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Rotation produced by electrolytic lesions of the superior cerebellar peduncle in rats modifying other forms of circling behavior
EXPERIMENTAL
Rotation
NEUROLOGY
52,
119-131
(1976)
Produced by Electrolytic Lesions of the Superior Cerebellar Peduncle in Rats Modifying Other Forms of Circling Behavior1 I. MAcG. DONALDSON, The
C. PYCOCK,~ AND C. D. MARSDEN
Uraiversity Department of Nezwology, I&it& of Psychiatry, and King’s College Hosbital Medical School, Delamark Hill, London, SE5 8AF, Englalad
Received
Janmary
15,1976;
wuision
received
March 29,1976
Unilateral electrolytic lesions were made at two different levels in the brain stems of rats. The caudally placed lesions frequently involved the superior cerebellar peduncle in the pons at the level 01 the locus coeruleus. Mild damage to the peduncle at this level produced no visible effect on motor activity, moderate damage resulted in a body tilt toward the side of the lesion, plus ataxia, and severe damage resulted in the addition of ipsiversive rotation. This spontaneous ipsiversive turning was capable of inhibiting the apomorphine- and dexamphetamine-induced contraversive circling seen in rats with unilateral electrolytic lesions of the adjacent locus coeruleus. The more rostrally placed lesions often injured the ascending fibers of the superior cerebellar peduncle at and rostra1 to their decussation, and resulted in contraversive rotation without body tilt or ataxia. Such spontaneous rotation seemed capable of inhibiting the ipsiversive circling response to apomorphine and dexamphetamine seen in rats with damage to the adjacent dorsal noradrenergic bundle area. Unilateral damage to the superior cerebellar peduncle in rats produces circling behavior, and t e direction of this depends on t:;e level of injury. Surh turning can modify t e rotational effects of lesions in adjacent brain stem structures. INTRODUCTION
Rotating grostriatal as models
rodents, which are produced by unilateral system in rats and mice, have been widely of the behavioral effects of asymmetrical
lesions of the niused and accepted doparnine receptor
1 This work was supported by grants from the Brain Research Trust, the Medical Research Council, and King’s College Hospital Research Fund. Thanks are due to Mr. Colin Brewer for expert technical assistance. 2 C. P. is a Fellow of the Parkinson’s Disease Society. 119 Copyright All rights
1976 by Academic Press, Inc. o3 reproduction in any form reserved.
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activity in this species (1, 13, 14). It appears that if there is an asymmetry in striatal dopamine receptor activity between the two sides the animals will turn in circles away from the side of higher activity (13, 14). This behavior has been seen to a small extent in unoperated rats treated with such as apomorphine or large doses of dopamine receptor stimulants, dexamphetamine, and attempts have been made to correlate this observation with an underlying asymmetry in striatal levels (6, 7). More pronounced circling is seen after unilateral lesions of the nigrostriatal system. Thus after injection of 6-hydroxydopamine into the substantia nigra there is spontaneous contraversive circling which may last for a few days; this behavior has been interpreted as being due to a build-up of dopamine in the remaining nerve terminals with release on to the ipsilateral supersensi,tive denervated receptors ( 13). After spontaneous rotation has stopped, the systemic administration of apomorphine produces circling contraversive to the damaged side, while dexamphetamine results in ipsiversive rotation. This result has been interpreted as due to preferential stimulation of the supersensitive denervated receptors by the dopamine receptor agonist apomorphine (14), and the release of dopamine on to striatal receptors on the intact side by dexamphetamine (13). Lesions of other brain stem structures also result in spontaneous and drug-induced circling behavior and in some cases this may be by an effect on the striatal dopamine receptors. Thus unilateral lesions involving the noradrenaline containing locus coeruleus produce circling, which has been interpreted as due to a loss of a facilitative pathway between it and the substantia nigra leading to “decentralization” supersensitivity (15) of the striatal dopamine receptors (11) . Simiiar contraversive rotation is also seen after unilateral lesions of the S-hydroxytryptamine-containing median raphe nucleus (4) and it has been shown that Iesions in this site in cats seem to alter the sensitivity of striatal receptors to directly applied dopamine (3). It is not widely appreciated that unilateral damage to other brain stem structures will produce spontaneous rotational behavior, but in view of the interpretations placed on experiments involving lesions of the brain stem, this effect is of considerable importance. In the course of making lesions in various brain stem structures it has become apparent that unilateral lesions involving the superior cerebellar peduncle in rats will produce rotational behavior and that its ‘direction depends on the level of the lesion. Such damage can modify circling due to lesions in other structures. METHODS Unilateral electrolytic lesions were made in the brain stems of Wistar rats of either sex, weighing 180 to 200 g at the time of operation. Animals
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were anesthetised with chloral hydrate (300 mg/kg, ip) and immobilized in a “Stoelting” stereotaxic frame. With the head level, a stainless-steel electrode (0.65 mm diameter), varnished except for 0.5 mm at the tip, was placed in the region of one locus coreuleus (A, anterior to the interaural line -1.2 ; L, lateral to the midline, 1.0 ; and V, ventral to the exposed surface of the brain, -6.4) (11 j or the ventral noradrenergic bundle (A + 1.0; L 1.6; V -6.4) (8, 12 j. Electrolytic lesions were made by passing a current of 2.5 mA for 7 set through the electrode as anode. The cathode was attached to the ear. The fibers of the superior cerebellar peduncle were damaged incidentally after aiming the lesions at the other structures. In a small group of animals, electrolytic lesions were placed directly in the region of one superior cerebellar peduncle at the level of the locus coeruleus (A -1.2; L 2.0; V -6.4). After recovery, all animals were observed for both spontaneous and drug-induced circling behavior. Rats were placed individually in plastic cages measuring 35 x 25 cm and the spontaneous activity recorded. Drug-induced circling was observed 30 min after dexamphetamine sulphate (5 mg/kg, ip j or 15 min after apomorphine hydrochloride (2 na%, ip 1. Histology was performed on tissues from all rats. Animals with either the locus coeruleus or ventral noradrenergic bundle lesions were killed at 2 months ; rats with superior cerebellar peduncle lesions were killed at 3 months. All brain stems were fixed for 10 days in 10% buffered formalin, processed, embedded in paraffin wax, sectioned transversely and stained with haematoxylin and eosin, Nissl’s stain, or by the KliiverBarrera technique. In addition, sections from rats with superior cerebellar peduncle lesions were stained with the Glees silver stain technique for the demonstration of axons. Assessments of the extent of damage caused by the lesions were made by use of a stage micrometer. Histological assessments were made and maps drawn without knowledge of the behavioral results. With lesions at the level of the locus coeruleus, where the superior cerebellar peduncle is clearly defined, it was possible to make an accurate estimate of the mean of the cross-sectional area of the peduncle that had been destroyed. This was always done at the point of maximal destruction to this structure, and the results were expressed as the percentage of damage to the fiber tract. At higher levels in the brain stem, where the fiber tracts are less well defined, the approximate cross-sectional areas were calculated (see Results section). The Kliiver-Barrera technique was used to assess the areas of demyelination, and this was taken as an index of axonal degeneration. The Glees silver technique was used to stain the remaining intact axons.
