Acta physiol. scand. 1975. 94. 368-377 From the Department of Physiology, University of Goteborg, Sweden
Effects on Gastric Motility from the Cerebellar Fastigial Nucleus BY BJORNLISANDER AND JAN MARTNER Received 10 January 1975
Abstract LISANDER, B. and J. MARTNER. Effects on gastric motility from the cerebellar fastigial nucleus. Acta physiol. scand. 1975. 94. 368-377. In acute experiments on chloralosed cats gastric motility, blood pressure and heart rate were investigated for influences exerted by the fastigial nucleus. Besides pressor responses, fastigial stimulation could produce either gastric excitation o r relaxation and the background of these responses was analysed by selective nerve sectioning and administration of suitable autonomic blocking agents. Suppression of prevailing gastric motility was found to be mediated mainly by increased discharge in adrenergic nerve Fibres but also by adrenal catecholamine release. - Gastric excitation could be induced in three different ways, first oia increased activity invagal cholinergic fibres, second, by fastigial suppression of thevago-vagal non-adrenergic relaxatory reflex. In .addition, when laparotomy or other noxioiis abdominal stimuli had induced inhibitory gastric reflexes, the consequent sympathetic discharge could be suppressed by fastigial stimulation resulting in enhanced gastric motility. - The importance of background activity in the various nervous pathways for the fastigially induced gastric responses is discussed.
Central nervous control of gastric function has been extensively investigated and is well documented. Gastric motility may be influenced from various parts of the central nervous system, such as certain cortical structures, hypothalamus and brain stem (for details see Thomas and Baldwin 1968). Also the cerebellum seems to be involved in the control of gastric function, although only few studies have been carried out to elucidate this matter. Bard et al. (1947) reported that motion sickness in dogs is abolished by extirpation of the uvula and nodulus. Wolfe (1969) showed that gastric ulceration sometimes follows restricted cerebellar lesions in cats. Gastric motility can be influenced from the anterior lobe in rabbits (Ban et al. 1956) and from the vermis and the fastigial nucleus in cats (Manchanda, Tandon and Aneja 1972). In general, most visceral functions can be modified from the cerebellum and the fastigial nucleus seems to be especially potent in giving autonomic responses. Thus, powerful pressor responses can be elicited by electrical stimulation of the ventromedial part of the rostra1 fastigial pole (Achari and Downman 1969, Miura and Reis 1969). However, this area can influence also other autonomically innervated organs, e.g. the intestinal tract (Lisander and Martner 1974, Martner 1975 a) and the urinary bladder (Martner 1975 b). The findings 368
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presented in these studies indicated that an augmentation of intestinal motility could be induced by a fastigial suppression of the adrenergically mediated, intestino-intestinal inhibitory reflex. This reflex inhibits motility throughout the gastrointestinal tract following distension of any part of the intestine (cf Pearcy and Liere 1926, Youmans 1968). Besides intestinal distension, any noxious stimulus to the abdomen, including laparotomy, depresses gastrointestinal motility and this is here included in the term intestino-intestinal inhibitory reflexes. Studies on the stomach offer certain advantages in the further investigation of cerebellar influences on this type of reflex, which below will be referred to as the intestino-gastric inhibitory reflex as far as the stomach is concerned. In the first place, it is possible to record gastric motility without laparotomy, a procedure which inevitably elicits the intestinogastric inhibitory reflex. Second, background cholinergic tone, which is necessary for demonstrating this reflex (Jansson and Martinson 1966, Jansson and Lisander 1969), is much easier to control in the stomach, e.g. by graded efferent vagal stimulation, than in the intestines which usually display more irregular intrinsic activity. The present study was undertaken to investigate the fastigial influence on gastric motility and, if such an influence could be demonstrated, to analyse the nervous mechanisms involved.
