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Diagnostic Test for Scottie Cramp
By Unknown Author
from an old Houston Club Newsletter
(EDITOR"S NOTE: This is the first article in a two part series on Scottie Cramp. Next month's article will be "Testing For Scottie Cramp". I wish to thank Dr. Alan and Judith Riga for supplying the article for my use.)
In a recent paper, Dr. R. M. Clemmons and his associates have discussed the use of the methysergide, in diagnostic testing for Scottie Cramp.
Scottie Cramp is an inherited disorder of the central nervous system. A dog affected with this disorder appears normal at rest and at the beginning of movement; however, with the continued locomotor activity, its gait becomes increasingly abnormal. The initial signs may be a tendency for the forelimbs to "wing" out from the body, the back near the hindlimbs to arch, or the rear legs to overflex. As movement continues, the extensor muscles become progressively more rigid; a dog that is severely affected may actually become unable to walk after a short time. Once movement ceases, the clinical signs progressively decrease until the dog once again appears normal. The disorder may first appear in puppies as young as 6-8 weeks of age, and because it is a genetic disorder, affected dogs will have Scottie Cramp for their entire lives. However, these dogs have no unusual health problems and have a normal intelligence and life span.
Scottie Cramp is inherited as a recessive trait controlled by a single pair of genes. In order for a dog to be affected with this disorder, both genes of the pair must be for Scottie Cramp. A carrier, that is a dog with one normal gene and one recessive gene for this trait, DOES NOT have the disorder. Conversely, BOTH the sire and the dam MUST be carriers of Scottie Cramp in order to produce affected offspring.
Not all dogs with Scottie Cramp are affected to the same extent; some dogs show very minor clinical signs, others are incapacitated. This is due to modifying effects of other genetic factors. Stress, excitement, and fear can exacerbate the signs, as can illness and nutritional factors. Clinical signs can be reduced, for example, by giving the dog some chocolate or other form of sugar about an hour before exposure to stress. The drug diazepam, is frequently used to treat this condition both acutely and chronically. Vitamin E at doses above 125 IU/kg body weight given once daily will decrease the incidence, but not the severity, of the episodes.
In spite of the name, dogs with Scottie Cramp do not have cramped muscles and do not suffer pain during an episode. The disorder is caused by a defect in the transmission of signals (IMPULSES) between nerve fibers within the central nervous system. There is no direct connection between two nerve fibers; a small space called a SYNAPSE separates the end of one fiber from the beginning of the next. In order to transmit on impulse across this gap, a chemical, called a NEUROTRANSMITTER, is released from one nerve fiber and migrates across the synapse to start an impulse in the next nerve fiber. Normal movement depends upon the proper production of, response to, and breakdown of neurotransmitter. In the case of Scottie Cramp, there is a functional defect involving one neurotransmitter, a compound called SEROTONIN or 5-HT. Drugs that increase the levels of serotonin in the central nervous system decrease the signs of Scottie Cramp; drugs that decrease these levels or block the effects of serotonin, increase the clinical signs.
Diagnosis of Scottie Cramp is made on observation of clinical signs. The disorder may be missed, therefore, if the dog is subclinical or only minimally affected. Such a dog might inadvertently end up in a breeding program, thus perpetuating the problem. A drug that temporarily blocks serotonin function without untoward side effects would be a useful tool in diagnosing the disorder in these animals. Dr. Clemmons and his associates report that the drug methysergide, offers great potential for this purpose. Oral administration of a single dose will increase the signs of Scottie Cramp within 2 hours. The effects of methysergide disappear within 8 hours and the only side effects seem to be some transient nausea and gastrointestinal irritation. For further information on this subject contact Dr. R.M. Clemmons, Dept. of Medical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 32611.
Original Doc: cramp02.doc
Evidence For A Small Functional Pool of Serotonin In Neurohumoral Transmission
By Robert G. Schaub and Kenneth M. Meyers
Department of Physiology and Pharmacology
College of Veterinary Medicine
Washington State University
Pullman, WA 99163
Source: Research Communications in Chemical Pathology and Pharmacology, Vol. 10, No. 1, January 1975, pp 29-36.
“Scottie Cramp” is a genetic neurologic disease which occurs in the Scottish terrier breed of dogs. Decreasing central nervous system (CNS) concentrations of serotonin (5-HT) via para-chlorophenylalanine (p-CPA) will profoundly increase the severity of the disease although the basic defect does not involve serotonergic neurons. The purpose of this study was to attempt to correlate the effect of p-CPA on the clinical signs of the disease with the alteration in serotonin synthesis and concentration in the CNS. Synthesis was estimated by following the rise in cisternal cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) concentrations with time following probenecid injection. Concentration of serotonin in the CNS was estimated by measuring cisternal CSF 5-HIAA concentrations. The results suggest that serotonin may be synthesized in excess of neuronal transmitter needs and that the estimation of whole brain turnover rates and concentrations of 5-HT may not yield a true measure of serotonergic neuronal activity.
It has been suggested that serotonin synthesis is greater than is necessary for adequate neuronal function and that only a small portion of 5-HT normally present in the neuron is necessary for neuronal activity (Grahame-Smith, 1974: Wenger et al, 1973). However, proof of this hypothesis has been limited by the inability of investigators to correlate CNS 5-HT concentration or turnover with neuronal function. Adequate assessment of this hypothesis would require the existence of some neuronal defect which is sensitive to alterations in 5-HT concentration and which could be used as an “end point” in assessment of 5-HT neuronal function. We feel that “Scottie Cramp” syndrome may provide such a model. “Scottie Cramp” is a genetic neurologic disease which occurs in the Scottish terrier breed of dogs. Daily administration of p-CPA, which has been shown to reduce CNS 5-HT concentration by inhibiting tryptophan-5-hydroxylase activity (Koe and Weissman, 1966), markedly increases the severity of the disease (Meyers et al, 1973). The purpose of this study was to determine if the effect of p-CPA treatment on clinical signs could be correlated with effects of the drug on 5-HT concentration or synthesis rate.
Five Scottish terrier dogs affected with the “Scottie Cramp” syndrome were used in this study. Oral p-CPA was administered for three days at a dose of 100 mg/kg/day. The clinical rating of each dog was determined prior to, during, and following cessation of treatment until it had returned to pre-treatment levels. Clinical signs were elicited and evaluated as previously described (Meyers et al, 1973).
5-hydroxyindoleacetic acid concentration was determined in cisternal cerebrospinal fluid. This was done prior to p-CPA administration, on the day of treatment, and at weekly intervals following the treatment until the CSF concentration of 5-HIAA had returned to pre-treatment values.
The measurement of the rise of cisternal CSF 5-HIAA concentration one hour following probenecid administration (150) mg/kg i./p.) was made in the untreated animals and one week following p-CPA administration. All CSF samples were obtained, handled, and measured as previously described (Meyers and Schaub, 1974).
Treatment of five affected dogs with p-CPA markedly increased the clinical rating of the disease with the maximum effect occurring on the third day of treatment. This effect remained constant for two days following the last drug dose. The p-CPA effect then became less pronounced and the clinical rating returned to pre-treatment levels within two days. In distinct contrast, the cisternal CSF 5-HIAA concentrations were depressed on the third day of treatment, remained depressed for one week, and required six weeks to return to pre-treatment concentrations. Cisternal CSF 5-HIAA concentrations were found to increase 127% over control concentrations in five dogs one hour after probenecid treatment. However, one week after p-CPA treatment not only were CSF 5-HIAA concentrations depressed, but the increase in 5-HIAA concentrations one hour following probenecid treatment was only 77% over control concentrations.