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RESULTS Lesions Involving the Superior Cerebellar Peduncle at the Level of the Locus Coeruleus. After lesions involving the superior cerebellar peduncle at the level of the locus coeruleus, a number of animals showed postural abnormalities and unsteadiness (Fig. 1). In its mildest form this consisted of a tendency to lean slightly to the side of the lesion. If severe
FIG. 1. (A) Map of the pons at the level of the locus coeruleus. c-cerebellum, nucleusof Vth cranial nerve, mc+motsr l-locus coeruleus, m-mesencephalic nucleus of Vth cranial nerve, o-olivary complex, p-superior cerekllar peduncle, scorticospinal tract, se-sensory nucleus of Vth cranial nerve, q-spinal tract of Vth cranial nerve. The dotted area represents the region shown in B. (B) Photomicrogra#ph of the dotted area in A. The electrolytic lesion destroyed the locus coeruleusand damaged the adjacerxtsuperiorcer’ebellar&uncle, the area of which has been outlined. Kltiver-Barrera stain. Magnification X25.
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there was unsteadiness of gait and staggering or falling to the operated side. This spectrum of disability was often associated with a spontaneous tendency to turn ipsiversively. The rotation was quite characteristic and always consisted of the forepart of the animal swivelling about stationary hindlimbs, which acted as a pivot. The trunk and neck were not laterally flexed. This form of rotation was termed “swiveling.” Although it tended to be seen in the most ataxic rats, it was occasionally present in animals which showed only body tilt with no unsteadiness. This turning was usually intermittent and at times the rats could walk straight. Eighteen of 77 rats with electrolytic lesions in this region showed this form of rotation and all had some of the other signs of superior cerebellar damage mentioned above. However, a total of 33 of the 77 rats showed some degree of unsteadiness, although it was usually mild and unassociated with ipsiversive swiveling. Swiveling and ataxia were transient and had disappeared by the end of the first postoperative week in all but two rats. The ipsiversive rotation was often enhanced by administration of systemic apomorphine (1 mg/kg. ip) or dexamphetamine (5 mg/kg ip), and this latent tendency was sometimes revealed by these drugs in rats which were only ataxic, or in which the spontaneous swiveling had disappeared. Table 1 shows the relationship between these motor abnormalities and the damage to the superior cerebellar peduncle. Some animals showed neither ataxia nor swiveling but had sustained some damage to the peduncle. TABLE
Correlation of Superior Cerebellar Locus Coeruleus
1
Spontaneous Ipsiversive Swiveling Peduncle
Group
in Rats
with
Superior
Unilateral
Cerebellar
with Histological Damage Electrolytic Lesions Aimed
Peduncle
Number
1) No ataxia and no swiveling 2) Ataxia but no swiveling 3) Ataxia and swiveling
Total
Absent
39 20 18
22 1 0
Damage Degreea cm
to the at the
Significance UT
Present
17 19 18
11.1 + 4.0 37.5 + 7.2 57.7 + 7.1
a Mean of maximal percentage of cross-sectional area of superior cerebellar damage or destroyed + 1 SEM. b Significance of difference in degree of damage to superior cerebellar peduncle pared to Group 1 using Student’s t test of nonpaired difference. c Significance of difference in degree of damage to superior cerebellar peduncle pared to Group 2 using Student’s t test of nonpaired difference.
<0.001*
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Of the 39 nonataxic and nonswiveling animals, 44% showed such damage, but it was relatively mild and the mean of the cross-sectional area of the peduncle involved was only 11%. In 20 rats which were ataxic but did not show spontaneous ipsiversive swiveling, 95% had damage to the peduncle, and this was of much greater extent (38%) than that in the nonataxic animals. All 18 rats which showed spontaneous ipsiversive swiveling were ataxic, and the area of the superior cerebellar peduncle damaged (58%) was even greater than in the group of animals showing ataxia alone. In general the swiveling animals seemed more unsteady than the ataxic rats which did not swivel. It is also of interest that of the 52 animals in which the locus coeruleus was completely destr,oyed, the only ones which did not circle contraversively in response to the systemic administration of apomorphine or dexamphetamine were 11 which showed spontaneous ipsiversive swiveling. The mean cross-sectional area of the peduncle damaged in these 11 rats was 65.0 -C 9.2 (1 SEM) %, significantly greater than that in rats which circled contraversively in response to these drugs, and had sustained damage that was 18.1 f 4.1 (1 SEM) % (P < 0.005 by Student’s t test of nonpaired differences). There was no correlation between the spontaneous ipsiversive rotation and extent of damage to other structures, including the locus coeruleus, mesencephalic nucleus of the fifth cranial nerve, and adjacent pontine reticular formation. Lesions Involving the Superior Cerebellar Peduncle in the Midbrain. There were 34 rats in which electrolytic lesions were, for other reasons, aimed at the ventral noradrenergic bundle in the midbrain, which lies close to the superior cerebellar peduncle (Fig. 2). Twenty-one of these showed spontaneous contraversive rotation in the first postoperative week. This took the form of turning in a circle about an axis which passed through the center of the trunk, so that the diameter of the circle was equal to the length of the rat. Sometimes the back was held slightly arched. There u-as no lateral flexion of the neck or trunk. This type of rotation was termed “spinning” and it was intermittent so that at times the animals could walk straight. There was no unsteadiness or tendency to lean to one side in any of the 34 rats. At the level of the locus coeruleus, the superior cerebellar peduncle forms a discrete structure and it is easy to be certain if it is involved by a lesion. At the more rostra1 level of the lesions aimed at the ventral noradrenergic bundle, the peduncle does not form such a compact structure and it is often difficult to distinguish it from other myelinated fibers crossing the midline. While it was possible to distinguish some cases in which damage had occurred, it was sometimes impossible to be certain that no peduncular
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FIG. 2. (A) Map of a section of the brain stem corresponding to level A 1020 ,u of Kiinig and Klippel. a-aqueduct, f-medial longitudinal fasiculus, m-medial lemniscus, p-superior cerebellar peduncle, s-corticospinal tract. The dotted area represents the region shown in B. (B). Photomicrograph of the dotted area in A. The electrolytic lesion damaged the lateral part of the decussating fibers of the superior cerebellar peduncle, the area of which has been outlined. Kltiver-Barrera stain. Magnification X2.5.
