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Lewis rats used in drug addiction testing

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Lewis rats are often used in pharmacology studies. For example, drug testings which includes the determination to the Effective Dose(ED50), Toxic Dose(TD50) and also the Lethal Dose(LD50).

The reason why Lewis rats are used is due the the fact it is more sensitive to experimental manipulations compared to stocks.

The uniformity of the genetic profile is also essential in ensuring the outcome of the experiment is not influenced by any genetic variation or if the researcher is interested in knowing the effects of a certain gene towards specific interventions.

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Lewis rat used as an immunological animal model.

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Lewis rat was used as a diabetic model and was compared with other strains.

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MHC Haplotype = RT1

High serum thyroxine levels

High insulin levels

High Growth Hormone levels

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GENERAL 🐁ANATOMY🐁 AND                                    🐁PHYSIOLOGY🐁

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GENERAL 🐁ANATOMY🐁 AND                                    🐁PHYSIOLOGY🐁

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Rats or Mice?. Photo from Elena Butinova, Eric Isselee/Shutterstock.com

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Diagram 8: Female Urogenital tract. From Functional Anatomy and Physiology. The Laboratory Rat

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Female reproductive system

Ovaries are located in the lateral border of the psoas muscle while embedded in fatty tissues near the kidneys.

Anogenital distance is shorter in females than in males.

Mature ovaries appear as mass of follicles.

Only the clitoris is connected to the urinary system.

Estrus cycle is about 4-5 days.

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Small in size

Large floppy ears compared to the head size

Snout is more blunt and triangular

Has long and thin hairy tails.

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Medium to Large sized rodents

Large ears as well but it is proportionate to the body size

Snout is more slender and pointed

Has long tails and is usually hairless

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A WORD file for the References used when making this Padlet.

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Some BREEDERS AND BREEDER CODES

Charles River Laboratories (Crl)

Taconic (Tac)

Janvier laboratories (OrlRj)

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1. Weight (male) =  400-500g

2. Weight (female) = 200-300g

3. Weight (newborn) = 5-6g

4. Daily Water consumption = 8-11ml per 100g of body weight

5. Daily Feed consumption = 5g per 100g of body weight

6. Body temperature = 35.9 - 37.5 degrees Celsius

7. Heart rate = 250-450 beats per minute

8. Rate of Respiration = 70-115 breaths per minute

9. Life span = 2.5 years to 3 years

10. Age of Puberty

Male-40 to 60 days

Female-40-49 days

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Streptozotocin (STZ) is chemically known as N-(methylnitorsocarbamoyl)-a-d-glucosamine. It is a compound found to be produced naturally by Streptomycin achromogenes. This compound contains antibacterial properties. It damages the beta cells of the pancreas which is essential in the secretion of insulin. The lack of insulin leads to hypoinsulinemia and hyperglycaemia to be observed in the STZ-induced diabetes rat. STZ is commonly used to induce diabetes in animal models.

Lewis rats are sensitive to obesity and diabetes induced by a high fat diet. These strains are used as an animal models for this human disease due to the relatively simple physiology to follow. Hence, it is easier to understand the disease profile in terms of the pathology and metabolic profile.

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Lewis rats are often used in Immunological studies as it is sensitive to the development of autoimmune diseases as it has an enhanced susceptibility towards a wide variety of inflammatory conditions such as ;

Rheumatoid arthritis (RA)

Adjuvant-induced arthritis

Autoimmune encephalitis

Autoimmune thyroiditis

Lewis rats have an evident differential T-cell proliferation and cytokine and antibody response. The Major Histocompatibility Complex (MHC) that is expressed by the cells of the Lewis rats are more susceptible to induced RA although they are the same MHC expressed by Fischer rats.

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Central nervous system

Composed of brain and spinal cord

The Meninges which has 3 layers covers these structures

Dura mater(outermost)

Arachnoid mater (middle)

Pia mater (innermost)

Spinal cord terminates at the slender filum terminale. (Cauda equina = caudal spinal nerves+filum terminale)

Peripheral nervous system.

It is composed of spinal nerves and cranial nerves

Spinal nerves 34 pairs

7 Cervical

13 Thoracic

6 Lumbar

4 Sacral

27-30 Caudal

Each nerve roots are formed by the dorsal and ventral roots. Dorsal root carries sensory impulses to the spinal cord. Ventral root carries nerve impulses away from the spinal cord.

The First cervical nerve lacks a ganglion.