If the increase in clinical signs following p-CPA administration can be attributed to a decreased serotonergic neuronal activity due to decreased 5-HT concentrations then the return of clinical signs following treatment may result from a restoration of 5-HT neuronal function. If 5-HT neuronal function is restored additional 5-HT must be synthesized. Jequier et al, (1967) demonstrated that following a single dose of p-CPA (300 mg/kg) brain serotonin concentrations follow tryptophan-5-hydroxylase activity. Koe and Weissman, (1966) reported that following 3 days of p-CPA administration (100 mg/kg i.p.) brain serotonin concentrations were approximately 10% of normal one day following cessation of treatment. On the third day following cessation of treatment the 5-HT concentration had increased to 20% of control values. Knapp and Mandell (1972) reported a similar response on tryptophan-5-hydroxylase activity in the rat. In the affected dogs, at the time when the p-CPA induced increase in neurological signs had returned to pre-treatment values, it is reasonable to propose that the concentration of serotonin and the tryptophan-5-hydroxylase activity had increased over the time when maximum neurologic effects were evident.
To relate the effect of p-CPA on 5-HT concentration the concentration of 5-HIAA in cisternal CSF was determined. Available evidence suggests that the acid metabolite of 5-HT may reflect the metabolism of the parent amine (Gottfries et al, 1971; Chase et al, 1970, Ashcroft and Sharman, 1962). The low concentration of cisternal CSF 5-HIAA after the severity of the disease had returned to pre-p-CPA levels suggests that the concentration of the 5-HT had not returned to the pre-treatment levels.
Blocking the acid transport system used to remove 5-HIAA from the brain with probenecid causes the accumulation of 5-HIAA in both cisternal CSF and the brain (Guldberg and Yates, 1968; Neff et al, 1967). The turnover rate of the amine has been calculated by following the rate of this accumulation (Neff and Tozer, 1968). In this study the increase in 5-HIAA concentration was measured in the cisternal CSF rather than the brain and as a result of the concentration gradient between the brain and cisterna magna it is not possible to precisely define turnover rate. However, such measurements can give an indication of turnover rate. From the data presented here it appears that even though the p-CPA effect on the clinical signs has subsided the turnover rate and hence the synthesis rate may be reduced. This premise is based on the decreased accumulation of 5-HIAA in cisternal CSF one week after p-CPA treatment.
The above data would appear to support the contention that a considerable portion of the brain content of serotonin may not be involved in a neurotransmitter role. It would also indicate that measurement of either whole brain turnover rates and synthesis or whole brain concentrations of either 5-HT or its metabolites may not reflect the neuronal function of the transmitter.
This investigation was supported by Grant F054-565 from the National Institute of Health and Washington State Medical and Biological Fund Grant 171-2457. The authors wish to thank Pfizer, Inc. For the gift of p-chlorophenylalanine.
Ashcroft, G.W. and D.F. Sharman (1962). Drug-induced changes in the concentration of 5-OR indole compounds in cerebrospinal fluid and caudate nucleus. Brit. J. Pharmacol. 19:153-160.
Chase, T.N., J.A. Schnur, and E.K. Gordon (1970). Cerebrospinal fluid monoamine catabolites in drug-induced extrapyramidal disorders. Neuropharmacology 9:265-268.
Gottfries, C.G., I. Gottfries, B. Johonsson, R. Olsson, T. Persson, B. -E. Roos, and R. Sjostrom (1971). Acid monamine metabolites in human cerebrospinal fluid and their relationship to age and sex. Neuropharmacology. 10:665-672.
Grahame-Smith, D.G. (1974). How important is the synthesis of brain 5-hydroxytryptamine in the physiological control of its central function. In Adv. Biochem. Psychoparmacol., E. Costs, (ed). 10:83-91.
Guldber, H.G. and C.M. Yates (1968). Some studies on the effects of chlorpromazine, reserpine, and dihydroxyphenylalanine on the concentrations of homovanillic acid, 3, 4-dihydroxyphenylacetic acid and 5-hydroxyindole-3-acetic acid in ventricular cerebrospinal fluid of the dog using the technique of serial sampling of the cerebrospinal fluid. Brit. J. Pharmacol. Chemother. 33:457-471.
Jequier, E., W. Lovenberg, and A. Sjoerdsma (1967). Tryptophan hydroxylase inhibition: The mechanisms by which p-chlorophenylanine depletes rat brain serotonin. Mol. Pharmacol. 3, 274-278
Knapp, S. And A. J. Mandell (1972). Parachlorophenylalanine. Its three phase sequence of interactions with the two forms of brain tryptophan hydroxylase. Life Sci. 11:part1. 761-771.
Koe, D. B. And A. Weissman (1966). P-Chlorophenylalanine: A specific depletor of brain serotonin. J. Pharm. Exp. Ther, 154(3):499-516.
Meyers, K.M., W.M. Dickson, and R.G. Schaub (1973). Serotonin involvement in a motor disorder in Scottish terrier dogs. Life Sci, 13:1261-1274.
Meyers, K.M. and R.G. Schaub (1974). The relationship of serotonin to a motor disorder in Scottish terrier dogs. Life Sci, 14:1895-1906.
Neff, N.H., T.N. Tozer, and B.B. Brodie (1967). Application of steady state kinetics to studies of the transfer of 5-hydroxyindoleacetic acids from brain to plasma. J. Pharmacol. Exp. Ther. 158:214-218.
Neff, N.H. and T.N. Tozer (1968). In vivo measurement of brain serotonin turnover. Adv. Pharmacol. 6A:97-109.
Wenger, G.R., R.E. Stitzel, and C.R. Craig (1973). The role of biogenic amines in the reserpine induced alternations of minimal electroshock seizure thresholds in the mouse. Neuropharmacology. 112:693-703.
Original Doc: cramp06.doc
Muscular Hypertonicity Episodes in Scottish Terrier Dogs
By Kenneth M. Meyers, PhD; William M. Dickson, DVM, PhD;
John E. Lund, DVM, PhD; and George A. Padgett, DVM, Pullman, WA
Source: Arch Neurol - Vol. 25, July 1971, pp. 61-67.
Accepted for publication Dec 29, 1970.
From the departments of physiology and pharmacology (Drs. Meyers and Dickson) and pathology (Dr. Padgett), College of Veterinary Medicine, Washington State University, Pullman, Wash. Dr. Lund is now with the College of Veterinary Science and Medicine, Purdue University, Lafayette, Ind.
This investigation was supported by grant FO54-565 from the National Institutes of Health and Washington State medical and biological fund grant 171-457.
Reprint requests to Department of Physiology and Pharmacology, College of Veterinary Medicine, Washington State University, Pullman, Wash 99163 (Dr. Meyers).
"Scottie Cramp" is a genetic disease in Scottish terrier dogs characterized by episodes of progressive muscular hypertonicity with associated postural and locomotive difficulties. The episodes are observed during exercise. Results of clinical laboratory tests and gross and histopathological examinations were normal. Telemetered electromyograms (EMG) revealed that the interference pattern from the muscles was of longer duration and higher amplitude during the episode when compared to the preepisode recording. A normal response from the muscle was observed following tubocurarine chloride administration, epidural anesthesia, or electrical stimulation below a procaine nerve block. These data suggest the disease is of central nervous system origin. During an episode when the dog was suspended in a sling, the EMG activity was not continuous. Dorsal root section, lumbar 3, 4 and 5, did not appear to alter the EMG activity during and episode.