injury had been sustained. If the damage was actually seen to involve the fibers of the superior cerebellar peduncle it was termed “definite” injury. If the lesion was sited in the area of the peduncular fibers as shown in the Atlas of Kijnig and Klippel (8)) without being able to clearly distinguish that it was those fibers that were damaged, it was termed “probable” injury. Table 2 shows the relationship between this spontaneous contraversive rotation and the incidence of damage to the superior cerebellar peduncle of the 21 rats which showed a spontaneous tendency to turn away from the lesioned side postoperatively; 14 had definite or probable damage, with 12
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TABLE
2
Relationship of Spontaneous Contraversive Superior Cerebellar Peduncle in Rats with Ventral Noradrenergic Bundle Group
Spontaneous Contraversive No Spontaneous Contraversive Totals
Number of rats
Rotation Rotation
21
Rotation Unilateral
Number with definitea damage
12
MARSDEN
and Histological Damage Electrolytic Lesions Aimed
Number with probableb damage
Total with
2
to the at the
number damage
14
13
1
2
3
34
13
4
17
a Refers to injury actually observed within the superior cerebellar peduncle lating positively to these fibers. b Refers to injury within the region of the superior cerebellar peduncle but being able to clearly distinguish the particular fibers that were damaged.
and
re-
without
in the definite category. However, of the 13 animals which showed no spontaneous contraversive turning, only one had definite injury to the fibers of the peduncle. Thus out of the 17 rats in which damage was definite or probable, 14 showed this type of spontaneous rotation, and all but one of the 13 animals with definite injury displayed this characteristic behavior. The presence of spontaneous contraversive spinning did not seem to correlate with histological damage to structures other than the superior cerebellar peduncle. The raphi nuclei, substantia nigra, rubrospinal tracts, and corticospinal tracts were not injured. Spinning was not related to damage to the ventral noradrenergic bundle which was injured in all 34 rats. The dorsal noradrenergic bundle was also damaged in 23 animals. Thirteen of these rats with extension of the lesion into the dorsal bundle area developed ipsiversive circhng in response to the systemic administration of apomorphine and dexamphetamine. Three of these 13 had shown mild contraversive spinning. The remaining ten rats with dorsal bundle area injury showed a mixed, inconsistent, or absent turning responses when given these drugs, and all of these animals had shown spontaneous contraversive spinning behavior. Degeneration Produced by Electrolytic Lesions of the Superior Cerebellar Peduncle. Unilateral electrolytic lesions aimed directly at the superior cerebellar peduncle at the level of the locus coeruleus produced an area of degeneration with vacuolation spreading rostrally through the pons and midbrain up to the contralateral red nucleus. In these rats the area of degeneration could be seen to cross the midline between the levels corresponding to A 620 p and A 1270 p of KGnig and Klippel (8). These
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animals showed the same ipsiversive swiveling and ataxia described above in rats with locus coeruleus lesions and incidental damage to the superior cerebellar peduncle. DISCUSSION In rats with electrolytic lesions in the region of the locus coeruleus there was a good correlation between the degree of damage to the superior cerebellar peduncle on the one hand and both ataxia and ipsiversive swiveling on the other. As the lesions were aimed at the more medially and ventrally placed locus coeruleus it was the ventromedial aspect of the peduncle which was damaged in cases of mild injury. As the damage became increasingly severe, the more laterally placed parts of the peduncle suffered as well. It is apparent from Table 1 that mild damage can be sustained by the medial part of the superior cerebellar peduncle without any observable deficit. However, ataxia was almost invariably associated with visible injury to the peduncle and only one out of 38 (2.5%) ataxic animals did not have obvious histological damage to this structure. It is possible that the unsteadiness in this single rat may have been explained by edema from the adjacent lesion affecting the peduncle, without visible evidence of injury. Not only was the proportion of animals showing injury greater in the ataxic group, but the degree of damage to the peduncle was more extensive than in nonataxic rats. The animals showing spontaneous ipsiversive swiveling were all ataxic and all had injury to the peduncle which was more extensive than in the other groups. There was thus a spectrum with minor injury to the ventromedial aspect of the superior cerebellar peduncle producing no effect, greater damage resulting in ataxia. and severe destruction causing ipsiversive swiveling plus ataxia. We have demonstrated elsewhere (11) that electrolytic damage to the locus coeruleus in rats results in contraversive circling on systemic administration of apomorphine or dexamphetamine. As this rotation is in the opposite direction to the ipsiversive swiveling seen with superior cerebellar peduncle lesions at the level of the locus coeruleus. it seems likely that these two forms of rotation might interfere with each other. In fact, the only animals which had the locus coeruleus completely destroyed and did not circle contraversively in response to apomorphine and dexamphetamine all showed ipsiversive swiveling. These rats had considerably greater damage to the superior cerebellar peduncle than those showing such druginduced contraversive circling. Thus it seems that severe damage to this structure results in spontaneous ipsiversive rotation which inhibits the contraversive drug-induced circling seen after locus coeruleus lesions.
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In the more rostrally placed lesions, which were aimed at the noradrenergic bundles in the midbrain, there was a positive correlation between spontaneous contraversive spinning and damage to the ascending and crossing fibers of the superior cerebellar peduncle. Thus 12 of the 13 rats (92%) with definite damage to the fibers of the superior cerebellar peduncle showed this spontaneous turning and only one of the 13 (8%) animals with no spinning behavior had definite injury. It is possible that damage to the fibers of the superior cerebellar peduncle is the cause of the spontaneous spinning, but experimentally it is very difficult to be certain which of the many decussating fibers within this region belong to the peduncle. This is especially so in the rostra1 areas where the fibers are more dispersed and there are many other myelinated nerves crossing the midline. While it is possible in many cases to establish that damage is present, it is often difficult to be certain that injury has not occurred. In addition, the function of fibers may be impaired by edema from adjacent lesions without seeing evidence of this on light microscopy. It seems likely, therefore, that the incidence of damage to the peduncle would be underestimated by the histological assessment. Part of the uncertainty of the amount of damage to the superior cerebellar peduncle, particularly at the more rostra1 levels, may arise from the use of the Khiver-Barrera technique for assessing the areas of demyelination. With the long survival time of the rats following the lesioning procedure (2 to 3 months), an area of demyelination was taken to represent an area of degenerated axons. However, the histological sections stained with the Glees silver technique for intact axons from the group of rats receiving direct superior cerebellar peduncle lesions at the level of the locus coeruleus gave little additional information from the same sections stained for myelin. Another approach to the problem would have been the use of specific silver techniques to demonstrate areas of degenerating axons, although a shorter survival time would have been required. Such a procedure might have yielded more positive information about the extent of damage to the superior cerebellar peduncle. From the position of the degeneration seen in the rats with lesions aimed at the superior cerebellar peduncle at the level of the locus coeruleus it was apparent that the fibers decussated between the sections corresponding to a A 620 p and A 1270 p of K&rig and Klippel (8). The lesions aimed at the ventral noradrenergic bundle, which involved fibers of the peduncle, were situated at and rostra1 to this level. There is a specific topographic arrangement of fibers within the mammalian superior cerebellar peduncle (2). Damage to the peduncle in rats with locus coeruleus lesions affected mainly medial fibers, whereas that seen in lesions aimed at the ventral noradrenergic bundle involved the lateral fibers at and rostra1