Methods 43 cats of either sex, deprived of food for 24 h, were used for the experiments. After induction with ether, anesthesia was maintained by i.v. administration of chloralose, 50-60 mg/kg b.w. For stereotaxic stimulation, the head of the animal was fixed in a Horsley-Clarke apparatus. Following trephination and partial removal of the tentorium, sharp monopolar stainless steel electrodes were inserted perpendicularly to the stereotaxic horisontal plane. Square wave pulses were delivered by a constant current stimulator at intensities varying from 0.05 to 0.3 mA, corresponding to a voltage range of 1-4 V. Pulse duration was set a t 1 ms and the impulse frequency usually at 50 Hz after recordings of the frequency-response relationship a t 10 to 60 Hz. Decerebration was performed at the intercollicular level, either with a blunt spatula or by using high frequency electric coagulation by a stereotaxically inserted needle electrode. After each experiment a small lesion was made around the cerebellar electrode tip by anodal direct current of 1 mA for 10 s. The head of the animal was then perfused with saline followed by a 10% solution of formaldehyde. In 1/3 of the cats, the cerebellum and adjacent brain stem structures were paraffin embedded, sectioned in slices of 1 5 p m and stained by the Nissl technique. In the rest of the material the cerebellum was frozen sectioned and mounted without staining. In the latter way the precise location of the intercollicular lesion was determined as well. Intestino-gastric inhibitory reflexes were elicited either by laparotomy or by repeated injections of 0.1-1 ml of acid (0.1 M HCl) or alkali (0.1 M NaOH) through the abdominal wall. The vagal nerves were dissected free in the neck and often cut in the course of the experiment. Th e distal ends were then placed on bipolar ring electrodes for graded efferent stimulation. When instead the vago-vagal gastric relaxatory reflex was studied, one vagal nerve was left intact but the other one cut with the central end mounted on a bipolar electrode (for details see Jansson 1969 a) for afferent stimulation (10-20 Hz, 1-2 ms and 6-15 V). In other cats arrangements were made for reversible blockade of vagal transmission by temporary nerve cooling a t the neck level. Spinal cord transection was performed between C,-C, or between C,-Thl. In cats subject to laparotomy adrenal secretion was eliminated by encircling ligatures around both glands. Adrenocortical substitution was then given by i.v. injection of hydrocortisone (Solu-Gluc", Erco) 10 mg/kg. To allow for graded baroreceptor stimulation in some experiments one carotid sinus region was partly isolated and via a polyethylene tubing connected to one of the femoral arteries. A sigma motor perfusion pump could change the pressure in the sinus within wide limits, pressure being measured from a side branch close to the sinus by means of a P23 A C transducer. I n these experiments the contralateral sinus nerve and also the vagal nerves were sectioned thus eliminating other baroreceptor stations. 24 - 755877
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Arterial pressure was measured through a femoral catheter connected to a Statham P23 A C transducer writing o n a Grass polygraph and heart rate was recorded by a Grass Tachograph unit. Gastric motility was measured as volume changes in a large intragastric waterfilled balloon, inserted into the stomach via the esophagus. Via a large caliber tube the balloon was connected to a volume reservoir whose weight was continuously recorded by a Grass force displacement transducer FT03. Th e water level was adjusted to obtain a constant intragastric pressure of 5-10 cm H,O (for details see Jansson 1969 a). Gallamine iodide (FlaxediP) 4 mg/kg b.w. i.v. o r diallyl-bis-nor-toxoferine-dichloride(Alloferina, Roche) 0.1 mg/kg b.w. i.v. was often used to eliminate any artifacts due to somatomotor changes. Artificial respiration was then maintained by a respiratory pump. Pharmacological adrenergic blockade was induced by guanethidine (Ismelin@, CIBA) 4-5 mg/kg b.w. i.v., in some cats in combination with phentolamine (Regitin@,CIBA) 3 mgjkg b.w. i.v. and propranolol (InderaP, ICI) 0.5-1 mg/kg b.w. i.v. For cholinergic blockade atropine (atropine sulphate) 0.5-1 mg/kg b.w. i.v. or methylscopolamine (Skopyl", Pharmacia) 0.015-0.03 mg/kg b.w. i.v. were used.
Results Fastigial stimulation was found to influence gastric motility in various ways. Background gastric tone, which to a great extent depends on the preparation procedures, was an important factor in determining the response pattern. Therefore the experiments were subdivided into different groups, depending on the initial operation and subsequent experimental arrangements. 1 . Fastigial influence on gastric motility in intact cats
Out of a total number of 23 cats in this group, 11 dispIayed either increased or decreased gastric motility while the remainder showed a biphasic response pattern. In the latter group the sequence of the responses was always the same, i.e. an initial suppression followed by an increased gastric tone, even if the net response in some cats was dominated by inhibition and in others by excitation. If the latter group was added to those cats exhibiting uniform excitation and the former group included in the total number of cats displaying inhibition, each group contained about the same number of cats. Gastric relaxations induced by fastigial stimulation were either abolished or substantially reduced by parasympathetic blockade. Thus, atropine (1 cat) or vagotomy (4cats) eliminated the response, while the latter procedure in 3 other cats substantially reduced suppression of gastric motility. If the distal ends of the cut vagal nerves were stimulated, gastric vagal tone could be reestablished artificially and it was then again possible to demonstrate fastigially induced gastric relaxation. After administration of the adrenergic blocking agent guanethidine (7 cats) the gastric relaxations were abolished in 3 cats but persisted in 4 cats though reduced and delayed in onset, suggesting a hormonal mechanism. The disappearance of gastric relaxation after adrenergic blockade is illustrated in Fig. 1. Spinal cord transection in 2 cats, displaying a biphasic gastric response, abolished the inhibitory phase while the excitation persisted. Surprisingly, in one other cat spinal cord transection failed to abolish gastric relaxation which was instead blocked by atropine. Excitatory gastric responses were completely abolished by atropine ( 2 cats) or by vagotomy (4 cats) while spinal cord transection failed to do so (4cats). In the spinal cats, however, the gastric contractions were abolished by administration of atropine or methylscopolamine as is illustrated in Fig. 2. Also evident from this figure is the abolition of fastigially induced tachycardia.