Key Words. Scottie cramp; hypertonic episodes; central origin
In 1942, Klarenbeek et al1 described a disease in Scottish terrier dogs characterized by painless episodes of progressive muscular hypertonicity which resulted in postural and locomotive difficulties. The disease has come to be known as "Scotch or scottie cramp".
There have been several attempts to explain the etiology of the muscular hypertonicity. From the appearance of the clinical signs, Joshua2 proposed that scottie cramp was a form of intermittent claudication similar to that observed in Raynaud's disease of man. Klarenbeek et al1 found a normal response of the skeletal muscle to faradic stimulation and theorized that the disease was of central nervous system (CNS) origin. In a pharmacologic blind study, a relationship of this disease to serotonin was found3; chlorophenylalanine, a compound which decreases the concentration of serotonin by inhibiting its synthesis4, markedly increased the severity of the affliction, while nialamide, a monoamine oxidase inhibitor, which increases serotonin concentration, was able to either prevent the elicitation of clinical signs or decrease the severity of established clinical signs. The promazine derivatives, chlorpromazine and acepromazine, and diazepam are used therapeutically to suppress clinical signs.5 Diazepam is the drug of choice as it produces complete cessation of clinical signs without unduly altering the psychological state of the dog. The disease is a genetic disease which appears to be transmitted as a simple autosomal recessive trait.6
The purpose of this paper is to describe the clinical features of the disease and to present further evidence that it is a CNS disease. Ten affected Scottish terrier dogs were used in this study.
The affected Scottish terrier dogs appear normal when at rest or on initial exercise. However, as the exercise continues, clinical signs are usually observed which progressively increase in severity during the episode. Initially, the front legs will be abducted while walking, and the back will become arched in the lumbar region and a stifflegged gait, appropriately called a "stringhalt" gait is observed. The facial muscles do not appear to be affected at this time. The head tends to be extended with the nose pointing downward. As the dog continues to exercise, the hind limbs become increasingly resistant to movement and are often extended, being positioned behind the dog. At this time, if movement is attempted, the hind legs will remain extended and forward progression is due entirely to movement of the front legs. If the severity of the episode increases, the dog assumes a pillarlike stance, unable to walk. Often the dog will fall down, with head, limbs, and tail tucked in. In some dogs, if suspended horizontally in the air during such a severe seizure, the front legs extend parallel to the ground, the head flexes toward the chest, and the tail and hind limbs are tightly flexed against the body. When a limb is passively moved during a severe episode, strong resistance is encountered throughout the movement, and upon release, the limb will spring back to the original position. In less severe episodes during passive flexion of a joint, the initial movement will be met with resistance; however, as flexion continues, the resistance will suddenly dissipate and the limb flexes freely. Respiration appears to be labored and will occasionally cease during severe episodes. However, the respiratory distress is of short duration, and the dog will suddenly appear relaxed and start panting. Often, during a severe episode, some dogs will lay down and appear relaxed, but when forced to stand or if they attempt to move, a generalized state of extreme muscular hypertonicity results. Just preceding, as well as during, a severe episode, the facial muscles are affected, and the dog is unable to open its jaws.
There is individual variation in the severity of the affliction. Not all dogs have the immobility described but merely have a stringhalt gait. Affected dogs do not lose consciousness during an episode. If allowed to rest, there is complete remission of clinical signs, but the signs reappear if the inducing factors are not eliminated. The duration of rest required to eliminate signs generally correlates with the severity of the attack and varies from less than one to more than 30 minutes. However, in most dogs, signs remit within ten minutes.
The psychological state of the dog is an important factor in predisposing a dog to an episode. When the affected dogs become excited or are in an apprehensive situation, clinical signs are quickly observed. The environment in which the dog is housed also affects the severity of the condition. A marked beneficial effect is noticed when affected dogs are taken from a kennel to a home environment.
Clinical Laboratory Studies
The concentrations of serum electrolytes and whole blood glucose were normal with affected dogs at rest or during a hypertonic episode (Table 1). Other clinical laboratory studies, evaluated with the dogs at rest, were also normal (Table 2). Blood pH, white blood cell count, packed cell volume, Benedict's test of the urine, complete body radiographs, electrocardiogram, blood pressure, and electroencephalograms at rest were all in the normal range for dogs. Blood lactate and pyruvate production and clearance following exercise was also within the range of that observed in control dogs. The glycogen content of biopsied skeletal muscle samples from a control and two affected dogs, using the anthione method as outlined by Hassid and Abraham,7 was normal (Table 2). Myophosphorylase activity in biopsied skeletal muscle samples from a control and an affected dog by the method described by Cori et al8 was normal (Table 2). Inorganic phosphate was measured by the Fiske and Subbarow method as outlined by Leloir and Cardini.9 The reactions for the determination of phosphorylase were carried out in the presence of adenosine monophosphate to estimate phosphorylase a and phosphorylase b activities.
Gross postmortem and histopathologic examination of three affected Scottish terrier dogs did not reveal lesions in the cardiovascular, digestive, respiratory, endocrine, excretory, reproductive, or nervous system or in connective tissue. Special emphasis was placed on the examination of the central and peripheral nervous systems as well as muscle. Postmortem and biopsied skeletal muscle samples were stained with sudan black, luxol fast blue, oil red 0, Best's carmine, Pollac's trichrom, PAS, phosphotungstic acid hematoxytlin and eosin, and Mallory's. Myophosphorylase was demonstrable by the method of Grillo10 in biopsied muscle from two affected dogs. The postmortem central and peripheral nervous system tissue was stained with hematoxylineosin, luxol fast blueÄHolme's silver nitrate, PAS, and cresyl violet. No lesions were observed in muscle or nervous tissue.
Electromyographic records from muscles of affected and normal Scottish terrier dogs were obtained both by telemetered and by conventional means. Telemetered electromyograms (EMG) were obtained by stainless steel subdermal electrodes positioned in the muscle and connected to a FM transmitter. The transmitted signal was sent to a FM receiver and then to a bandÄpass filter with ??? to 4000 hertz bandpass. The signal was then recorded on a magnetic tape recorder, and after proper amplification, was simultaneously displayed on an oscilloscope and heard over a loud speaker. Photographs were obtained by a camera (Polaroid) attached to the oscilloscope. Telemetered EMGs were recorded from quadriceps, biceps, femoris, gastrocnemius, anterior brachii, supraspinatus, deltoideus, and the pectoralis muscle of six affected dogs.
Table 1. Blood Serum electrolyte and Whole Blood Glucose Concentration in Affected Scottish Terrier Dogs*
Preceding an During an
Test Episode Episode
Sodium (mEq/liter)+ 149 + 1.4 150 + 3.0 (4)**
Potassium (mEq/liter) 4.5 + 1.7 4.6 + 0.53 (4)
Calcium (mg/100 ml) 10.7 + 0.56 11.1 + 0.7 (4)
Phosphate (mg/100 ml) 4.1 + 0.2 3.95 + 0.9 (4)
Chloride (mEq/liter) 107 + 1.0 109 + 1.8 (4)
Glucose (mg/100 ml) 56.6 + 6.0 60.5 + 6.0 (4)
* In blood samples collected from jugular vein prior to and during an episode of muscular hypertonicity.
+ All values are mean + SE.