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to the decussation. If these fibers maintained their mediolateral positions relative to each other throughout the decussation, these two types of lesions could be affecting the same fibers at the two different levels. Thus they could produce spontaneous ipsiversive turning with lesions caudal to the decussation, and spontaneous contraversive rotation with lesions rostra1 to it. In support of the hypothesis that damage to the superior cerebellar peduncle can produce such rotation, it should be mentioned that Carrea and Mettler (2) noticed occasional spontaneous ipsiversive circling in monkeys with damage to this structure, and that the direction of rotation changed if the injury was rostra1 to the decussation. This is also consistent with the results of Mussen (10) who found that eiectrical stimulation of the red nucleus in cats resulted in ipsiversive rotation with pivoting about the hind legs. This seems of a similar nature to the ipsiversive swiveling behavior seen in the present study in rats with peduncle damage incidental to locus coeruleus lesions. In attempting to make unilateral electrolytic lesions of the ascending noradrenergic system in the midbrain of rats, Marsden and Gulberg (9) noticed spontaneous contraversive turning which was potentiated by amphetamine into active rotation. They found that the potentiation was blocked by dopamine receptor blocking agents but that the spontaneous asymmetry was not. Those workers concluded that the spontaneous turning was due to damage to nonnoradrenergic structures but were unable to define them. As their maps show that the superior cerebellar peduncle was involved in the lesions this may well have been the cause of those observations. One striking difference between the two types of spontaneous turning associated with damage to the superior cerebellar peduncle is that the rotation occurring with the more caudally placed lesions was associated with body tilt and ataxia, whereas that occurring with the more rostrally cited injury did not show these features. It has been shown in monkeys that only damage to certain fibers within the superior cerebellar peduncle results in ataxia (2)) and that these fibers have a specific anatomical localization. They leave the peduncle before the red nucleus is reached and pass caudally toward the spinal cord. Thus the lack of unsteadiness in these spontaneously spinning rats with lesions rostra1 to the decussation does not exclude the possibility that the rotation is due to superior cerebellar peduncle damage as the fibers involved in the production of ataxia may have been spared by the laterally placed lesions. The evidence presented above suggests that the spontaneous contraversive rotation seen after electrolytic lesions of the midbrain is due to damage to fibers of the superior cerebellar peduncle. We have described elsewhere that electrolytic lesions involving the region of the dorsal noradrenergic bundle result in ipsiversive circling in response to systemically administered
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apomorphine or dexamphetamine (5). In the present study 23 of the electrolytic lesions also involved the area of the dorsal noradrenergic bundle, but only 13 of these rats showed such drug-induced ipsiversive rotation. There did not seem to be any difference in the amount of damage to the noradrenergic bundle areas between the rats which showed this ipsiversive rotation and those which did not. However, all ten animals in which the apomorphine- and dexamphetamine-induced response was absent displayed spontaneous contraversive spinning, whereas it was present in a weak form in only three of the 13 rats which circled ipsiversively after administration of these drugs. It thus seems likely that superior cerebellar peduncle damage at this level, with its associated contraversive rotation, can interfere with ipsiversive drug-induced circling. This effect is of a similar nature, but in the opposite direction, to the more caudally placed superior cerebellar peduncle damage inhibiting the contraversive rotation seen with locus coeruleus lesions. The results presented above suggest that unilateral damage to the superior cerebellar peduncle in rats can result in rotational behavior and that this need not be associated with other signs of peduncular injury. Such damage may modify the circling activity produced by lesions in other structures, and it is important to allow for the effect when assessing the results of unilateral brain stem lesions. Rotation produced by superior cerebellar peduncle injury has a characteristic appearance and this fact highhghts the need for careful observation of the nature of the circling behavior, rather than just assessments of the rate of rotation. REFERENCES N.-E., A. DAHLSTR~M, K. FUXE, and K. LARSSON. 1966. Functional role of the nigrostriatal dopamine neurons. Acta Pharmacol. Toxicol. 24: 263-274. CARREA, R. E. M., and F. A. METTLER. 1955. Function of the primate brachium conjunctivum and related structures. J. Co@. Neural. 102: 151-322. COOLS, A. R., and H.-J. JANSSEN. 1974. The nucleus linearia intermedium raphe and behaviour evoked by direct and indirect stimulation of the dopamine sensitive sites within the caudate nucleus of cats. Europ. J. Picarmacol. 28: 266-275. COSTALL, B., and R. J. NAYLOR. 1974. Stereotyped and circling behaviour induced by dopamine agonists after lesions of the midbrain raphe nuclei. Eur. J. Pharmcol. 29 : 206-222. DONALDSON, I. MAcG., A. C. DOLPHIN, P. JENNER, C. PYCOCK, and C. D. MARSDEN. 1976. Rotational behaviour produced in rats by electrolytic lesions of the ascending noradrenergic bundles. I. Lesions of the dorsal noradrenergic bundle. (Submitted for publication). JERUSSI, T. P., and S. D. GLICK. 1974. Amphetamine-induced rotation in rats without lesions. Neuropharmacology 13 : 283-286. JERUSSI, T. P., and S. D. GLICK. 1975. Apomorphine-induced rotation in normal rats and interaction with unilateral caudate lesions. Psychopharmacologia 40 : 329-334.
1. AND&N, 2.
3. 4. 5.
6. 7.
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8. KGNIG, J. F. R., and R. A. KLIPPEL. 1963. “The Rat Brain. A Stereotaxic Atlas.” Williams & Wilkins Baltimore. 9. MARSDEN, C. A., and H. C. GULDBERG. 1973. The role of monoamines in rotation induced or potentiated by amphetamine after nigral, raphe and mesencephalic reticular lesions in the rat brain. Neuro#hurmacology 12: 195-211. 10. MUSSEN, A. 1934. Cerebellum and red nucleus. Arch. Neural. Psych. 31: 110-126. 11. PYCOCK, C., I. MAcG. DONALDSON, and C. D. MARSDEN. 1975. Circling behaviour produced by unilateral lesions in the region of the lorus coeruleus in rats. Brain Res. 97: 317-329. 1.2. UNGERSTEDT, U. 1971. Stereotaxic mapping of the monoamine pathways in the rat brain. Acta Physiol. Stand. (Suppl.) 367 : 1118. 13. UNGERSTEDT, U. 1971. Striatal dopamine release after amphetamine or nerve degeneration revealed by hotational behaviour. Acta Physiol. Stand. (Suppl.) 367: 49-68. 14. UNGERSTEDT, U. 1971. Postsynaptic supersensitivity after 6-hydroxydopamine induced degeneration of the nigro-striatal dopamine system. Acta Physiol. Scared. (Suppl.) 367 : 69-93. 15. UNGERSTEDT, U., T. LJUNGBERG, B. HOFFER, and G. SICGENS. 1975. Dopaminergic supersensitivity in the striatum, pp. 57-65. In “Advances in Neurology,” vol. 9. D. B. Calne, T. N. Chase, ,and A. Barbeau [Eds.] Raven Press, New York.