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2. Fastigial influence on gastric motility in cats subject to laparotomy Laparotomy invariably induced a profound, adrenergically induced depression of gastric tone by the intestino-gastric inhibitory reflex. Independent of the type of fastigial response obtained before laparotomy the response pattern following this procedure was always that of excitation. The total number of cats in this group amounted to 14 if 5 cats receiving intraabdominal injections of acid or alkali (see later) were included. Bilateral vagotomy eliminated or reduced the excitatory responses to fastigial stimulation. However, the responses could always be restored or even potentiated if the distal ends of the cut vagal nerves and the fastigial nucleus were concomitantly stimulated. Fig. 3 clearly illustrates the importance of background vagal cholinergic activity. Fastigial stimulation in the absence of vagally induced gastric tone evokes no response while there is a substantial increase in gastric tone when fastigial stimulation is performed during concomitant vagal stimulation, usually the more so the higher the frequency of vagal stimulation up to about 6 Hz - If time was allowed to elapse after vagotomy, stomach motility often returned without vagal stimulation
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Fig. 2. Cat 3.6 kg; the spinal cord transected between C, and Th,. Fastigial stimulation (50 Hz;1 ms, 0.1 mA) produces an excitatory gastric response which is eliminated by subsequent administbation of methylscopolamine. ,, ,/
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Fig. 3. Cat 3.1 kg; vagotomized and laparotomized, with adrenals ligated. A: Fastigial stimulation (50 Hz, 1 ms, 0.2 mA) with and without efferent vagal nerve stimulation (6 Hz, 2 ms, 8 V). Note that gastric responses are only elicited against a background of vagal activity. B: When adrenergic inhibitory discharge is blocked by guanethidine, 4 mg/kg i.v., even low frequency vagal stimulation (4 Hz) induces the same level of gastric excitation that required a combined vagal and fastigial stimulation in A. Moreover, no fastigial effects can now be demonstrated.
and it was then again possible to enhance this motility by fastigial stimulation. Administration of acid (HCI) or alkali (NaOH) also induced a transient intestino-gastric inhibitory reflex, which could be abolished by guanethidine. When gastric tone was reflexly inhibited in this way, fastigial stimulation again induced excitatory gastric responses, evidently mediated by adrenergic mechanisms since they were eliminated by guanethidine (4 laparotomized cats and one injected with acid).
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Fig. 5. Frequency-response curves for fastigial stimulation, compiled from 11 cats comparing blood pressure rise, excitatory and inhibitory gastric responses. The excitations are in these cats due to suppression of the intestinogastric inhibitory reflex while gastric inhibitions are produced by increased adrenergic discharge. Note that all 3 curves follow a similar course. Bars indicate S.E.
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The excitatory gastric responses in laparotomized cats remained after decerebration (3 expts.). The fastigially induced gastric effects were not secondary to baroreceptor reflexes since the motility responses were not influenced by artificially varied carotid sinus pressure in three animals. 3. Fastigial influence on the uago-uagal nonadrenergic gastric relaxatory reflex
Electrical stimulation of the central end of one cut vagal nerve, with the other left intact, regularly induced profound and longlasting gastric relaxations that persisted after both adrenergic and cholinergic blockade (Jansson 1969 a). In 7 out of 9 cats treated with atropine and adrenergic blockade (6 cats treated by guanethidine and 3 by spinal cord section) it was possible to inhibit this vago-vagal gastric relaxation by fastigial stimulation. The range of fastigial inhibition varied from merely changing the speed of the gastric relaxation to almost complete blocking of the reflex (Fig. 4). In this experiment fastigial stimulation per se induced a modest but prolonged gastric relaxation, probably due to adrenal catecholamine release, and if this relaxation is taken into account (third signal in Fig. 4) the fastigial suppression of the vago-vagal reflex seems to be nearly complete. 4. Stimulus-response relationships
The fastigial pressor response displays a gradually rising frequency-response curve from 10 Hz up to 5 0 Hz which in most experiments was the optimal frequency level. When compared with the frequency-response curves for the fastigially induced gastric inhibitions and excitations, respectively, they show a conspicuous congruence in virtually all respects (Fig. 5). No difference in threshold could be observed for these three types of responses if instead current was varied. 5 . Responsive cerebellar structures Almost all gastric responses were elicited from the fastigial pressor area. As seen from Fig. 6, showing three frontal sections; 8 , 8.5 and 9 mm posterior to the interaural line, the signs
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Fig. 6. Frontal sections 8, 8.5 and 9 mm posterior to the interaural line. For the sake of clarity the same types of gastric responses are always gathered on the same side of the drawings. Open circles: N o response. Open triangles: Gastric relaxations. Open squares: Suppression of intestinogastric inhibitory reflex. Filled triangles: Gastric excitatory responses. Filled dots: Suppression of the vago-vagal inhibitory reflex. Nf, nucleus fastigius; N.i., Nucleus interpositus; N.d., Nucleus dentatus; V.q., Ventriculus quartus; N . v . ~ . ,Nucleus vestibularis lateralis.