Brachial plexus = give rise to ulnar nerve, axillary nerve, musculocutaneous nerve, radial nerve.

Lumbar plexus = femoral nerve and saphenous nerve.

Pelvic plexus = connects to the genitourinary tract.

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Diagram 7 : Male Urogenital System. From Functional Anatomy and Physiology. The Laboratory Rat

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Male reproductive system

Testes is located in scrotal sacs between anus and prepuce.

Anogenital distance is longer in males than in females.

The male rats possesses 5 types of accessory sex glands which are ampullary glands, prostate gland, vesicular gland, coagulating gland, Cowper’s gland.

Penis lies within a loose prepuce with a single bony process.

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Kidneys function to filter blood, excrete waste products and maintain renin-angiotensin-aldosterone-system(RAAS).

The right kidney and adrenal gland are located slightly more cranial as compared to the left kidney and adrenal gland.

Kidneys are located in the retroperitoneal space.

The nephron is functional unit of the kidney.

The nephron is made up the glomerulus, Bowman’s capsule, proximal convoluted tubule, loop of Henle, Distal convoluted tubule and collecting tubes.

There is the presence of both short and long-looped nephrons with the short-looped nephrons predominating.

Rats have about twice as much of short-looped nephrons compared to long-looped nephrons

The ability of a rat to concentrate urine is two times more than humans. This is due to a significant osmotic gradient in the medulla rising form the corticomedullary junction to the tip of the papilla.

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Diagram 6 : Longitudinal cross-section of the rat heart. From Constantinescu, G.M., 2011. Comparative Anatomy of the Mouse and the Rat: A Color Atlas and Text.

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The heart is located between the second and sixth intercostal space .

It has 4 chambers = 2 atria and 2 ventricles

The Aortic valve, pulmonary valve and tricuspid valve each have 3 leaflets

Only the Mitral valve has 2 leaflets.

These leaflets are less distinct individually

Cardiac output, total peripheral resistance and venous capacity us constantly regulated in order to maintain blood pressure with the help from baroreceptors, chemoreceptors and cardiopulmonary receptors.

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Diagram 5 = Anatomy of Lungs. From Elsevier, Inc., www.netterimages.com.

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Rat lungs have 5 lobes =  1 left lobe, 4 lobes on the right (cranial, middle, accessory and caudal).

The middle lobe is in contact with diaphragm and apex of heart.

The lungs of a newborn rat is immature, it has no alveoli, no alveolar ducts and gaseous exchange occurs in smooth walls of the channels.

Once the newborn rat reaches 4 days old, rapid restructuring of the lungs occurs whereby alveolarization begins.

Respiratory bronchioles are not present at birth but by day 10 can be identified.

Pulmonary vein is thicker than other species because presence of striated muscle fibers that are contiguous with those of the heart. Cardiomyocytes in rats extend from atrium to the hilus of lungs

Lung innervation is complex it has no adrenergic supply to smooth muscle or intrapulmonary arteries.

Bronchoconstriction action is controlled by vagal tone.

Lung weight related to body size but surface area is related to the oxygen consumption.

Alveolar diameter is related to metabolic rate and measured by Oxygen use per unit of body weight.

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Diagram 4: Rat liver and its 4 major lobes. From Comparative Anatomy and Histology: A Mouse, Rat, and Human Atlas, second ed.

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PANCREAS

Pancreas is not a singular mass but is diffuse and extends from duodenal loop end.

There are 3 regions = duodenal, gastric and splenic OR left, middle and right.

Pancreas has a role in digestion by synthesizing and secreting enzymes.

LIVER

The Liver functions to process nutrients, maintain energy homeostasis and clearing toxins.

It also functions to support and regulate the immune system.

The liver is divided into 4 lobes = right, median, left and caudate lobes.

Bile ducts from each lobe come together and form a common bile duct and empty into descending duodenum.

No bile concentration occurs as there is no gallbladder.

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Diagram 3: Anatomy of Rat stomach. From Comparative Anatomy and Histology: A Mouse, Rat, and Hu- man Atlas, second ed.

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Rats are nocturnal rodents.

Feed semi-continuously when active at night.

ConsumeS 5g per 100g of body weight of feed in 24-Hour period.

Consumes 8-11mL per 100g body weight of water in a 24-Hour period.

Rats lacks tonsils and gallbladder.

Rats have a diffuse pancreas.

Mouth and Buccal Cavity

Dental formula = 2(I 1/1, C 0/0, Pm 0/0, M 3/3) = 16

Oesophagus

The oesophagus enters stomach at the inner curvature through fold if the limiting ridge that separates forestomach from glandular stomach.

