properties measured using the nasal transepithelial potential difference (TEPD) assay are believed to reflect these cystic fibrosis transmembrane conductance regulator (CFTR)-dependent chloride transport defects. Although the response to forskolin is CFTR mediated, the mechanisms responsible for the response to a chloride gradient are unknown. TEPD measurements performed on inbred mice were used to compare the responses to low chloride and forskolin in vivo. Both responses show little correlation between or within inbred strains of mice, suggesting they are mediated through partially distinct mechanisms. In addition, these responses were assayed in the presence of several chloride channel inhibitors, including DIDS, diphenylamine-2-carboxylate, glibenclamide, and 5-nitro-2-(3-phenylpropylamino)-benzoic acid, and a protein kinase A inhibitor, the Rp diastereomer of adenosine 3′,5′-cyclic monophosphothioate ( Rp-cAMPS). The responses to low chloride and forskolin demonstrate significantly different pharmacological profiles to both DIDS and Rp-cAMPS, indicating that channels in addition to CFTR contribute to the low chloride response.

THE EFFECT OF PYRIDOXINE DEFICIENCY ON BLOOD UREA IN MICE

1958 ◽  
Vol 36 (1) ◽  
pp. 1143-1148
Author(s):  
John B. Lyon Jr. ◽  
Eugene A. Arnold ◽  
Rita Farmer
Keyword(s):  
Environmental Changes ◽  
Strain Differences ◽  
Inbred Strains ◽  
Vitamin B ◽  
Age Group ◽  
Pyridoxine Deficiency ◽  
Inbred Strains Of Mice

Blood urea levels were determined in weanling, young, and adult C57 and I strain mice fed vitamin B6-deficient or complete rations. Elevations in blood urea were found in some of the deprived groups, but they were transient, and the maxima occurred early in the deficiency, at 2 weeks. Although the I strain is more susceptible to a B6 deficiency, strain differences were found in only one age group. Increases in blood urea were also induced by simple environmental changes. It was concluded that elevations in blood urea are not directly related to a pyridoxine deficiency in these inbred strains of mice.

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