Rabbits

Last modified on January 27, 2010

Taxonomy Genetics/nomenclature Anatomy Physiology Behavior

Taxonomy

Lagomorphs (Phylum Cordata, Class Mammalia, Order Lagomorpha, Family Leporidae, Subfamily Leporinae) are defined taxonomically as having three pairs of incisors, one pair located behind the large upper pair. There are 22 species of hares or jackrabbits, which belong to the genus Lepus. Cottontail rabbits belong to the genus Sylvilagus. The laboratory rabbit is Oryctolagus cuniculus, the European rabbit or Old World rabbit.{3573, 4731}.

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Uses in Research

Approximately 300,000-500,000 rabbits are used for research each year in the US (and this hasn't changed much since 1973 when the USDA started keeping records). One of the most common uses for rabbits is the production of polyclonal antibodies. Disease models can broadly be divided into cancer and infectious diseases. The major cancer models are the VX-2 carcinoma (resulting from transformation of the viral-induced Shope papilloma), spontaneous endometrial adenocarcinoma (with an incidence of 79% in does at 5 years of age), and induced tumors. Infectious disease models include Campylobacter enteritis, Chagas' disease, cryptococcal meningitis, Herpes simplex encephalitis, and staphylococcal blepharitis. Finally, rabbits are models of both hyper- and hypovitaminosis A, acute respiratory distress syndrome induced by phorbol myristate acetate, inflammatory bowel disease, diabetes mellitus, and the Pelger-Huet anomaly.{4731}

Genetics/nomenclature

Rabbits have been bred in captivity since Roman times, when they were kept in leporaria for viewing and hunting. There are over 50 well-established breeds, based mostly on coat color, coat characteristics, size, and ear length.{3573}

The wild-type Oryctolagus is a white-bellied agouti in color. Mutations at the C allele reduce pigmentation, beginning with chinchilla colors and progressing to Himalayan (pigmented extremities) and finally albinism (cc) as seen in the New Zealand White and other white breeds. The Himalayan allele is temperature-sensitive. If fur is shaved in one place and the rabbit kept in cool temperatures, the new fur grows in with pigmented tips.{3573}

Other color alleles in Oryctolagus include the A locus (aa is black), B locus (bb is a brown rabbit), dilute locus (dd rabbits are blue, yellow, lilac or cream depending upon other genes), E locus (reduced agouti hairs which are black), and the Vienna white (vv or Beverens White breed has no pigment in the hair or the iris, and is a blue-eyed white rabbit). Other factors controlling appearance of the coat include Dutch and English spotting and silvering. Hair morphology is modified at the rex, angora, wuzzy, satin, wirehair, waved, furless and naked loci.{3573}

Genetics of rabbits have been shown to affect several pathological conditions, including skull variations, pregnancy toxemia, uterine adenocarcinoma, pituitary dwarfism, brachydactylia, achondroplasia and osteopetrosis. The Watanabe heritable hyperlipidemic (Hc) allele was described by Watanabe in 1985. These rabbits develop spontaneous hypercholesterolemia and are a model of human familial hypercholesterolemia. The WHHL rabbit is deficient in LDL receptors. Selective breeding produces rabbits which develop coronary but not aortic atherosclerosis. The St. Thomas Hospital strain has normal LDL receptors but is still hypercholesterolemic. A transgenic rabbit has been produced containing a human apolipoprotein A-I antisense gene; in one of these lines the synthesis of HDL was suppressed. Another transgenic rabbit develops acute B-lymphoblastic leukemia as a weanling{3573, 4731}

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Anatomy

Skeletal

When rabbits fracture their backs it is usually at L7. According to previous literature, the rabbit vertebral formula includes 7 cervical, 12 thoracic, 7 lumbar and 4 sacral vertebrae. However, in a study of 64 mixed-gender New Zealand White rabbits (from Charles River), only 43.8% had 12T and 7L. 32.8% had 13T/6L with an extra pair of ribs, and 23.4% had 13T/7L implying an extra vertebral bone. Several (23.4%) had rudimentary, asymmetrical 13th ribs. The point at which the spinal cord ends (conus medullaris) is S2 in 79.3%, S1 in 19%, and S3 in 1.7%. Age, weight and gender have no bearing on the termination of the spinal cord. The origin of several spinal nerves also varies with vertebral length. In a "typical" 12T/7L rabbit, the femoral nerve comes from L4-5-6, the obturator nerve from L6-7, the sciatic nerve from L6-7 S1-2-3, and the pudendal nerve from S2-3. In 13T/6L rabbits these are shifted forward by one vertebra. This is similar to the cat and horse, but different from the dog and human, which have shorter spinal cords. Note that the finding that the obturator nerve usually arises from L6-7 is in contradiction to Harkness and Wagner which states it comes from L5-6.{4248}