The way the oesophagus enters the stomach and together with the  lack of neurologic component to induce vomiting prevents rats from vomiting.

Stomach

The stomach is located in left proximal portion of abdomen and comes into contact with liver.

2 regions – forestomach and glandular stomach, glandular is further divided into 3 -small cardia, fundus and antrum.

The stomach secretes only pepsinogen C and cathepsins D and E, there is no secretion of pepsinogen A.

Small intestine

Major site of digestion and absorption of nutrients.

Longest portion of the Gastrointestinal tract.

Comprises of the duodenum, jejunum, ileum.

Mucosal surface is covered by villi with intestinal crypts, crypts of Lieberkühn located at the base.

Enterocytes = absorb nutrients from the lumen of the small intestine and allow it to be transported to a nearby blood vessel.

Goblet cells = synthesises mucus

Paneth cells = produces dense granules which contain antimicrobial peptide

Caecum

It is a llarge-thin walled, blind pouch consisting of apical and basal portion.

The base of caecum include ileocecal and colocecal junctions.

The size of cecum reflects the omnivorous nature of rats, it is smaller than herbivores but larger than carnivores.

The presence of bacteria supports its function as a fermentation vat to breakdown plant materials.

Large intestines

It is shaped like an inverted V and is divided into 2 segments the ascending and descending colon.

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TASTE BUDS

Taste buds are the sense organ for taste. They are ovoid bodies located on the tongue, hard and soft palate and pharynx. The rat's tasting abilities may decline with age.

3 different cell types

Type 1 = glial-like supporting cells responsible for detecting salt

Type II = sweet, bitter, umami

Type III = sour, sweet, bitter, umami

Type II AND Type III ARE SENSORY CELLS FOR MAIN TASTE.

HEARING

Same like humans, ears consists of external, middle and inner ear.

External ear = Auricle and Ear Canal (has Zymbal's glands which secrete secretions to into the ear canal.

Middle ear = Consists of Hammer, Anvil, and Stirrup. It is separated from external ear by the Tympanic membrane. Eustachian tube is part of the middle ear.

Inner ear = Consists of Vestibule, Semicircular canal and Cochlea.

TOUCH

Main tactile organs = vibrissae which is used for the rats to navigate location, recognise objects, as well as it plays an essential role in social interactions, body balance and orientation.

Mystacial vibrissae present in supraorbital, postero-orbital, lateral cervical, median cervical, submental and carpal forelimbs.

Each vibrissae is sunken in a follicle sealed within blood sinus.

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The nose is for olfaction, to protect the lower respiratory tract by filtering, humidifying and controlling temperature of inhaled air.

Rats are obligate nasal breather due to close positioning of the epiglottis to the soft palate.

Various rat behaviours and social activity such as determining social class or standing, kinship and estrus stage in female rats is communicated by odour. Reproduction, maternal care, alarm responses, and anxiety-like behaviour is influenced by Vomeronasal organ which is a chemoreceptor organ enclosed in the cartilaginous capsule separated from the main olfactory epithelium. It is important in pheromone detection from individuals of the same species.

Olfactory epithelium consist of olfactory sensory neurons, basal cells, and sustentacular cells.

Dams detect pheromone released by pups, dodecyl proprionate which stimulates maternal anogenital licking of the pups. If disrupted leads to poor maternal care and inadequate licking and stimulation of the pups to urinate and defecate.

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Diagram 2: Superficial glands of head and neck. From Greene, E.C., 1935. Anatomy of the Rat, vol. 27. American Philosophical Society, Philadelphia, PA.

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Main glands which lubricate and moisten the cornea and eye.

Lacrimal gland and Harderian gland secrete porphyrin-pigmented and lipid-waden tears.

Little to no aqueous component in tear film.

Ocular surface covered by glycocalyx to resist desiccation.

Rats are susceptible to light-induced damage (should be kept in levels  of 130-325 lux).

Albino rats can develop retinal damage in light levels as little as 80 lux light.

Rats have 2 types of retinal cones.

One type has ultraviolet sensitive photopigment at 358nm.

One type has pigment which is sensitive at middle wavelengths of visible spectrum at 510nm.

Rats have low visual acuity compared to humans.

Albino rats have 20/1200 vision.

Lacrimal gland

Extraorbital= located ventral and rostral to ear

Intraorbital= open into conjunctiva in dorsolateral region of the eye

Fucntions to secrete lacrimal fluid.