** Figures in parentheses indicate the number of animals.
Table 2. Results of Clinical Laboratory Studies in Affected Scottish Terrier Dogs at Rest
Cholesterol (mg/100 ml)-serum* 215 + 41.3 (8)+
Triiodothyronine erythrocyte uptake corrected to 40% 12.3 + 1.3 (6)
Percent sulfobromophthalein retention in 30 minutes 0.81+ 0.45 (6)
Glycogen (%) 0.9 (2)
Myophosphorylase 10.2 ?
(umol/min/gm muscle) 15.4 (1)**
Glucose tolerance test intravenous (mg/100 ml)
Whole blood Minutes
0 56.6 + 7.6 (3)
30 116.6 + 20.8 (3)
60 68.3 + 30.1 (3)
120 65.0 + 23.0 (3)
240 56.6 + 10.4 (3)
* All values represent mean + SE.
+ Figures in parentheses indicate the number of animals.
** Unaffected Scottish terrier dogs.
Electrical activity from skeletal muscles was telemetered when the affected dogs were and were not exhibiting clinical signs while walking or running. Whenever feasible, the dogs were recorded preceding and during an episode with the electrode position remaining constant. When not exhibiting clinical signs, the EMGs from affected dogs were quite similar. Myoelectric activity at rest and a myotonic percussion response was not present. During the episode, the EMG would first increase in amplitude and as the episode progressed in severity, the duration of the interference pattern increased. While exhibiting a stringÄhalt gait during the periods of electrical silence of a muscle, the antagonistic muscle was contracting. As the episode increased in severity, these electrical quiescent periods became less frequent and would finally disappear. At this time, the dogs would be in a pillarlike stance.
In order to determine at what level of the neuromuscular system the functional abnormality was occurring, the following individual experiments were performed.
After three dogs were anesthetized with diethyl ether, tubocurarine chloride was administered until respiration ceased; artificial respiration was then begun and the muscle mechanically and electrically stimulated (20 v, 0.6 and 1.8 seconds pulse duration, 100 Hz and 6 Hz). In these animals, a poststimulation electrical discharge from the muscle could not be elicited.
Following epidural administration of a 2% procaine solution to four unanesthetized affected dogs, repeated electrical stimulation of the muscle (20 v, 1.8 msec pulse duration, 100 Hz and 2 Hz) did not elicit poststimuation EMG activity. When three affected dogs were anesthetized with diethyl ether and a 2% procaine solution was infiltrated around the sciatic nerve, repeated stimulation of the nerve (0.5 v, 1.8 msec pulse duration, 2 Hz) below the block did not produce poststimulation EMG activity.
Amphetamine sulfate, 0.5 mg/kg, when administered intramuscularly to affected dogs, will induce clinical signs within 15 minutes. Two dogs received 0.5 mg/kg of amphetamine sulfate intramuscularly and were placed in a cage. After 15 minutes, they were removed, and the typical abnormal gait was immediately apparent. The dogs were then suspended in a sling and the EMG recorded from the biceps femoris muscle of the right hind limb. While resting undisturbed in the sling, the muscles had neither abnormal tone nor myoelectric activity. The muscles did not exhibit percussion myotonia. If the animals were subjected to a sudden visual or auditory stimulus, or to a sudden tactile stimulus on the back, general body muscle tone increased, and the associated postural changes were observed. The hind limbs were flexed toward the body and the head tended to be drawn toward the chest. When removed from the sling, the abnormal gait was observed while walking.
The dorsal roots of the third, fourth, and fifth lumbar nerves on the left side were severed in one severely affected dog. The tendon jerk of the ipsilateral quadriceps muscle could not be elicited following surgery. While walking, the left leg would often be flexed tightly against the body during and episode. As the episode progressed, the limb would be extended and the dog would not move. The telemetered EMG activity from the left quadriceps muscle was similar to that recorded before the surgery or from the right quadriceps muscle during an episode in that the abnormal interference pattern was still present.
The motor unit can be subdivided into the following five parts: (1) the motoneuron soma, (2) the peripheral axon, (3) the myoneural junction, (4) the muscle membrane, and (5) the contractile proteins. Pathologic processes of the skeletal motor unit produce different effects depending upon the physiologic mechanisms disturbed.
Of the reported myopathies affecting the contractile proteins, few have a clinical picture of hypertonia. McArdle11 described a disease characterized by painful muscle stiffness on exercise and inability to produce lactate on exercise. Schmid and Mahler12 and Mommaerts et al13 described other cases and concurrently found the disease was caused by lack of muscle phosphorylase. McArdle11 and Rowland et al14 found that the contracted muscles were electrically silent. Bethlem et al15 described a familial myopathy associated with painless muscular cramping after exercise. In this syndrome, 75% of the biopsied skeletal muscle fibers contained an inner zone of abnormal myofibrils that stained blue with Mallory's aniline blue and orange G stain which they termed muscle cores. The outer normal fibrils stained a normal orangered. Cores were not demonstrable in our dog specimens. Myophosphorylase was demonstrable both on sections of muscle and in extracts. Muscle glycogen was present in normal quantities. The EMG revealed that the increased hypertonicity in the dogs was accompanied by increased electrical activity of the muscle.
Neuromuscular disorders classified as myotonia are characterized by prolonged contraction of skeletal muscles upon voluntary contraction or upon mechanical, pharmacologic, and electrical stimulation.16 The EMG in these diseases reveal that delayed relaxation is accompanied by prolonged electrical activity.17 Both the prolonged muscle contraction and electrical activity are present after peripheral nerve block with procaine,18,19 after spinal anesthesia20 and after administration of tubocurarine.21,22 These observations indicate an abnormal myomembrane. The abnormal responses described above were not present in our dogs.
Nor does scottie cramp appear to result from an abnormality affecting the myoneural junction or peripheral axon. Repeated electrical stimulation of a peripheral nerve below a procaine block did not elicit a prolonged contraction or a poststimulation electrical discharge from the innervated muscle. These results indicate that the peripheral axon, myoneural junction, myomembrane, and contractile proteins are normal in this disease and that the condition is therefore of CNS origin.
The muscular hypertonicity in this disease could result from increased activity of the alpha motoneuron directly or indirectly by way of the gamma efferentÄmuscle spindle afferent reflex arc. The presence of abnormal EMG and postural attitudes in a dog in which the spindle afferents and alpha motoneuron connection has been removed revealed that the hypertonicity could be sustained by the alpha system alone. However, it has been pointed out by Gilman and van der Meulen23 that the actual contribution of the spindle can only be assessed by directly recording spindle activity.
Eluclidation of the basic defect of the disorder is far from complete. The clinical signs suggest the possibility of an abnormal physiologic response to a neurotransmitter. The transmitter could either exert a prolonged physiologic response on the postsynaptic neuron or there could be a functional deficiency. In the former case, an increased amount of transmitter could accumulate at the postsynaptic neuron to cause the progressive increase in severity of clinical signs during and episode. A period of rest might alleviate the signs by allowing for the dissipation of the transmitter. If there were a functional deficiency of the transmitter, clinical signs would be manifest due to progressive inability of the transmitter to exert an effect on the postsynaptic neuron. A short period of rest would allow for a physiologic increase in the transmitter. Excitement may affect this disease by increasing release of the neurotransmitter from the presynaptic neurons.
When serotonin degradation is inhibited, it becomes more difficult to induce clinical signs in these dogs.3 Also, once elicited, the severity of the hypertonic episode is reduced. Inhibition of serotonin synthesis results in increased severity of the clinical signs and a lowered threshold for induction of a hypertonic episode. It is possible that this disease results from a functional deficiency of serotonin.