Rotation
NEUROLOGY
52,
119-131
(1976)
Produced by Electrolytic Lesions of the Superior Cerebellar Peduncle in Rats Modifying Other Forms of Circling Behavior1 I. MAcG. DONALDSON, The
C. PYCOCK,~ AND C. D. MARSDEN
Uraiversity Department of Nezwology, I&it& of Psychiatry, and King’s College Hosbital Medical School, Delamark Hill, London, SE5 8AF, Englalad
Received
Janmary
15,1976;
wuision
received
March 29,1976
Unilateral electrolytic lesions were made at two different levels in the brain stems of rats. The caudally placed lesions frequently involved the superior cerebellar peduncle in the pons at the level 01 the locus coeruleus. Mild damage to the peduncle at this level produced no visible effect on motor activity, moderate damage resulted in a body tilt toward the side of the lesion, plus ataxia, and severe damage resulted in the addition of ipsiversive rotation. This spontaneous ipsiversive turning was capable of inhibiting the apomorphine- and dexamphetamine-induced contraversive circling seen in rats with unilateral electrolytic lesions of the adjacent locus coeruleus. The more rostrally placed lesions often injured the ascending fibers of the superior cerebellar peduncle at and rostra1 to their decussation, and resulted in contraversive rotation without body tilt or ataxia. Such spontaneous rotation seemed capable of inhibiting the ipsiversive circling response to apomorphine and dexamphetamine seen in rats with damage to the adjacent dorsal noradrenergic bundle area. Unilateral damage to the superior cerebellar peduncle in rats produces circling behavior, and t e direction of this depends on t:;e level of injury. Surh turning can modify t e rotational effects of lesions in adjacent brain stem structures. INTRODUCTION
Rotating grostriatal as models
rodents, which are produced by unilateral system in rats and mice, have been widely of the behavioral effects of asymmetrical
lesions of the niused and accepted doparnine receptor
1 This work was supported by grants from the Brain Research Trust, the Medical Research Council, and King’s College Hospital Research Fund. Thanks are due to Mr. Colin Brewer for expert technical assistance. 2 C. P. is a Fellow of the Parkinson’s Disease Society. 119 Copyright All rights
1976 by Academic Press, Inc. o3 reproduction in any form reserved.
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activity in this species (1, 13, 14). It appears that if there is an asymmetry in striatal dopamine receptor activity between the two sides the animals will turn in circles away from the side of higher activity (13, 14). This behavior has been seen to a small extent in unoperated rats treated with such as apomorphine or large doses of dopamine receptor stimulants, dexamphetamine, and attempts have been made to correlate this observation with an underlying asymmetry in striatal levels (6, 7). More pronounced circling is seen after unilateral lesions of the nigrostriatal system. Thus after injection of 6-hydroxydopamine into the substantia nigra there is spontaneous contraversive circling which may last for a few days; this behavior has been interpreted as being due to a build-up of dopamine in the remaining nerve terminals with release on to the ipsilateral supersensi,tive denervated receptors ( 13). After spontaneous rotation has stopped, the systemic administration of apomorphine produces circling contraversive to the damaged side, while dexamphetamine results in ipsiversive rotation. This result has been interpreted as due to preferential stimulation of the supersensitive denervated receptors by the dopamine receptor agonist apomorphine (14), and the release of dopamine on to striatal receptors on the intact side by dexamphetamine (13). Lesions of other brain stem structures also result in spontaneous and drug-induced circling behavior and in some cases this may be by an effect on the striatal dopamine receptors. Thus unilateral lesions involving the noradrenaline containing locus coeruleus produce circling, which has been interpreted as due to a loss of a facilitative pathway between it and the substantia nigra leading to “decentralization” supersensitivity (15) of the striatal dopamine receptors (11) . Simiiar contraversive rotation is also seen after unilateral lesions of the S-hydroxytryptamine-containing median raphe nucleus (4) and it has been shown that Iesions in this site in cats seem to alter the sensitivity of striatal receptors to directly applied dopamine (3). It is not widely appreciated that unilateral damage to other brain stem structures will produce spontaneous rotational behavior, but in view of the interpretations placed on experiments involving lesions of the brain stem, this effect is of considerable importance. In the course of making lesions in various brain stem structures it has become apparent that unilateral lesions involving the superior cerebellar peduncle in rats will produce rotational behavior and that its ‘direction depends on the level of the lesion. Such damage can modify circling due to lesions in other structures. METHODS Unilateral electrolytic lesions were made in the brain stems of Wistar rats of either sex, weighing 180 to 200 g at the time of operation. Animals
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were anesthetised with chloral hydrate (300 mg/kg, ip) and immobilized in a “Stoelting” stereotaxic frame. With the head level, a stainless-steel electrode (0.65 mm diameter), varnished except for 0.5 mm at the tip, was placed in the region of one locus coreuleus (A, anterior to the interaural line -1.2 ; L, lateral to the midline, 1.0 ; and V, ventral to the exposed surface of the brain, -6.4) (11 j or the ventral noradrenergic bundle (A + 1.0; L 1.6; V -6.4) (8, 12 j. Electrolytic lesions were made by passing a current of 2.5 mA for 7 set through the electrode as anode. The cathode was attached to the ear. The fibers of the superior cerebellar peduncle were damaged incidentally after aiming the lesions at the other structures. In a small group of animals, electrolytic lesions were placed directly in the region of one superior cerebellar peduncle at the level of the locus coeruleus (A -1.2; L 2.0; V -6.4). After recovery, all animals were observed for both spontaneous and drug-induced circling behavior. Rats were placed individually in plastic cages measuring 35 x 25 cm and the spontaneous activity recorded. Drug-induced circling was observed 30 min after dexamphetamine sulphate (5 mg/kg, ip j or 15 min after apomorphine hydrochloride (2 na%, ip 1. Histology was performed on tissues from all rats. Animals with either the locus coeruleus or ventral noradrenergic bundle lesions were killed at 2 months ; rats with superior cerebellar peduncle lesions were killed at 3 months. All brain stems were fixed for 10 days in 10% buffered formalin, processed, embedded in paraffin wax, sectioned transversely and stained with haematoxylin and eosin, Nissl’s stain, or by the KliiverBarrera technique. In addition, sections from rats with superior cerebellar peduncle lesions were stained with the Glees silver stain technique for the demonstration of axons. Assessments of the extent of damage caused by the lesions were made by use of a stage micrometer. Histological assessments were made and maps drawn without knowledge of the behavioral results. With lesions at the level of the locus coeruleus, where the superior cerebellar peduncle is clearly defined, it was possible to make an accurate estimate of the mean of the cross-sectional area of the peduncle that had been destroyed. This was always done at the point of maximal destruction to this structure, and the results were expressed as the percentage of damage to the fiber tract. At higher levels in the brain stem, where the fiber tracts are less well defined, the approximate cross-sectional areas were calculated (see Results section). The Kliiver-Barrera technique was used to assess the areas of demyelination, and this was taken as an index of axonal degeneration. The Glees silver technique was used to stain the remaining intact axons.