Rabbit kits can be declawed to provide a measure of safety when they are destined for use in a BSL-4 facility. Brief isoflurane anesthesia (with monitoring for frequent apnea) combined with buprenorphine analgesia (0.03mg/kg SQ tid) appears to be safe for use with 3-8-day-old kits. Forceps are used to clamp between P2-3, a scalpel is used to incise the tissue, and the wound is closed with cyanoacrylate glue. It was determined that the acceptable age range is 6-8 days. At less than 6 days it is more difficult to assess the doe's acceptance of the operated kits, and the kits weigh more than 90 grams. At 8 days, hair growth around the toes becomes very problematic.{3943}

Respiratory and cardiovascular

There are six lung lobes, but references differ on their distribution. The first edition of Laboratory Animal Medicine states there are 4 on the right and 2 on the left {3561}, but the second edition states there are cranial, middle and caudal lobes on both sides, with the right caudal lobe having a lateral and medial portion. In rabbits, lung volume increases with age, in contrast to dogs and humans.{4731}

The rabbit was the first animal in which the exact site of the cardiac pacemaker structures was identified. This was due to the simplicity of the rabbit’s conductive tissue and the relative paucity of connective tissue and fat. {3561}

The tricuspid (right atrioventricular) valve of the rabbit heart has only two valve leaflets instead of three as found in other mammals.{3768}{4731}

The blood supply to the brain is restricted to the internal carotid artery, with limited contribution from the vertebral arteries.{4731}

Gastrointestinal

Rabbit molars are hypsodont. The dental formula is I2/1 C0/0 PM 3/2 M 2-3/3=26-28.

During their domestication, Oryctolagus lost most of their taste buds.{3573}

The rabbit esophagus has three muscle layers, all striated. These muscle layers extend to the cardiac portion of the stomach. This trait is different from humans and other species, which have separate portions of striated and smooth muscle in the esophagus. The rabbit stomach is never empty, and usually contains hair ingested during grooming.{4731}

Humans have a major duodenal papilla near their bile duct, and an accessory duct entering at the minor papilla. The rabbit duct enters separately from the bile duct, but there are many small ducts too.{4003}

At the terminal small intestine there is a bulblike expansion of lymphatic tissue called the sacculus rotundus. Nearly half of the rabbit’s lymphoid tissues are in the gut: Peyer’s patches, sacculus rotundus and appendix.{3768}

The cecum has 10 times the capacity of the stomach. The cecum ends in a narrow blind appendix.

The colon is attached to the duodenum near its end, and may be mistaken for it.

The colon is divided into proximal and distal parts separated by the fusus coli. This regulates the elimination of normal day feces and soft cecotrophs. Cecotrophs have a high content of nitrogen, water, electrolytes, and B vitamins (niacin, riboflavin, pantothenate and cyanocobalamin). Whereas domestic rabbits produce cecotrophs at night, wild rabbits produce them during the day while they are in their burrows.{3561}{4731}

Genitourinary

Rabbit kidneys are unipapillate, a unique feature in the mammals, so it is possible to cannulate them easily. Additionally it is possible to dissect away individual kidney tubules with the basement membrane intact. {3561}

Adult rabbit urine is cloudy due to the presence of ammonium magnesium phosphate and calcium carbonate monohydrate precipitates; the red or brown hues are probably due to green feed and cereal grains. Normal urine pH is about 8.2; the adult rabbit produces about 50-75ml/kg/day of urine.{4731}

Sexing rabbits is aided by the fact that the urethral orifice of the doe is slitlike, whereas that of the buck is round. Since the inguinal canal remains open, the testes can slide in and out of the abdomen, making it mandatory to close the canal when bucks are castrated to prevent herniation. The rabbit uterus has two cervices. The placentation is hemochorial.{4731}

Inguinal pouches, located on either side of the genitalia in both sexes, contain scent glands producing white or brown secretions.{4731}

Hematopoietic

Heterophils or amphophils or pseudoeosinophils are the counterpart of neutrophils, and possess distinct acidophilic granules. The Pelger-Huet anomaly, occasionally seen in rabbit neutrophils, causes the nucleus to fail to segment.{3561, 4731}

Lymphocytes are the predominant WBC in the circulating blood. Both large and small lymphocytes can be identified on peripheral blood smears. Small lymphocytes are 7-10µm in diameter while large lymphocytes are 10-15µm. {3561}

Basophils may account for up to 30% of the total circulating WBC population.{3768}

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Physiology

Cardiovascular

The rabbit myocardium has very little xanthine oxidase, so that free radicals contributing to ischemia-reperfusion injury have to be generated by other pathways.