Scottie cramp has certain similarities to the human neurological disorder referred to as the stiffman syndrome. The stiffman syndrome generally occurs at middle age.24 Although scottie cramp is generally first observed before 1 year of age, there have been reports of the disorder "spontaneously" appearing at 3 years of age.25 Once observed, both diseases progress in severity to a certain point then tend to remain constant.24,26 A variety of sensory inputs such as noise, jar, or emotion associated with distress or fright will elicit a muscular spasm in the stiffÄman syndrome which lasts for several minutes.24,26,27 These spasms are often accompanied by pain but this is not invariable.24,26 In both conditions, rigidity is not observed during sleep, the intellect appears to be normal, motor and sensory examinations are normal, and diazepam has a beneficial effect.24,26,27 The major difference between the stiffÄman syndrome and scottie cramp is absence of persistent tonic muscle contractions with accompanying EMG activity at rest in the latter condition. However, following administration of chlorophenylalanine, severely affected dogs have constant tonic muscular hypertonicity with arching of the back and abnormal gait. If these dogs are excited, the clinical signs quickly increase in severity until they become immobile. If a functional deficiency of serotonin is the defect in the Scottish terrier dogs, it would be feasible for the deficiency to be of sufficient severity that the dogs exhibit constant clinical signs. Some apparent differences between the disease of dogs and the disease of man may result from the fact that the pathogenetic mechanism responsible for the stiffman syndrome has not been defined, and there may be more than one disease involved though all are given the same clinical diagnosis. Although they appear similar, more information on the basic defect(s) of the two conditions is necessary before scottie cramp can be called the stiffdog syndrome.
Scottie cramp does not appear to be related to other hypertonic disorders of man. A disease in two human siblings characterized by intermittent muscle spasms precipitated by voluntary movement was reported by Satoyoshi and Yamada.28 However, the spasms were decreased by continued exercise. The absence of tremor and involuntary movements and the episodic nature of the hypertonicity readily differentiates scottie cramp from the typical diseases of the basal ganglia in man.29
Nonproprietory and Trade Names of Drug
Chlorpromazine - Thorazine.
1. Klarnebeek A, Koopmans S, Winser J: Een Aavalsgewija Optrendende Stoornes in de Regulatie van de Spiertonus: Waargenomen bij Schotsche Terriers. T Diergeneesk 6 9:14-21, 1942.
2. Joshua JO: Scottie cramp. Vet Rec68:411-412, 1956.
3. Meyers KM, Dickson WM: Indolealkylamines and hyperkinetic episodes in Scottish terrier dogs. Fed Proc 28:794, 1969.
4. Koe BK, Weissman A: pÄChlorophenylalanine: A specific depletor of brain serotonin. J Pharmacol Exp Ther 154:499-515, 1966.
5. Meyers KM, Lund JE, Padgett, GA, et al: Hyperkinetic episodes in Scottish terrier dogs. Jam Vet Med 155:129-133, 1969.
6. Meyers KM, Padgett GA, Dickson WM: The genetic basis of a kinetic disorder of Scottish terrier dogs. J Hered 61:189-192, 1970.
7. Hassid WF, Abraham S: Chemical procedures for analysis of polysaccharides, in Colowick SP, kaplan N (eds): Methods in Enzymology. New York, Academic Press, 1957, vol 3 pp 34-36.
8. Cori GT, Illingworth B, Keller PJ: Muscle phosphorylase, in Colowick SP, Kaplan N (eds): Methods in Enzymology. New York, Academic press, 1955, vol 1, pp 200-202.
9. Leloir LF, Cardini CE: Characterization of phosphorys compounds by acid lability, in Colowick SP, Kaplan N (eds): Methods in Enzymology. New York, Academic Press, 1957, vol 3, pp 843-844.
10. Grillo TA: A quantitative and histochemical study of phosphorylase in the placenta. J Histochem Cytochem 14:582-589, 1966.
11. McArdle B: Myopathy due to a defect in muscle glycogen breakdown. Clin Sci 10:13-33, 1951.
12. Schmid R, Mahler R: Clinic progressive myopathy with myoglobinuria: Demonstration of glycogenolytic defect in muscle. J clin Invest 38:2044-2058, 1959.
13. Mommaerts WF, Allingworth HM, Pearson CM, et al: A functional disorder of muscle associated with the absence of phosphorylase. Proc Nat Acad Sci 45-791, 1959.
14. Rowland LP, Lovelace RE, Scotland DL, et al: The clinical diagnosis of McArdle's sease; Identification of another family with deficiency of muscle phosphorylase. Neurology 16:93-100, 1966.
15. Bethlem J, van Cool J, Hulsmann WS, et al: Familial nonÄprogressive myopathy with muscle cramps after exercise. Brain 89:569-598, 1966.
16. Johns R: Potential changes in normal and diseased muscle cell, in Wallin JN (ed): Disorders of Voluntary Muscle. London, J & A Churchill Ltd, 1965.
17. Brown GL, Harvey AM: Congenital myotonia in the goat. Brain 62:1-18, 1941.
18. Schaffer H: Sur Analyse der myonis. Bewegunestornung. Deutsch Z Nevernheilk 67:225-243, 1921.
20. Kennedy F, Wolfe A: Experiments with quinine and postigmine in the treatment of myotonia and myasthenia. Arch Neurol Psychiat 37:68-74, 1937.
21. Landau WM: The essential mechanism in myotonia: An electromyographic study. Neurology 2:369-388, 1952.
22. Floyd WF, Kent P, Page F: An electromyographic study of myotonia. Electroencephh Clin Neurophysiol 7:621-630, 1955.
23. Gilman S, van der Meulen JP: Muscle spindle activity in dystonic and spastic monkeys. Arch Neurol 14:553-563, 1966.
24. Moersch FP, Woltman HW: Progressive fluctuating muscular rigidity and spasm (stiffÄman syndrome). Proc Staff Meet May Clin 31:421-427, 1956.
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Orginal Doc: cramp09.doc
Hyperkinetic Episodes In Scottish Terrier Dogs
By K. M. Meyers, Ph.D.; J. E. Lund, D.V.M., Ph.D.; G. Padgett, D.V.M.; W. M. Dickson, D.V.M., Ph.D.
Source: Reprinted from The Journal of the American Veterinary Medical Association, Vol. 155, No. 2, Part 1, Pages: 129-133
From the Department of Physiology and Pharmocology and the Department of Pathology, School Of Veterinary Medicine, Washington State University, Pullman, Wash. 99163. Dr. Lund's present address is Animal Care Facility, Stanford University School of Medicine, Palo Alto, Calif. 94304.
This report was supported by NIH Grant F-05465.
"Scottie cramp" can be elicited by excitement, exercise, and amphetamine sulfate* (0.5 to 2.0 mg/kg). Chlorpromazine** (1.0 to 1.75 mg/kg), acepromazine+ (0.075 to 0.1 mg/kg), and diazepam# (0.50 to 1.50 mg/kg) when injected intramuscularly were effective in suppressing the signs of the disease.
SCOTTIE CRAMP IS a descriptive term for a hyperkinetic disorder which has been observed for some years in Scottish Terriers by kennel owners and veterinarians. Recent studies have demonstrated the disease to be a central nervous system (CNS) disorder which results in profound locomotion and postural signs. The purpose of this report is to describe the disease, criteria for its diagnosis, and methods of treatment.