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RESULTS Lesions Involving the Superior Cerebellar Peduncle at the Level of the Locus Coeruleus. After lesions involving the superior cerebellar peduncle at the level of the locus coeruleus, a number of animals showed postural abnormalities and unsteadiness (Fig. 1). In its mildest form this consisted of a tendency to lean slightly to the side of the lesion. If severe
FIG. 1. (A) Map of the pons at the level of the locus coeruleus. c-cerebellum, nucleusof Vth cranial nerve, mc+motsr l-locus coeruleus, m-mesencephalic nucleus of Vth cranial nerve, o-olivary complex, p-superior cerekllar peduncle, scorticospinal tract, se-sensory nucleus of Vth cranial nerve, q-spinal tract of Vth cranial nerve. The dotted area represents the region shown in B. (B) Photomicrogra#ph of the dotted area in A. The electrolytic lesion destroyed the locus coeruleusand damaged the adjacerxtsuperiorcer’ebellar&uncle, the area of which has been outlined. Kltiver-Barrera stain. Magnification X25.
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there was unsteadiness of gait and staggering or falling to the operated side. This spectrum of disability was often associated with a spontaneous tendency to turn ipsiversively. The rotation was quite characteristic and always consisted of the forepart of the animal swivelling about stationary hindlimbs, which acted as a pivot. The trunk and neck were not laterally flexed. This form of rotation was termed “swiveling.” Although it tended to be seen in the most ataxic rats, it was occasionally present in animals which showed only body tilt with no unsteadiness. This turning was usually intermittent and at times the rats could walk straight. Eighteen of 77 rats with electrolytic lesions in this region showed this form of rotation and all had some of the other signs of superior cerebellar damage mentioned above. However, a total of 33 of the 77 rats showed some degree of unsteadiness, although it was usually mild and unassociated with ipsiversive swiveling. Swiveling and ataxia were transient and had disappeared by the end of the first postoperative week in all but two rats. The ipsiversive rotation was often enhanced by administration of systemic apomorphine (1 mg/kg. ip) or dexamphetamine (5 mg/kg ip), and this latent tendency was sometimes revealed by these drugs in rats which were only ataxic, or in which the spontaneous swiveling had disappeared. Table 1 shows the relationship between these motor abnormalities and the damage to the superior cerebellar peduncle. Some animals showed neither ataxia nor swiveling but had sustained some damage to the peduncle. TABLE
Correlation of Superior Cerebellar Locus Coeruleus
1
Spontaneous Ipsiversive Swiveling Peduncle
Group
in Rats
with
Superior
Unilateral
Cerebellar
with Histological Damage Electrolytic Lesions Aimed
Peduncle
Number
1) No ataxia and no swiveling 2) Ataxia but no swiveling 3) Ataxia and swiveling
Total
Absent
39 20 18
22 1 0
Damage Degreea cm
to the at the
Significance UT
Present
17 19 18
11.1 + 4.0 37.5 + 7.2 57.7 + 7.1
a Mean of maximal percentage of cross-sectional area of superior cerebellar damage or destroyed + 1 SEM. b Significance of difference in degree of damage to superior cerebellar peduncle pared to Group 1 using Student’s t test of nonpaired difference. c Significance of difference in degree of damage to superior cerebellar peduncle pared to Group 2 using Student’s t test of nonpaired difference.
<0.001*
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Of the 39 nonataxic and nonswiveling animals, 44% showed such damage, but it was relatively mild and the mean of the cross-sectional area of the peduncle involved was only 11%. In 20 rats which were ataxic but did not show spontaneous ipsiversive swiveling, 95% had damage to the peduncle, and this was of much greater extent (38%) than that in the nonataxic animals. All 18 rats which showed spontaneous ipsiversive swiveling were ataxic, and the area of the superior cerebellar peduncle damaged (58%) was even greater than in the group of animals showing ataxia alone. In general the swiveling animals seemed more unsteady than the ataxic rats which did not swivel. It is also of interest that of the 52 animals in which the locus coeruleus was completely destr,oyed, the only ones which did not circle contraversively in response to the systemic administration of apomorphine or dexamphetamine were 11 which showed spontaneous ipsiversive swiveling. The mean cross-sectional area of the peduncle damaged in these 11 rats was 65.0 -C 9.2 (1 SEM) %, significantly greater than that in rats which circled contraversively in response to these drugs, and had sustained damage that was 18.1 f 4.1 (1 SEM) % (P < 0.005 by Student’s t test of nonpaired differences). There was no correlation between the spontaneous ipsiversive rotation and extent of damage to other structures, including the locus coeruleus, mesencephalic nucleus of the fifth cranial nerve, and adjacent pontine reticular formation. Lesions Involving the Superior Cerebellar Peduncle in the Midbrain. There were 34 rats in which electrolytic lesions were, for other reasons, aimed at the ventral noradrenergic bundle in the midbrain, which lies close to the superior cerebellar peduncle (Fig. 2). Twenty-one of these showed spontaneous contraversive rotation in the first postoperative week. This took the form of turning in a circle about an axis which passed through the center of the trunk, so that the diameter of the circle was equal to the length of the rat. Sometimes the back was held slightly arched. There u-as no lateral flexion of the neck or trunk. This type of rotation was termed “spinning” and it was intermittent so that at times the animals could walk straight. There was no unsteadiness or tendency to lean to one side in any of the 34 rats. At the level of the locus coeruleus, the superior cerebellar peduncle forms a discrete structure and it is easy to be certain if it is involved by a lesion. At the more rostra1 level of the lesions aimed at the ventral noradrenergic bundle, the peduncle does not form such a compact structure and it is often difficult to distinguish it from other myelinated fibers crossing the midline. While it was possible to distinguish some cases in which damage had occurred, it was sometimes impossible to be certain that no peduncular
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FIG. 2. (A) Map of a section of the brain stem corresponding to level A 1020 ,u of Kiinig and Klippel. a-aqueduct, f-medial longitudinal fasiculus, m-medial lemniscus, p-superior cerebellar peduncle, s-corticospinal tract. The dotted area represents the region shown in B. (B). Photomicrograph of the dotted area in A. The electrolytic lesion damaged the lateral part of the decussating fibers of the superior cerebellar peduncle, the area of which has been outlined. Kltiver-Barrera stain. Magnification X2.5.