representing effective stimulation points are localized in the rostra1 ventromedial part of the fastigial nucleus and adjacent cerebellar white matter anatomically corresponding to the fastigial pressor area. In only 3 cats clearcut excitatory gastric responses were obtained in the absence of a pressor response, all points localized dorsally to the pressor area. It was not possible demonstrate any anatomic separation between points giving different types of gastric responses, they were all intermingled and, moreover, from the same electrode position both excitatory and inhibitory gastric responses could be elicited in different phases of the experiment, depending on e.g. operative procedures.
Discussion Gastric motility was found to be influenced by the fastigial pressor area in a most complex way. Thus, in the anesthetized but otherwise intact animals, either increases or decreases in gastric tone could be elicited and biphasic responses were often seen, with an initial suppression followed by excitation. Concerning the excitatory gastric responses to fastigial stimulation seen in these intact animals they were, at least in part, mediated via the vagi and of cholinergic nature, since they were eliminated, or greatly reduced, by vagotomy or anticholinergic agents, but not by spinal cord section. The neurogenic sympathetic inhibitory influence on gastric motility is predominantly exerted by means of inhibitory connections with the intramural cholinergic excitatory neurons (e.g. Jansson and Martinson 1966). This was taken into account when the inhibitory gastric responses to fastigial stimulation were analysed. They were abolished by cholinergic
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blockade, or by vagotomy but reappeared if the peripheral ends of the cut vagi were stimulated simultaneously with the fastigial pressor area. After guanethidine the inhibitory responses were either abolished or reduced. In the latter case they appeared with a delay of about 20 s, indicating a hormonal mechanism, in all likelihood adrenal catecholamine release. It is known that guanethidine does not prevent adrenal catecholamine release whose peripheral effects are instead potentiated (Abercrornbie and Davies 1963). These findings clearly indicate that the relaxations from fastigial pressor area stimulation in intact animals were adrenergically mediated. Laparofomy profoundly changed the gastric responses to fastigial pressor area stirnulation. Noxious stimuli to the abdominal cavity, including laparotomy, intestinal distension etc. induce a marked, adrenergically mediated depression of gastric motility via intestino-gastric inhibitory reflexes. Independent of the direction of fastigially induced gastric responses seen before laparotomy, the animal always displayed excitatory gastric responses after this procedure. Such excitatory gastric responses might be explained either by increased activity in vagal cholinergic fibres, by an inhibition of adrenergic discharge or by a suppression of prevailing activity in the vagal relaxatory fibres (Martinson 1965). Again, the gastricexcitatory responses were abolished by vagotomy, or in some cases reduced. In the laparotomized cats, it was possible to increase gastric tone by fastigial stimulation even after bilateral vagotomy, provided that the distal ends of the vagal nerves were simultaneously stimulated but these gastric excitatory responses were abolished by guanethidine. This indicates that the excitatory responses seen in the laparotomized cats were due to fastigial suppression of a prevailing sympathetic influence on the stomach. This situation should be compared to that before laparotomy, where fastigial stimulation led to an increased sympathetic activity to the stomach in about half the animals. Evidently laparotomy caused an activation of the intestino-gastric inhibitory reflex and this reflex is inhibited from the fastigial pressor area. Further, when transient intestino-gastric inhibitory reflexes were induced by intraabdominal injections of irritant solutions, fastigial stimulation led to a gastric motility increase by suppressing this transient reflex, while the same fastigial stimulation produced motility inhibition as long as basal gastric motility was present. It is known that the intestinointestinal inhibitory reflex can be suppressed from supraspinal levels, e.g. from the medullary “depressor area” (Johansson, Jonsson and Ljung 1965, 1968). The arterial baroreceptors were, on the other hand, of no importance for the excitatory gastric responses induced by fastigial stimulation in laparotomized animals, even though they are activated along with the fastigial pressor response. The cerebellum has been found to influence also hypothalamically induced autonomic responses (Lisander and Martner 1971, 1973), and diencephalic lesions (Sawyer, Hilliard and Ban 1961) or precollicular decerebration (Ban et aZ. 1956) abolish some autonomic responses elicited from the cerebellum. On the other hand, the fastigial pressor response persists after midbrain transection (Miura and Reis 1969, Achari and Downman 1970) while fastigially induced effects on intravesical pressure were changed (Manchanda and Bhattarai 1972). In the present study, the fastigial inhibition of the intestino-gastric inhibitory reflex persisted after intercollicular decerebration indicating that the effects were not