Rabbit myocardium also has different sodium and potassium gradients than other mammals; the cells are higher in calcium and the potassium gradient is lower. A sudden increase in extracellular calcium may induce ventricular fibrillation, at least in isolated heart preparations.

They are a valuable model for the study of Purkinje fibers, because there are fewer ion channels than in the dog or NHP, and resistance and perfusion problems are much less in in vitro preparations.

Finally, the pulmonary artery of the rabbit has a unique thickening that is extremely sensitive to acetylcholine, making it the most sensitive vasoconstrictive Ach response known. In fact, anaphylaxis can cause the pulmonary artery to constrict so tightly that the right ventricle cannot push blood through it.{3573}

Respiratory

Rabbits have an acute sense of smell.

Approximately 60% of laboratory rabbits produce atropine esterase, which inactivates atropine. Rabbits are thought to be difficult to intubate using an endotracheal tube due to some anatomic features. The oropharynx is narrow, the tongue large, and the laryngeal opening small. They are also very prone to laryngospasm.{3573}

Pulmonary flow is different between the right and left lungs, being higher in the left lung. Therefore, airway resistance is lower on the left, a feature that may be important in studies in which substances are delivered to one side or the other. Their pleura is thin and there is little connective tissue in the lungs; this enables air to flow.{3573}

Alimentary

The mandibular salivary gland is the one that produces saliva continuously in the rabbit (in the dog and cat it is the sublingual gland, and in ruminants it is the parotid salivary gland).

The rabbit, like the rat and the horse, cannot vomit, because of the anatomic arrangement of the cardia of the stomach and the cardiac sphincter.

Newborn rabbits have already absorbed most of the maternal immunity prior to birth, like humans and guinea pigs; the small intestine is permeable to immunoglobulins for only a few hours postpartum.

Small intestinal motility is controlled in part by motilin, a peptide active also in human GIT. Motilin is secreted by cells in the duodenum and jejunum.

In the cecum the pH changes daily, from alkaline in the morning to acid in the mid-afternoon. This pH change causes transfaunation, a change in the microbial flora.

Cecotrophs are formed in the proximal colon and cecum. They are rich in vitamins, minerals, and nitrogen.{3573

Rabbits secrete more bile than practically any other animal, about 250 ml/day from a 2-kg rabbit. This is 7 times more than the dog.{3573}

Ligation of an animal’s pancreatic duct usually causes pancreatic insufficiency, but the rabbit probably has numerous ducts that each connect to the duodenum. Ligation will therefore not cause pancreatic insufficiency in the rabbit.{3573}

Nutrition

Left to their own devices rabbits prefer a diet low in fiber and high in carbohydrate and protein; however since this predisposes to obesity, lab rabbit maintenance diets are generally high in fiber and low in energy. Rabbits on high-fiber diets consume more cecotrophs. Commercial rabbitries provide 70% clover hay, 29.5% oats and grain, and .5% salt, whereas diets for growth, pregnancy and lactation utilize alfalfa hay in amounts varying from 40-50%. Alfalfa meal is high in calcium and may cause renal problems. The Subcommittee on Rabbit Nutrition (1977) recommended 10-14% crude fiber, 12-17% crude protein, and 2% fat for rabbits fed ad lib. {4731}

Either low or high levels of vitamin A cause reproductive problems including congenital hydrocephalus. Diets should contain approximately 10,000 IU/kg.{4731}

Vitamin E deficiency is associated with poor fertility, muscular dystrophy, fetal and neonatal death, and microphthalmos. {4731}

Relative to other species, rabbits need a lot of water-- 120ml/kg/day depending on temperature, disease and feed intake. {4731}

Urinary

Since rabbit kidney tubules can be teased from slices and studied in vitro, much is known about the physiology of the rabbit kidney. The urine is the major pathway of calcium and magnesium excretion in the rabbit, which is why it appears thick and creamy. Urinary calcium is proportional to serum calcium in rabbits{3573}.

Bicarbonate resorption is very different in the rabbit, because they do not have carbonic anhydrase in the cells of the tubules as do humans, NHPs, and rats. They do not reabsorb bicarbonate efficiently. Sources of bicarbonate include catabolism and gut microflora.