injury had been sustained. If the damage was actually seen to involve the fibers of the superior cerebellar peduncle it was termed “definite” injury. If the lesion was sited in the area of the peduncular fibers as shown in the Atlas of Kijnig and Klippel (8)) without being able to clearly distinguish that it was those fibers that were damaged, it was termed “probable” injury. Table 2 shows the relationship between this spontaneous contraversive rotation and the incidence of damage to the superior cerebellar peduncle of the 21 rats which showed a spontaneous tendency to turn away from the lesioned side postoperatively; 14 had definite or probable damage, with 12
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2
Relationship of Spontaneous Contraversive Superior Cerebellar Peduncle in Rats with Ventral Noradrenergic Bundle Group
Spontaneous Contraversive No Spontaneous Contraversive Totals
Number of rats
Rotation Rotation
21
Rotation Unilateral
Number with definitea damage
12
MARSDEN
and Histological Damage Electrolytic Lesions Aimed
Number with probableb damage
Total with
2
to the at the
number damage
14
13
1
2
3
34
13
4
17
a Refers to injury actually observed within the superior cerebellar peduncle lating positively to these fibers. b Refers to injury within the region of the superior cerebellar peduncle but being able to clearly distinguish the particular fibers that were damaged.
and
re-
without
in the definite category. However, of the 13 animals which showed no spontaneous contraversive turning, only one had definite injury to the fibers of the peduncle. Thus out of the 17 rats in which damage was definite or probable, 14 showed this type of spontaneous rotation, and all but one of the 13 animals with definite injury displayed this characteristic behavior. The presence of spontaneous contraversive spinning did not seem to correlate with histological damage to structures other than the superior cerebellar peduncle. The raphi nuclei, substantia nigra, rubrospinal tracts, and corticospinal tracts were not injured. Spinning was not related to damage to the ventral noradrenergic bundle which was injured in all 34 rats. The dorsal noradrenergic bundle was also damaged in 23 animals. Thirteen of these rats with extension of the lesion into the dorsal bundle area developed ipsiversive circhng in response to the systemic administration of apomorphine and dexamphetamine. Three of these 13 had shown mild contraversive spinning. The remaining ten rats with dorsal bundle area injury showed a mixed, inconsistent, or absent turning responses when given these drugs, and all of these animals had shown spontaneous contraversive spinning behavior. Degeneration Produced by Electrolytic Lesions of the Superior Cerebellar Peduncle. Unilateral electrolytic lesions aimed directly at the superior cerebellar peduncle at the level of the locus coeruleus produced an area of degeneration with vacuolation spreading rostrally through the pons and midbrain up to the contralateral red nucleus. In these rats the area of degeneration could be seen to cross the midline between the levels corresponding to A 620 p and A 1270 p of KGnig and Klippel (8). These
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animals showed the same ipsiversive swiveling and ataxia described above in rats with locus coeruleus lesions and incidental damage to the superior cerebellar peduncle. DISCUSSION In rats with electrolytic lesions in the region of the locus coeruleus there was a good correlation between the degree of damage to the superior cerebellar peduncle on the one hand and both ataxia and ipsiversive swiveling on the other. As the lesions were aimed at the more medially and ventrally placed locus coeruleus it was the ventromedial aspect of the peduncle which was damaged in cases of mild injury. As the damage became increasingly severe, the more laterally placed parts of the peduncle suffered as well. It is apparent from Table 1 that mild damage can be sustained by the medial part of the superior cerebellar peduncle without any observable deficit. However, ataxia was almost invariably associated with visible injury to the peduncle and only one out of 38 (2.5%) ataxic animals did not have obvious histological damage to this structure. It is possible that the unsteadiness in this single rat may have been explained by edema from the adjacent lesion affecting the peduncle, without visible evidence of injury. Not only was the proportion of animals showing injury greater in the ataxic group, but the degree of damage to the peduncle was more extensive than in nonataxic rats. The animals showing spontaneous ipsiversive swiveling were all ataxic and all had injury to the peduncle which was more extensive than in the other groups. There was thus a spectrum with minor injury to the ventromedial aspect of the superior cerebellar peduncle producing no effect, greater damage resulting in ataxia. and severe destruction causing ipsiversive swiveling plus ataxia. We have demonstrated elsewhere (11) that electrolytic damage to the locus coeruleus in rats results in contraversive circling on systemic administration of apomorphine or dexamphetamine. As this rotation is in the opposite direction to the ipsiversive swiveling seen with superior cerebellar peduncle lesions at the level of the locus coeruleus. it seems likely that these two forms of rotation might interfere with each other. In fact, the only animals which had the locus coeruleus completely destroyed and did not circle contraversively in response to apomorphine and dexamphetamine all showed ipsiversive swiveling. These rats had considerably greater damage to the superior cerebellar peduncle than those showing such druginduced contraversive circling. Thus it seems that severe damage to this structure results in spontaneous ipsiversive rotation which inhibits the contraversive drug-induced circling seen after locus coeruleus lesions.
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In the more rostrally placed lesions, which were aimed at the noradrenergic bundles in the midbrain, there was a positive correlation between spontaneous contraversive spinning and damage to the ascending and crossing fibers of the superior cerebellar peduncle. Thus 12 of the 13 rats (92%) with definite damage to the fibers of the superior cerebellar peduncle showed this spontaneous turning and only one of the 13 (8%) animals with no spinning behavior had definite injury. It is possible that damage to the fibers of the superior cerebellar peduncle is the cause of the spontaneous spinning, but experimentally it is very difficult to be certain which of the many decussating fibers within this region belong to the peduncle. This is especially so in the rostra1 areas where the fibers are more dispersed and there are many other myelinated nerves crossing the midline. While it is possible in many cases to establish that damage is present, it is often difficult to be certain that injury has not occurred. In addition, the function of fibers may be impaired by edema from adjacent lesions without seeing evidence of this on light microscopy. It seems likely, therefore, that the incidence of damage to the peduncle would be underestimated by the histological assessment. Part of the uncertainty of the amount of damage to the superior cerebellar peduncle, particularly at the more rostra1 levels, may arise from the use of the Khiver-Barrera technique for assessing the areas of demyelination. With the long survival time of the rats following the lesioning procedure (2 to 3 months), an area of demyelination was taken to represent an area of degenerated axons. However, the histological sections stained with the Glees silver technique for intact axons from the group of rats receiving direct superior cerebellar peduncle lesions at the level of the locus coeruleus gave little additional information from the same sections stained for myelin. Another approach to the problem would have been the use of specific silver techniques to demonstrate areas of degenerating axons, although a shorter survival time would have been required. Such a procedure might have yielded more positive information about the extent of damage to the superior cerebellar peduncle. From the position of the degeneration seen in the rats with lesions aimed at the superior cerebellar peduncle at the level of the locus coeruleus it was apparent that the fibers decussated between the sections corresponding to a A 620 p and A 1270 p of K&rig and Klippel (8). The lesions aimed at the ventral noradrenergic bundle, which involved fibers of the peduncle, were situated at and rostra1 to this level. There is a specific topographic arrangement of fibers within the mammalian superior cerebellar peduncle (2). Damage to the peduncle in rats with locus coeruleus lesions affected mainly medial fibers, whereas that seen in lesions aimed at the ventral noradrenergic bundle involved the lateral fibers at and rostra1