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mediated v i a structures cranial to the midbrain. It is possible that the fastigial inhibition is mediated v i a the medullary “depressor area”, which, as mentioned, can suppress the spinally conveyed intestino-intestinal (gastric) reflexes. The possibility that the fastigial nucleus might increase gastric tone also by suppressing the discharge in the vagal relaxatory fibres was investigated in connection with their activation in vago-vagal reflexes. It was clearly demonstrated that this reflex could be inhibited by fastigial stimulation. This suppression was not exerted at the effector level by e.g. adrenergic or cholinergic mechanisms since the inhibition was still present after combined cholinergic (atropine) and adrenergic blockade (guanethidine or spinal cord transection). The vago-vagal relaxatory reflex is relayed in the lower brainstem since it is unaffected both by intercollicular decerebration and spinal cord transection at CI-C, (Jansson 1969 b). Evidence for a relay center for this reflex close to the obex has been presented by Nakazato and Ohga (1971) and the fastigial influence is likely to be exerted at this bulbar level. Histological examination revealed that the cerebellar area from which gastric responses could be elicited was quite restricted (Fig. 6). Although the intention was primarily to investigate the fastigial pressor area, considerable parts of the fastigial nucleus and adjacent cerebellar areas were stimulated before the pressor area was identified. However, it was a regular finding that the gastric effects were almost exclusively obtained from the fastigial pressor area. There were no signs of any gross anatomical differentiation between the points causing different types of gastric responses. The technique utilized, however, does not allow for a more detailed analysis of the neuron pools involved due to current spread, etc. The frequency-response curves (Fig. 5 ) representing the fastigially induced blood pressure rise, the gastric relaxation in intact animals and the suppression of the intestino-gastric inhibitory reflex all follow a similar course, suggesting that the neuron pools responsible for these effects operate through functionally similar mechanisms. The results indicate that the fastigial pressor area can induce gastric relaxation by increased adrenergic sympathetic discharge, and also by adrenal catecholamine release. Increased gastric tone can, on the other hand, be elicited via inhibition of the sympathetic intestino-gastric inhibitory reflex, by increasing vagal excitatory cholinergic discharge and also by inhibition of reflexly induced activity in the vagal relaxatory fibres. Neurogenic control of the stomach is most complex and exerted at several levels. Thus, intramural neurons give rise to a basic activity which is modified by intramural ganglionic, by spinal sympathetic and by bulbar vagal reflexes. Several parts of the central nervous system, not the least hypothalamic and cortical sections, are able to influence gastric motor activity. The question arises whether these higher autonomic “centres” exert their effects mainly, or only, by modifying the activity in reflexes affecting stomach motility. In the present experiments evidence was obtained indicating that the cerebellar fastigial nucleus is able to suppress two autonomic reflexes inhibiting the stomach. Further, if gastric motor activity was high, as in intact animals, the fastigial nucleus often lowered this basal (cholinergic) activity by inducing an increased sympathetic activity, perhaps by modulation of spinal sympathetic reflex arcs. In any case, the present study reveals that the cerebellum tends to increase gastric tone when it is low and decrease it when it is high. The results thus also stress the importance of the prevailing experimental conditions during explorations of central nervous control of autonomic mechanisms,
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This study has been sponsored by grants from the Swedish Medical Research Council(No. B74-14X-16-10C), from Svenska Sallskapet for Medicinsk Forskning and from the Faculty of Medicine, University of Goteborg.