Materials and Methods
Ten Scottish Terriers considered to have scottie cramp by their owners were sent to Washington State University from various locations in the United States and Canada. The tentative diagnosis was confirmed by clinical, physiologic, and pharmacologic means.
The electromyogram (EMG) was obtained by photographing the telemetered bioelectric activity of the biceps femoris muscle of the right hindlimb while the dog was walking.
**Thorazine, supplied by Smith, Kline & French Laboratories, Philadelphia, Pa.
+Acepromazine, Ayerst Laboratories, Incorporated, New York, N.Y.
#Valium, supplied by Hoffmann-LaRoche, Incorporated, Nutley, N.J.
Hyperkinetic episodes could be elicited by normal physical activity or by psychic changes. The dogs appeared normal when at rest or when first exercised, but with continued exercise the signs of the disease became apparent. The time interval and intensity of exercise required to elicit signs of the disease were variable. We have observed signs after walking the dog as little as 10 yd. (9.1 m.). According to one report, the distance varied from 100 yd. (91.4 m.) to 3/4 of a mile (0.69 km.).9 The psychic state of the dog was found to be more important than the amount or intensity of exercise. Excitement and fear facilitated the hyperkinetic episodes, whereas anxiety and apprehension were often inhibitory.
Amphetamine sulfate (0.5 to 2.0 mg./kg.) elicited a hyperkinetic episode within 15 minutes when injected intramuscularly. The clinical signs were indistinguishable from those observed after exercise or excitement.
During exercise, the onset of a hyperkinetic episode was usually indicated by a slight abduction of the front legs, resulting in an arclike motion of the limbs while extending. The back then became arched in the lumbar region, and the hind legs were quickly overflexed and then swiftly returned to the ground. This motion has been appropriately described as a "stringhalt" gait.8 The front legs became increasingly stiff, and while walking were quickly extended then flexed. In rare cases where the back was not arched, the dog walked with a "goose step" gait. Forward movement was usually hindered, and in severe cases was completely absent, resulting in the dog walking in place. Facial muscles did not appear to be affected at this time; the dogs had free jaw movement and were often seen panting, with the tongue hanging freely. The head tended to be extended, with the nose pointed downward; at times, the nose would be pulled toward the ground. The tail was often flexed. occasionally, when the younger dogs were running, the hindquarters would suddenly and strongly become elevated, often to such a degree that the dog somersaulted. If the inducing stimulus was continued, the hind legs became increasingly resistant to flexion, which finally resulted in a pillarlike stance, with the dog unable to walk. If the dog fell down, it would curl into a ball with its head, limbs, and tail tucked in; breathing would appear to cease. The severe seizure would last approximately 15 seconds, after which the dog appeared relaxed and panting. During or just preceding a severe episode, the facial muscles were often affected, and the dog was unable to open its jaws. None of the dogs lost consciousness during an episode, nor did they appear to be in pain. A short period of rest would alleviate the hyperkinetic episode in most dogs, but the signs would quickly reappear if the inducing factors were not eliminated.
Considerable variation was found in the frequency and the severity of the hyperkinetic episodes in the same or in different dogs. In some dogs, signs were hardly noticeable; others were nearly incapacitated. A perplexing feature of the disease was the variation in severity of signs in a given dog. The dog would have severe signs after a short period of exercise or excitement for a period of weeks or months, then suddenly, or over a period of days, it would become much more difficult to elicit signs of the disease. The signs, when manifested, were usually milder and more transient than those observed during the period when the threshold for eliciting the hyperkinetic episode was lower. We have not observed complete and permanent recovery in any dog we have studied. Environmental temperature may have an inverse relationship with the signs of the disease, but if so, it is certainly not the only factor involved. Except for the variations mentioned, the severity of the manifestations appeared to remain relatively constant in dogs personally observed. However, 2 Scottish Terrier breeders told us that they observed a steady increase in the severity of the sings as their dogs aged.
The age at which the disease first became apparent to the dog's owner was variable, but the clinical signs were usually noticed before the dog was 18 months old. In the dogs observed in our laboratory, signs were noticed from 6 weeks to 18 months of age. According to one report, an affected dog was 3 years old before the disease was first noticed.20 The variation might be explained by the owner's unfamiliarity with the signs of the disorder. The degree of affliction and frequency of episodes are certainly factors which would alter the age at which the disease would first be recognized. A review of the kennel records of several Scottish Terrier breeders did not reveal a high death loss during puppyhood or a decreased longevity in the dogs with the disease. The clinical signs observed in our dogs were similar to those described previously.8,9,20
Since it has been demonstrated that the hyperkinesis was of CNS origin, various drugs which act upon the CNS were evaluated for their therapeutic value.
Chlorpromazine had been shown to decrease classical Sherrington decerebrate rigidity and to antagonize some of the actions of amphetamine.5,7,11 Because of the appearance of the affected dogs and their response to amphetamine, chlorpromazine was given. Five dogs were given chlorpromazine, 1.0 to 1.75 mg./kg. of body weight, intramuscularly during a hyperkinetic episode. A complete remission of signs of the disease was observed within 15 minutes after the injection. Some sedation was apparent at this dose level. Acepromazine maleate, a phenothiazine derivative and a commonly used tranquilizer, effectively eliminated signs at a dose of 0.1 to 0.75 mg./kg.
Diazepam, a benzodiazepine derivative used extensively as an antianxiety drug, has certain CNS muscle-relaxant properties23 that suggested it might be beneficial.
While 6 dogs were in a hyperkinetic state, induced either by exercise, excitement, or amphetamine, diazepam, 0.50 to 1.5 mg./kg. of body weight, was injected intramuscularly. Prompt cessation of signs occurred, and a normal-appearing EMG resulted. Hyperkinesis could not be induced by any means when the affected dogs were given an oral dose of diazepam, 0.5 mg./kg. t.i.d. When treatment was reduced to twice daily (mornings and evenings), mild signs occurred before the evening administration. We have had dogs on daily treatment for 1 month without apparent side effects. The psychological state of the dogs was not affected. The increased activity induced by amphetamine administration was not hindered. The dogs were not depressed, and their aggressiveness toward rodents was not modified.
Vitamin E as alphatocopherol acetate has been reported to have therapeutic value in high doses.8 A Scottish Terrier breeder reported that large daily doses of vitamin B complex produced improvement within 2 weeks of treatment. In this laboratory, an 8 month old male dog that was mildly affected (i.e., the episodes were easily precipitated, but their duration was extremely short) was given vitamins once a day for 2 weeks without improvement. Treatment consisted of vitamin A, 5,500 IU/lb.; vitamin D2, 883 IU/lb.; vitamin E, 0.55 IU/lb.; thiamine, 0.33 mg./lb.; riboflavin, 0.33 mg./lb.; pyridoxine HCI, 0.138 mg./lb.; vitamin B12, 0.111 ug./lb.; calcium pantothenate, 0.555 mg./lb.; desiccated liver, 16167 mg./lb.; and brewer's yeast, 8.33 mg./lb.