Harderian gland

Horseshoe shaped.

Occupies a huge portion of the orbit and extends medially and caudally circling the optic nerve.

Functions to secrete secretions containing porphyrins which fluoresce.

Overexpression during stress leads to red porphyrin to be secreted and cause a condition known as chromodacyorrhea.

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Perimysium is composed of bundles of collagen fibres that connect the epimysium as well as the endomysium.

Amount of collagen in each component depends on the function of the muscle.

Skeletal muscle is made up of many muscle fibers. These muscle fibres are made up of many myofibrils. The myofibrils contain contractile elements of the muscles.

Skeletal muscle function declines with age.

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Diagram 1: Rat skeleton. From Constantinescu, G.M., 2011. Comparative Anatomy of the Mouse and the Rat: A Color Atlas and Text

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Consists of AXIAL and APPENDICULAR skeleton.

AXIAL

Consists of  the Skull, vertebral column, sternum and ribs.

Function = To give support to the body of the rat, protects the brain, protects the vertebral column, protects the lungs and heart within the thoracic basket which is made up of the vertebral bones, ribs and sternum.

VERTEBRAL COLUMN = C7 T13 L6 S4 C27-30

STERNUM = Forms the ventral support of the thoracic basket.

RIBS =These are 12, 13, or 14 pairs of slender curved bones, all articulating dorsally with thoracic vertebrae and some ventrally with the sternum, hence forming the thoracic basket.

APPENDICULAR

Pectoral and Pelvic Girdles and Appendages (limbs and attachments)

GIRDLE= Each pectoral girdle consists of dorsal scapula and ventral clavicle.

LIMBS= The bones of the forelimb are humerus, radius and ulna, eight carpals, five metacarpals, five first phalanges, four second phalanges, and five third phalanges with their tips.

Peak growth rate of skeleton in rat is at about 7 weeks old

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Lewis rat. Photo from Charles River Laboratories.

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Has Long & Slender body.

Rounded snout.

Hairless tail.

Hair coat covers body surfaces except nose, lips, tail, palmar & plantar surface of feet.

Both front and hind limbs both have 5 digits each.

Footpads are present to provide cushioning support against the force during walking and resting.

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The Lewis rat was first developed by Dr. Margaret Lewis in the early years of 1950s. This rat was successfully created by the inbreeding of the the Wistar stock. At the 20th generation of the Lewis rat or also denoted as F20, it was then transferred to APTEKMAN and BODGEN in the year 1954. Subsequently, in the year 1958 to SILVERS at F31. At F34 it was then transferred to Charles River from TULANE in 1970.

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Docile

These rats are social animals and are less likely to start a fight between each other. Hence, the male rats could be housed together.

CAUTION!

The rats become nervous when they hear their friends squeal. This will cause the rats to become refractory towards handling.

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Image from Grzimek(1968) and Musser and Calton (2005)

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KINGDOM : ANIMALIA
PHYLUM : CHORDATA
CLASS : MAMMALIA
ORDER : RODENTIA
FAMILY : MURIDAE
GENUS : Rattus
SPECIES : Rattus norvegicus

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Immunology

Pharmacology & Toxicology

Transplant medicine

STZ-induced Diabetes

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INBREEDING

To produce offsprings with minimal genetic variation

Offsprings share the same characteristics

Considered inbred after more than 20 generations of inbreeding

Monogamous- 1 male rat paired with 1 female rat during the duration of breeding. This makes record keeping process easier.

Polygamous-1 male rat paired with 2 or more female rats during the duration of breeding. This results in a large number of offsprings

REPRODUCTIVE INFORMATION

High rate of sterility.

Type of Sexual cycle : Polyestrus and Nonseasonal

Duration of Sexual cycle : 4-5 days

Estrus duration : 12 hours

Gestation period : 21 to 23 days

Postpartum Estrus : Fertile

Number of offspring : 8 to 14 pups

Weaning age : 20 to 21 days

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ALBINO!

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It is an INBRED STRAIN

Its abbreviation is LEW

ADVANTAGE OF USING STRAINS

The genetic similarity which exists contributes to phenotypes expressed to be uniform.

Small number of animals is needed to be used in order to gain a good statistical power.

It is sufficient to just genotype one single animal from that strain which can represent the whole strain.

Strains do not change or in other words stay constant for many generations as long as there is no contamination due to new mutations being passed on which is rare.

Experiments can be done by using small numbers of the animal model.