References ABERCROMBIE, G. F. and B. N. DAVIES,The action of guanethidine with particular reference to the sympathetic nervous system. Brit. J. Pharmacol. 1963. 20. 171-177. Autonomic responses evoked by stimulation of fastigial nuclei ACHARI,N. K. and C. B. B. DOWNMAN, in the anaesthetized cat. J. Physiol. (Lond.) 1969. 204. 130P. Autonomic effector responses to stimulation of nucleus fastigius. ACHARI,N. K. and C. B. B. DOWNMAN, J. Physiol. (Lond.) 1970. 210. 637-650. BAN, T., K. INOUE,S. OZAKIand T. KUROTSU,Interrelation between anterior lobe of cerebellum and hypothalamus in rabbit. Med. J. Osaka Uniu. 1956. 7. 101-115. R. S. SNIDER,V. B. MOUNTCASTLE and R. B. BROMILEY, Delimitation of central BARD,P., C. N. WOOLSEY, nervous mechanisms involved in motion sickness. Fed. Proc. 1947. 6. 72. G., Vago-vagal reflex relaxation of the stomach in the cat. Actaphysiol. scand. 1969 a. 75.245-252. JANSSON, JANSSON, G., Extrinsic nervous control of gastric motility. An experimental study in the cat. Acta physiol. scand. 1969 b. Suppl. 326. JANSSON,G . and B. LISANDER, On adrenergic influence on gastric motility in chronically vagotomized cats. Acta physiol. scand. 1969. 76. 463471. Studies o n the ganglionic site of action of sympathetic outflow to the JANSSON,G. and J. MARTINSON, stomach. Acta physiol, scand. 1966. 68. 184-192. and B. LJUNG, Supraspinal control of the intestino-intestinal inhibitory reflex. JOHANSSON, B., 0. JONSSON Acta physiol. scand. 1965. 63. 442-449. JOHANSSON, B., 0. JONSSON and B. LIUNG, Tonic supraspinal mechanisms influencing the intestinointestinal inhibitory reflex. Acta physiol. scand. 1968. 72. 200-204. LISANDER, B. and J. MARTNER, Cerebellar suppression of the autonomic components of the defence reaction. Acta physiol. scand. 1971. 81. 84-95. LISANDER, B. and J. MARTNER, Interaction between the fastigial pressor response and the defence reaction. Acta physiol. scand. 1973. 87. 359-367. LISANDER, B. and J. MARTNER, Influences on gastrointestinal and bladder motility by the fastigial nucleus. Acta physiol. scand. 1914. 90. 792-794. S. K. and R. BHATTARAI, Autonomic responses to stimulation of paleocerebellum-effects MANCHANDA, of intercollicular section. Indian J. Physiol. Pharmacol. 1972. 14. 329-338. S.K., 0. P. TANDON and I. S.ANEJA,Role of the cerebellum in the control of gastro-intestinal MANCHANDA, motility. J. Neural Transmission 1972. 33. 195-209. J., Studies on the efferent vagal control of the stomach. Actaphysiol. scand. 1965. 65. Suppl. MARTINSON, 255. MARTNER, J., Influences o n colonic and small intestinal motility by the cerebellar fastigial nucleus. Acta physiol. scand. 1975 a. 94. 82-94. MARTNER, J., Influences o n the defecation and micturition reflexes by the cerebellar fastigial nucleus. Acra physiol. scand. 1975 b. 94. 95-104. MIURA,M. and D. J. REIS, Cerebellum: A pressor response elicited from the fastigial nucleus and its efferent pathway in brainstem. Brain. Res. 1969. 13. 595-599. NAKAZATO, Y. and A. OHGA,Intramedullary pathways of the vago-vagal reflexes with special reference to those evoked by stimulation of the abdominal vagus. Jap. J. Physiol. 1971. 21. 175-188. J. F. and E. J. VAN LIERE,Studies on the visceral nervous system. XVII. Reflexes from thecolon. PEARCY, I. Reflexes to the stomach. Amer. J. Physiol. 1926. 78. 64-73. and T. BAN,Autonomic and EEG responses to cerebellar stimulation in rabbits. SAWYER, C . H., J. HILLIARD Amer. J. Physiol. 1961. 200. 405-412. THOMAS, J. E. and M. V. BALDWIN,Pathways and mechanisms of regulation of gastric motility. In: Handbook of Physiology. Sect. 6. Vol. 4. Washington. American Physiological Society. 1968. WOLFE,J. W., Chronic gastric ulceration associated with experimentally induced posterior cerebellar vermal lesions. Physiol. Behao. 1969. 4. 101 1-1013. W. J., Innervation of the gastro-intestinal tract. In: Handbook of Physiology. Sect. 6 . Vol. 4. YOUMANS, Washington. American Physiological Society. 1968.
Effects on Gastric Motility from the Cerebellar Fastigial Nucleus BY BJORNLISANDER AND JAN MARTNER Received 10 January 1975
Abstract LISANDER, B. and J. MARTNER. Effects on gastric motility from the cerebellar fastigial nucleus. Acta physiol. scand. 1975. 94. 368-377. In acute experiments on chloralosed cats gastric motility, blood pressure and heart rate were investigated for influences exerted by the fastigial nucleus. Besides pressor responses, fastigial stimulation could produce either gastric excitation o r relaxation and the background of these responses was analysed by selective nerve sectioning and administration of suitable autonomic blocking agents. Suppression of prevailing gastric motility was found to be mediated mainly by increased discharge in adrenergic nerve Fibres but also by adrenal catecholamine release. - Gastric excitation could be induced in three different ways, first oia increased activity invagal cholinergic fibres, second, by fastigial suppression of thevago-vagal non-adrenergic relaxatory reflex. In .addition, when laparotomy or other noxioiis abdominal stimuli had induced inhibitory gastric reflexes, the consequent sympathetic discharge could be suppressed by fastigial stimulation resulting in enhanced gastric motility. - The importance of background activity in the various nervous pathways for the fastigially induced gastric responses is discussed.