The rabbit is unusually susceptible to small acid loads, partly because it cannot form ammonia from glutamine in the kidney as other mammals do in response to decreased plasma pH or bicarbonate. The collecting ducts of the rabbit are an important site of acid secretion, bicarbonate resorption and secretion, but they are not sensitive to loop diuretics as they are in most mammals.

Finally, although humans have a very low excretion ratio of uric acid, producing only 700mg per day, the rabbit has one of the highest excretions, at around 160% of the filtered urate load.{3573}

Thermoregulation

The rabbit’s normal rectal temperature ranges from 38.5°–39.5° C (101.3°-103.1°F). The rabbit ear is an important thermoregulatory site, accounting for around 12% of body surface area. There is a countercurrent exchange in the ear which allows the rabbit to maintain body temperature. However, the rabbit is very sensitive to high temperatures, because it can’t sweat and salivation and panting are very inefficient.{3573}

Rabbits will not drink water if they take in sufficient fresh greens. However, when fasted, rabbits and guinea pigs will increase their water intake.{3573}

Reproductive

Does reach sexual maturity at about 5-7 months, and their breeding life may last 5-6 years.{3561} Light cycles for breeding does should be somewhat longer, i.e. 14-16 hours light.{4731} They do not have a regular estrous cycle, and vaginal cytology is not useful in determining estrus or receptivity. Does have regular periods of receptivity (with 1-2 days of anestrus every 4-17 days). During periods when does are receptive, the vulva is swollen, moist and darker pink.{4731}When the doe is placed in the buck’s cage, they should be watched carefully to make sure the doe is receptive.{3561}

Rabbits are induced ovulators; ovulation can be induced by mating, contact with other females, cervical stimulation, or hormonal treatment. Ovulation occurs 10-13 hours after mating. Ovulation can be induced by copulation or with LH or HCG.{3561}

Embryos take 4 days to travel to the uterotubal junction. The embryos are covered with a thick coat of mucin which is secreted by epithelial cells in the isthmus. Implantation takes place on days 6-7.{3929}

Infertile matings result in pseudopregnancy, with the corpora lutea secreting progesterone for 16-17 days{3929}. Extrauterine pregnancy has been published several times. Causes can be either trauma and rupture of the uterus (resulting in extrauterine pregnancy), or escape of fertilized eggs from the Fallopian tube (resulting in ectopic pregnancy), which is less common. There is rarely a clinically-apparent reaction in the doe. Does that go beyond the expected delivery date should be radiographed to check for this condition.{4600}

Pregnancy lasts for 30-33 days, with 8-10 per litter common in NZWs. They kindle in the early morning, usually in about 30 minutes.

Pregnancy toxemia is rare in the rabbit, but can occur in both pregnant and pseudopregnant does. A major outbreak was documented in the mid-1930s in 72 does. Signs included increased BUN, increased phosphate, and decreased calcium. The rabbits were ketoacidotic. There was severe focal necrosis and fatty infiltration of the liver.{4532}

The does have four pairs of mammary glands (although LAM2 claims the number is 4 or 5), and nurse only once a day. Maximum milk production occurs 2-3 weeks after kindling. Lactation in does that are bred again shortly after kindling peaks sooner and drops more rapidly than lactation in does that are not re-bred until 35-56 days after kindling.{3574, 4731}

Rebreeding is generally best after weaning at 6-8 weeks.{3561}

High levels of vitamin A (hypervitaminosis) can cause cleft palate, hydrocephalus, and microcephaly in rabbit kits. Similarly, hypovitaminosis A during pregnancy can cause hydrocephalus. Rabbit diets should contain 580 IU/kg of diet for growth, and 1160 IU/kg of diet for gestation (page 300 in blue book; covered frequently in CL Davis slides).

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Behavior

Mature bucks will fight, but females generally do well housed in groups. Laboratory rabbits exhibit diurnal behavior, whereas wild rabbits are more nocturnal. {4731}

Rabbits, like some other species (rats, reptiles, birds, marine mammals, and ungulates) are able to distinguish between similar-appearing humans. This was shown by Davis and Gibson in a carefully-controlled study. It took an average of 5 10-minute daily sessions (range 3-9) for a rabbit to learn to move a ball in order to receive a food reward. Discrimination training, in which the rabbit was rewarded only by one tester but not the other, took an additional 10 sessions (range 7-15) to learn. The significance of this is unknown, but we certainly need to be aware that rabbits and other animals recognize us, and perhaps take this into consideration in some types of research studies.{4102}

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