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to the decussation. If these fibers maintained their mediolateral positions relative to each other throughout the decussation, these two types of lesions could be affecting the same fibers at the two different levels. Thus they could produce spontaneous ipsiversive turning with lesions caudal to the decussation, and spontaneous contraversive rotation with lesions rostra1 to it. In support of the hypothesis that damage to the superior cerebellar peduncle can produce such rotation, it should be mentioned that Carrea and Mettler (2) noticed occasional spontaneous ipsiversive circling in monkeys with damage to this structure, and that the direction of rotation changed if the injury was rostra1 to the decussation. This is also consistent with the results of Mussen (10) who found that eiectrical stimulation of the red nucleus in cats resulted in ipsiversive rotation with pivoting about the hind legs. This seems of a similar nature to the ipsiversive swiveling behavior seen in the present study in rats with peduncle damage incidental to locus coeruleus lesions. In attempting to make unilateral electrolytic lesions of the ascending noradrenergic system in the midbrain of rats, Marsden and Gulberg (9) noticed spontaneous contraversive turning which was potentiated by amphetamine into active rotation. They found that the potentiation was blocked by dopamine receptor blocking agents but that the spontaneous asymmetry was not. Those workers concluded that the spontaneous turning was due to damage to nonnoradrenergic structures but were unable to define them. As their maps show that the superior cerebellar peduncle was involved in the lesions this may well have been the cause of those observations. One striking difference between the two types of spontaneous turning associated with damage to the superior cerebellar peduncle is that the rotation occurring with the more caudally placed lesions was associated with body tilt and ataxia, whereas that occurring with the more rostrally cited injury did not show these features. It has been shown in monkeys that only damage to certain fibers within the superior cerebellar peduncle results in ataxia (2)) and that these fibers have a specific anatomical localization. They leave the peduncle before the red nucleus is reached and pass caudally toward the spinal cord. Thus the lack of unsteadiness in these spontaneously spinning rats with lesions rostra1 to the decussation does not exclude the possibility that the rotation is due to superior cerebellar peduncle damage as the fibers involved in the production of ataxia may have been spared by the laterally placed lesions. The evidence presented above suggests that the spontaneous contraversive rotation seen after electrolytic lesions of the midbrain is due to damage to fibers of the superior cerebellar peduncle. We have described elsewhere that electrolytic lesions involving the region of the dorsal noradrenergic bundle result in ipsiversive circling in response to systemically administered
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apomorphine or dexamphetamine (5). In the present study 23 of the electrolytic lesions also involved the area of the dorsal noradrenergic bundle, but only 13 of these rats showed such drug-induced ipsiversive rotation. There did not seem to be any difference in the amount of damage to the noradrenergic bundle areas between the rats which showed this ipsiversive rotation and those which did not. However, all ten animals in which the apomorphine- and dexamphetamine-induced response was absent displayed spontaneous contraversive spinning, whereas it was present in a weak form in only three of the 13 rats which circled ipsiversively after administration of these drugs. It thus seems likely that superior cerebellar peduncle damage at this level, with its associated contraversive rotation, can interfere with ipsiversive drug-induced circling. This effect is of a similar nature, but in the opposite direction, to the more caudally placed superior cerebellar peduncle damage inhibiting the contraversive rotation seen with locus coeruleus lesions. The results presented above suggest that unilateral damage to the superior cerebellar peduncle in rats can result in rotational behavior and that this need not be associated with other signs of peduncular injury. Such damage may modify the circling activity produced by lesions in other structures, and it is important to allow for the effect when assessing the results of unilateral brain stem lesions. Rotation produced by superior cerebellar peduncle injury has a characteristic appearance and this fact highhghts the need for careful observation of the nature of the circling behavior, rather than just assessments of the rate of rotation. REFERENCES N.-E., A. DAHLSTR~M, K. FUXE, and K. LARSSON. 1966. Functional role of the nigrostriatal dopamine neurons. Acta Pharmacol. Toxicol. 24: 263-274. CARREA, R. E. M., and F. A. METTLER. 1955. Function of the primate brachium conjunctivum and related structures. J. Co@. Neural. 102: 151-322. COOLS, A. R., and H.-J. JANSSEN. 1974. The nucleus linearia intermedium raphe and behaviour evoked by direct and indirect stimulation of the dopamine sensitive sites within the caudate nucleus of cats. Europ. J. Picarmacol. 28: 266-275. COSTALL, B., and R. J. NAYLOR. 1974. Stereotyped and circling behaviour induced by dopamine agonists after lesions of the midbrain raphe nuclei. Eur. J. Pharmcol. 29 : 206-222. DONALDSON, I. MAcG., A. C. DOLPHIN, P. JENNER, C. PYCOCK, and C. D. MARSDEN. 1976. Rotational behaviour produced in rats by electrolytic lesions of the ascending noradrenergic bundles. I. Lesions of the dorsal noradrenergic bundle. (Submitted for publication). JERUSSI, T. P., and S. D. GLICK. 1974. Amphetamine-induced rotation in rats without lesions. Neuropharmacology 13 : 283-286. JERUSSI, T. P., and S. D. GLICK. 1975. Apomorphine-induced rotation in normal rats and interaction with unilateral caudate lesions. Psychopharmacologia 40 : 329-334.
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8. KGNIG, J. F. R., and R. A. KLIPPEL. 1963. “The Rat Brain. A Stereotaxic Atlas.” Williams & Wilkins Baltimore. 9. MARSDEN, C. A., and H. C. GULDBERG. 1973. The role of monoamines in rotation induced or potentiated by amphetamine after nigral, raphe and mesencephalic reticular lesions in the rat brain. Neuro#hurmacology 12: 195-211. 10. MUSSEN, A. 1934. Cerebellum and red nucleus. Arch. Neural. Psych. 31: 110-126. 11. PYCOCK, C., I. MAcG. DONALDSON, and C. D. MARSDEN. 1975. Circling behaviour produced by unilateral lesions in the region of the lorus coeruleus in rats. Brain Res. 97: 317-329. 1.2. UNGERSTEDT, U. 1971. Stereotaxic mapping of the monoamine pathways in the rat brain. Acta Physiol. Stand. (Suppl.) 367 : 1118. 13. UNGERSTEDT, U. 1971. Striatal dopamine release after amphetamine or nerve degeneration revealed by hotational behaviour. Acta Physiol. Stand. (Suppl.) 367: 49-68. 14. UNGERSTEDT, U. 1971. Postsynaptic supersensitivity after 6-hydroxydopamine induced degeneration of the nigro-striatal dopamine system. Acta Physiol. Scared. (Suppl.) 367 : 69-93. 15. UNGERSTEDT, U., T. LJUNGBERG, B. HOFFER, and G. SICGENS. 1975. Dopaminergic supersensitivity in the striatum, pp. 57-65. In “Advances in Neurology,” vol. 9. D. B. Calne, T. N. Chase, ,and A. Barbeau [Eds.] Raven Press, New York.