Central nervous control of gastric function has been extensively investigated and is well documented. Gastric motility may be influenced from various parts of the central nervous system, such as certain cortical structures, hypothalamus and brain stem (for details see Thomas and Baldwin 1968). Also the cerebellum seems to be involved in the control of gastric function, although only few studies have been carried out to elucidate this matter. Bard et al. (1947) reported that motion sickness in dogs is abolished by extirpation of the uvula and nodulus. Wolfe (1969) showed that gastric ulceration sometimes follows restricted cerebellar lesions in cats. Gastric motility can be influenced from the anterior lobe in rabbits (Ban et al. 1956) and from the vermis and the fastigial nucleus in cats (Manchanda, Tandon and Aneja 1972). In general, most visceral functions can be modified from the cerebellum and the fastigial nucleus seems to be especially potent in giving autonomic responses. Thus, powerful pressor responses can be elicited by electrical stimulation of the ventromedial part of the rostra1 fastigial pole (Achari and Downman 1969, Miura and Reis 1969). However, this area can influence also other autonomically innervated organs, e.g. the intestinal tract (Lisander and Martner 1974, Martner 1975 a) and the urinary bladder (Martner 1975 b). The findings 368
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presented in these studies indicated that an augmentation of intestinal motility could be induced by a fastigial suppression of the adrenergically mediated, intestino-intestinal inhibitory reflex. This reflex inhibits motility throughout the gastrointestinal tract following distension of any part of the intestine (cf Pearcy and Liere 1926, Youmans 1968). Besides intestinal distension, any noxious stimulus to the abdomen, including laparotomy, depresses gastrointestinal motility and this is here included in the term intestino-intestinal inhibitory reflexes. Studies on the stomach offer certain advantages in the further investigation of cerebellar influences on this type of reflex, which below will be referred to as the intestino-gastric inhibitory reflex as far as the stomach is concerned. In the first place, it is possible to record gastric motility without laparotomy, a procedure which inevitably elicits the intestinogastric inhibitory reflex. Second, background cholinergic tone, which is necessary for demonstrating this reflex (Jansson and Martinson 1966, Jansson and Lisander 1969), is much easier to control in the stomach, e.g. by graded efferent vagal stimulation, than in the intestines which usually display more irregular intrinsic activity. The present study was undertaken to investigate the fastigial influence on gastric motility and, if such an influence could be demonstrated, to analyse the nervous mechanisms involved.
Methods 43 cats of either sex, deprived of food for 24 h, were used for the experiments. After induction with ether, anesthesia was maintained by i.v. administration of chloralose, 50-60 mg/kg b.w. For stereotaxic stimulation, the head of the animal was fixed in a Horsley-Clarke apparatus. Following trephination and partial removal of the tentorium, sharp monopolar stainless steel electrodes were inserted perpendicularly to the stereotaxic horisontal plane. Square wave pulses were delivered by a constant current stimulator at intensities varying from 0.05 to 0.3 mA, corresponding to a voltage range of 1-4 V. Pulse duration was set a t 1 ms and the impulse frequency usually at 50 Hz after recordings of the frequency-response relationship a t 10 to 60 Hz. Decerebration was performed at the intercollicular level, either with a blunt spatula or by using high frequency electric coagulation by a stereotaxically inserted needle electrode. After each experiment a small lesion was made around the cerebellar electrode tip by anodal direct current of 1 mA for 10 s. The head of the animal was then perfused with saline followed by a 10% solution of formaldehyde. In 1/3 of the cats, the cerebellum and adjacent brain stem structures were paraffin embedded, sectioned in slices of 1 5 p m and stained by the Nissl technique. In the rest of the material the cerebellum was frozen sectioned and mounted without staining. In the latter way the precise location of the intercollicular lesion was determined as well. Intestino-gastric inhibitory reflexes were elicited either by laparotomy or by repeated injections of 0.1-1 ml of acid (0.1 M HCl) or alkali (0.1 M NaOH) through the abdominal wall. The vagal nerves were dissected free in the neck and often cut in the course of the experiment. Th e distal ends were then placed on bipolar ring electrodes for graded efferent stimulation. When instead the vago-vagal gastric relaxatory reflex was studied, one vagal nerve was left intact but the other one cut with the central end mounted on a bipolar electrode (for details see Jansson 1969 a) for afferent stimulation (10-20 Hz, 1-2 ms and 6-15 V). In other cats arrangements were made for reversible blockade of vagal transmission by temporary nerve cooling a t the neck level. Spinal cord transection was performed between C,-C, or between C,-Thl. In cats subject to laparotomy adrenal secretion was eliminated by encircling ligatures around both glands. Adrenocortical substitution was then given by i.v. injection of hydrocortisone (Solu-Gluc", Erco) 10 mg/kg. To allow for graded baroreceptor stimulation in some experiments one carotid sinus region was partly isolated and via a polyethylene tubing connected to one of the femoral arteries. A sigma motor perfusion pump could change the pressure in the sinus within wide limits, pressure being measured from a side branch close to the sinus by means of a P23 A C transducer. I n these experiments the contralateral sinus nerve and also the vagal nerves were sectioned thus eliminating other baroreceptor stations. 24 - 755877