There are many diseases in man and animals which affect the musculature and produce locomotion and postural problems. The diseases in man result from a wide variety of defects. McArdle's disease12,16,19 results from a deficiency in myophosphorylase. The affected persons have electrically silent muscle cramping after exercise. Persons with myotonia congenita have painless tonic muscle contractions which may be produced by voluntary movement. The muscle spasms appear to be the result of an abnormal myomembrane and are not affected by curare or nerve block.24,10,11 A disease in 2 siblings was characterized by painful muscle spasms induced by attempted movement.18 The spasms became milder and less frequent with continued muscular activity. The stiffman syndrome14,15,21,22 is a neurologic disorder wherein muscle spasms are precipitated by various sensory inputs and are characterized by constant electrical activity even at rest. The disease was reported to be effectively controlled by diazepam.6 A familial myopathy has been characterized by mild proximal muscle weakness and painless muscle cramp following exercise.1 In the center of 75% of the skeletal muscle fibers from biopsy specimens, a zone of abnormal myofibrils was found which stained blue with Mallory's aniline blue and orange G stain. The outer fibrils stained a normal orangered.
Transient hyperkinesis in Scottish Terriers does not appear to have a direct human counterpart. The muscular hypertonicity appears to be the result of a CNS rather than a muscle defect. The muscle contractions are inhibited by curare and nerve block.13 There were no histopathologic lesions in biopsy and postmortem muscle sample we have examined. The condition resembles most closely the condition in man of painful muscle spasms18 and the stiffman syndrome. It differs from the former in that the muscular hypertonicity does not decrease with continued exercise and, unlike the latter, the electrical activity is transient rather than continuous.
A spastic syndrome in cattle17 has many clinical signs similar to the Scottish Terrier disease. It is a CNS disorder characterized by spastic muscle contractions, particularly noticeable in the muscles of the back and hindquarters when the animal tries to stand or move.
A positive diagnosis of scottie cramp in a Scottish Terrier required the fulfillment of 3 criteria: (1) The clinical history should indicate an abnormality in gait or seizures during excitement; (2) an injection of amphetamine should induce transient hyperkinetic episodes; and (3) the administration of diazepam or promazine derivative during a natural or induced seizure should produce prompt remission. Diazepam has qualifications for a practical suppressant. It is fast acting, produces complete cessation of clinical signs, does not appear to have adverse side effects, does not depress the animal, and can be administered orally. The only disadvantage is the relative short duration of action. The dosage of either diazepam or phenothiazine derivatives depends upon the severity and frequency of seizures and should be separately established in each case. The dosages given in this report ar for fairly severe cases and are intended to serve as a basis for establishing individual treatment.
If amphetamine is to be administered, the induced psychic stimulation should be counteracted by one of the phenothiazine derivatives.
1. Bethlem, J., Van Cool, J., Hulsmann, W.S., and Meijer, A.E.F.H.: Familial Non-Progressive Myopathy with Muscle Cramps After Excercise. Brain, 89, (1966):569-587.
2. Brown, G.L., and Harvey, A.M.: Congenital Myotonia in the Goat. Brain, 62, (1941):1-18.
3. DennyBrown, D., and Nevin, S.: The Phenonomenon of Myotonia. Brain, 64, (1941): 1-18.
4. Grund, G.: Uber myokymische Kontraktur. Deutsche Z. Nervenheilk., 64, (1919): 1--18.
5. Henatsch, H.D., and Ingvar, B.H.: Chlorpromazin and Spastizitat, eine experiementelle elektrophysiologische Untersuchung. Arch. Psychiat, 195, (1956): 77-93.
6. Howard, F.M.: A New and Effective Drug in The Treatment of The Stiff-Man Syndrome: Preliminary Report. Proc.Staff Meet. Mayo Clin., 38, (1963): 203-212.
7. Hudson, R.D., and Domino, E.F.: Comparative Effects of Three Substituted Phenothiazine on the Patellar Reflex and Mean Arterial Blood Pressure in the Rabbit. Arch. internat. pharmocodyn., 147, (1964):36-42.
9. Klarenbeek, A., Koopmans, S., and Winsser, J.: Een Aanvalsgewijs Optredende Stoornis in de Regulatie van de Spiertonus, Waargenomen bij Schotsche Terriers. Tijdschr. Diergeneesk., 69, (1942):14-21.
10. Landau, W.M.: The Essential Mechanism in Myotonia: An Electromyographic Study. Neurology, 2, (1952): 369-388.
11. Lasagna, L., and McCann, W.P.: Effect of Tranquilizing Drugs on Amphetamine Toxicity in Aggregated Mice. Science, 125, (1957): 1241-1242.
12. McArdle, B.: Myopathy Due to a Defect in Muscle Glycogen Breawn. Clin. Sci., 10, (1951): 13, 33.
13. Meyers, K.M., Lund, J.E., and Boyce, J.T.: Muscular Cramping of Central Nervous System Origin in Scottish Terrier Dogs: Fed. Proc., 27, (1968).
14. Moersch, F.P., and Woltman, H.W.: Progressive Fluctuating Muscular Rigidity and Spasm ("Stiff-Man Syndrome"): Report of a Case and Some Observations in 13 Other Cases. Proc. Staff Meet. Mayo Clin., 31, (1956):421-427.
15. Olafson, R.A., Mulder, D.W., and Howard, F.M.: "Stiff-Man" Syndrome: A Review of the Literature, Report of Three Additional Cases and Discussion of Pathophysiology and Therapy. Proc. Staff Meet. Mayo Clin., 39, (1964): 131-144.
16. Pearson, C.M., Rimer, D.C., and Mommaerts, W.F.H.M.: A Metabolic Myopathy Due to Absence of Muscle Phosphorylase. Am. J. Med., 30, (1961): 503-517.
17. Roberts, S.J.: Herditary Spastic Diseases Affecting Cattle in New York State. Cornell Vet., 55, (1965): 637-644.
18. Satoyoshi, E., and Yamada, K.: Recurrent Muscle Spasms of Central Origin. Arch. Neurobiol., 16, (1967): 254-264.
19. Schmid, R., and Mahler, R.: Clinic Progressive Myopahty iwth Myoglobinuria: Demonstration of Glycogenolytic Defect in Muscle. J. Clin. Invest. 38, (1959): 2044-2058.
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21. Stuart, F.S., Henry, M., and Holley, H.L.: The Stiff Man Syndrome: Report of a Case. Arth. & Rheum., 3, (1960): 229-232.
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23. Zebinden, G., and Randall, L.O.: Pharmacology of Benzadiazepines: Laboratory and Clinical Correlations. Advances in Pharmacol., 5, (1967):213-291.
original Doc: cramp10.doc
Precursor regulation of serotonergic neuronal function in Scottish Terrier dogs
By R. I. Peters, Jr.
K. M. Meyers
Veterinary and Comparative Anatomy,
Pharmacology and Physiology Departments,
Washington State University,
Pullman, WA 99164,
Source: Journal of Neurochemistry, 1977, Vol. 29, pp. 753-755. Pergamon Press. Printed in Great Britain.
(Received 19 January 1977. Accepted 6 April 1977)
This work was supported by Grants GM 7125, FR 5465 and RR 00515 from the National Institutes of Health.
5-HIAA, 5-hydroxyindoleacetic acid;
CSF, cerebrospinal fluid.
The possibility that the availability of tryptophan (TRP), the amino acid precursor of serotonin (5-HT), may control 5-HT biosynthesis and functionality has received much attention in recent literature. Alterations in plasma TRP have been induced by a variety of means, and concomitant alterations in brain 5-HT concentrations have been noted (BENDER, 1976; ETIENNE et al., 1976; FERNSTROM & WURTMAN, 1971b; MADRAS et al., 1974; TAGLIAMONTE et al., 1973; WURTMAN & FERNSTROM, 1972). Despite these findings, there is little unequivocal evidence that alterations in TRP availability alter the functional capabilities of serotonergic neurons.
The Scottish terrier breed of dog is subject to an heritable locomotor defect which we believe can yield important insights into means of regulation of serotonergic neuronal function. When presented with an exciting stimulus affected dogs are able to locomote normally for a period of time, after which they begin to exhibit the clinical signs of the defect. The defect has been found to be of CNS origin (MEYERS et al., 1971), and the latency between stimulus presentation and onset of the clinical signs has been found to be dependent upon the functional capabilities of 5-HT neurons. Parachlorophenylalanine (PCPA) markedly decreases the latency, and 5-hydroxytryptophan treatment lengthens it in PCPA depleted dogs (MEYERS et al., 1973). Thus, these dogs provide an animal model with which the functional capabilities of 5-H neurons may be assayed by a quantifiable behavior. We have utilized this animal model to study the relationship between precursor availability, 5-HT metabolism, and 5-HT neuronal function.
Alterations in precursor availability were established by both natural and artificial means. Circadian oscillations in plasma and cerebrospinal fluid (CSF) TRP and brain 5-HT concentrations are well documented in other species (ELEFTHERIOU, 1974; GLOWINSKI, 1972; HANSELMANN & BORBELY, 1976; MORGAN & YNDO, 1973; MORGAN et al., 1974; REIS et al., 1969; WURTMAN & FERNSTROM, 1972), and we were interested in whether these natural alterations in precursor might be related to alterations in 5-HT metabolism and functionality in these dogs. Additionally, we were interested in the effects of TRP loading. Exogenous TRP has been shown to increase brain 5-HT metabolism and functionality in these dogs. Additionally, we were interested in the effects of TRP loading. Exogenous TRP has been shown to increase brain 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) concentrations in dogs (ECCLESTON et al, 1968; MOIR & ECCLESTON, 1968), but the dose dependence and functional significance of this effect have not been established.
Dogs were housed in indoor kennels maintained on a 10:14 light-dark cycle with natural twilights. Food and water were provided ad lib., except that food was withdrawn 6 h prior to behavioral testing or body fluid sampling. The dogs were exercised daily at the time of kennel cleaning, around 1400 h.
Blood samples were taken from the cephalic vein into heparinized syringes. The blood was immediately centrifuged to separate the plasma, and then assayed for TRP by the method of DENCKLA & DEWEY (1967). Cisternal CSF samples (0.7 ml) were obtained by percutaneous puncture from dogs anesthetized with Thiamylal sodium (Surital, Parke-Davis, Detroit, MI). CSF samples were immediately placed in a freezer maintained at -20 C. and assayed for TRP (DENCKLA & DEWEY, 1967) and 5-HIAA (HAUBRICH & DENZER, 1973 within 1 week.
Behavioral testing was conducted as previously described (MEYERS et al., 1973). Briefly, the dogs were taken out of their kennels and presented with a stimulus which consistently elicited the clinical signs. The latency before onset of the clinical signs and maximum severity of the episode were recorded. Description of the clinical signs and criteria used for evaluating their severity have been previously reported (MEYERS et al., 1969; 1971, 1973). For the TRP injection experiment, L-tryptophan (Nutritional Biochemicals, Cleveland, OH) was dissolved in sterile saline (15 mg/ml) buffered to pH 7.4, and injected into the cephalic vein at 1300 h. One hour later, the clinical signs were evaluated or cisternal CSF sample obtained.
RESULTS AND DISCUSSION
There was a close temporal relationship between total plasma and CSF TRP, 5-HIAA, and the latency between stimulus presentation and the appearance of the clinical signs. These variables reached their maximum values towards the middle of the dark phases, and were minimal at the end of the light phase. Thus, naturally occurring alterations in the ultimate precursor of 5-HT were temporally related to alterations in the concentration of the primary metabolite as well as a behavioral indicator of 5-HT neuronal function. We found no circadian fluctuation in the severity of the clinical signs or their persistence after removal of the stimulus.
It is apparent that the lowest dose of TRP used, 30 mg/kg, increased the latency and TRP and 5-HIAA concentrations in the CSF. Doubling and quadrupling the TRP dose resulted in a nearly linear increase in CSF TRP, similar to what has been found when brain TRP has been assayed (GRAHAME-SMITH, 1971). It is apparent that CSF 5-HIAA, an indicator of 5-HT metabolism; and the latency, an indicator of functionality, did not follow the same pattern. When the CSF TRP had risen to 97.8 nmol/ml (1600% of control) the CSF 5-HIAA and latency had risen to 1.08 nmol/ml and 50 s, or slightly more than 200% of control. Although a doubling of these values is not trivial, the fact that the rate of increase of these measures of 5-HT neuronal metabolism and function was much lower than the rate of increase of precursor concentration suggests that these neurons became functionally saturated with a relatively low exogenous TRP load. It is noteworthy that previous authors have found a similar saturation effect when rat brain 5-HT concentrations were monitored after TRP loads ranging from 12.5 mg/kg to 125 mg/kg (FERNSTROM & WURTMAN, 1971a).
In both experiments reported here, we found that the relative values of TRP and 5-HIAA in the cisternal CSF were closely related. This finding is contrary to that of YOUNG et al. (1974), who found no relationship between TRP and 5-HIAA in human lumbar CSF. It should be noted, however, that an unspecified number of those patients were undergoing surgery at the time of sampling. Volatile gas anesthesia has profound effects on CSF 5-HIAA (MEYERS & SCHAUB, 1974), and could have led to spurious results. The contradictory results are probably not due to differences in species or sampling site, since other workers have found that TRP and 5-HIAA in human lumbar CSF were significantly correlated following TRP administration (ASHCROFT et al., 1973). Although as YOUNG et al. (1974) suggest, CSF TRP and 5-HIAA may not both be accurate indicators of 5-HT turnover, it appears that the concentrations of these substances vary in unison in some situations.
There is considerable disagreement in the literature regarding the validity of CSF 5-HIAA concentration as an index of 5-HT neuronal function (GARELIS et al., 1974; GREEN & GRAHAME-SMITH, 1976), and our results bear on this controversy. In both the study on circadian rhythms and the study on effects of exogenous TRP, the patterns of 5-HIAA concentration and latency between stimulus presentation and onset of the clinical signs were very similar. Thus, in this preparation at least, there seems to be a close relationship between cisternal CSF 5-HIAA concentration and a behavioral index of 5-HT neuronal function. Additionally, the percentage increase which we found in CSF 5-HIAA after 30 mg/kg was around half of the increase in the brain 5-HT seen by others after 50 mg/kg (ECCLESTON et al., 1968). These facts give us confidence that the 5-HIAA values reported here are not the result of non-specific presynaptic catabolism, but are a true reflection of serotonergic neuronal function.
The study on circadian fluctuations showed that small, physiological alterations in CSF TRP may influence the functional capabilities of serotonergic neurons, as reflected by latency measurements. However, the TRP loading experiment showed that this system became saturated with exogenous TRP loads much smaller than are often employed in behavioral experiments. The principal hypothesis under investigation was that alterations in precursor availability would alter the functional capabilities of the serotonergic neuronal systems involved in the expression of this genetic defect. The data reported here indicate that this hypothesis may be answered in the affirmative, provided that the precursor alterations are physiological in extent. In light of these findings it would be informative to note the functional consequences of other physiological means of altering TRP concentrations, such as dietary alteration or insulin administration.
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