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Arterial pressure was measured through a femoral catheter connected to a Statham P23 A C transducer writing o n a Grass polygraph and heart rate was recorded by a Grass Tachograph unit. Gastric motility was measured as volume changes in a large intragastric waterfilled balloon, inserted into the stomach via the esophagus. Via a large caliber tube the balloon was connected to a volume reservoir whose weight was continuously recorded by a Grass force displacement transducer FT03. Th e water level was adjusted to obtain a constant intragastric pressure of 5-10 cm H,O (for details see Jansson 1969 a). Gallamine iodide (FlaxediP) 4 mg/kg b.w. i.v. o r diallyl-bis-nor-toxoferine-dichloride(Alloferina, Roche) 0.1 mg/kg b.w. i.v. was often used to eliminate any artifacts due to somatomotor changes. Artificial respiration was then maintained by a respiratory pump. Pharmacological adrenergic blockade was induced by guanethidine (Ismelin@, CIBA) 4-5 mg/kg b.w. i.v., in some cats in combination with phentolamine (Regitin@,CIBA) 3 mgjkg b.w. i.v. and propranolol (InderaP, ICI) 0.5-1 mg/kg b.w. i.v. For cholinergic blockade atropine (atropine sulphate) 0.5-1 mg/kg b.w. i.v. or methylscopolamine (Skopyl", Pharmacia) 0.015-0.03 mg/kg b.w. i.v. were used.
Results Fastigial stimulation was found to influence gastric motility in various ways. Background gastric tone, which to a great extent depends on the preparation procedures, was an important factor in determining the response pattern. Therefore the experiments were subdivided into different groups, depending on the initial operation and subsequent experimental arrangements. 1 . Fastigial influence on gastric motility in intact cats
Out of a total number of 23 cats in this group, 11 dispIayed either increased or decreased gastric motility while the remainder showed a biphasic response pattern. In the latter group the sequence of the responses was always the same, i.e. an initial suppression followed by an increased gastric tone, even if the net response in some cats was dominated by inhibition and in others by excitation. If the latter group was added to those cats exhibiting uniform excitation and the former group included in the total number of cats displaying inhibition, each group contained about the same number of cats. Gastric relaxations induced by fastigial stimulation were either abolished or substantially reduced by parasympathetic blockade. Thus, atropine (1 cat) or vagotomy (4cats) eliminated the response, while the latter procedure in 3 other cats substantially reduced suppression of gastric motility. If the distal ends of the cut vagal nerves were stimulated, gastric vagal tone could be reestablished artificially and it was then again possible to demonstrate fastigially induced gastric relaxation. After administration of the adrenergic blocking agent guanethidine (7 cats) the gastric relaxations were abolished in 3 cats but persisted in 4 cats though reduced and delayed in onset, suggesting a hormonal mechanism. The disappearance of gastric relaxation after adrenergic blockade is illustrated in Fig. 1. Spinal cord transection in 2 cats, displaying a biphasic gastric response, abolished the inhibitory phase while the excitation persisted. Surprisingly, in one other cat spinal cord transection failed to abolish gastric relaxation which was instead blocked by atropine. Excitatory gastric responses were completely abolished by atropine ( 2 cats) or by vagotomy (4 cats) while spinal cord transection failed to do so (4cats). In the spinal cats, however, the gastric contractions were abolished by administration of atropine or methylscopolamine as is illustrated in Fig. 2. Also evident from this figure is the abolition of fastigially induced tachycardia.
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2. Fastigial influence on gastric motility in cats subject to laparotomy Laparotomy invariably induced a profound, adrenergically induced depression of gastric tone by the intestino-gastric inhibitory reflex. Independent of the type of fastigial response obtained before laparotomy the response pattern following this procedure was always that of excitation. The total number of cats in this group amounted to 14 if 5 cats receiving intraabdominal injections of acid or alkali (see later) were included. Bilateral vagotomy eliminated or reduced the excitatory responses to fastigial stimulation. However, the responses could always be restored or even potentiated if the distal ends of the cut vagal nerves and the fastigial nucleus were concomitantly stimulated. Fig. 3 clearly illustrates the importance of background vagal cholinergic activity. Fastigial stimulation in the absence of vagally induced gastric tone evokes no response while there is a substantial increase in gastric tone when fastigial stimulation is performed during concomitant vagal stimulation, usually the more so the higher the frequency of vagal stimulation up to about 6 Hz - If time was allowed to elapse after vagotomy, stomach motility often returned without vagal stimulation
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Fig. 2. Cat 3.6 kg; the spinal cord transected between C, and Th,. Fastigial stimulation (50 Hz;1 ms, 0.1 mA) produces an excitatory gastric response which is eliminated by subsequent administbation of methylscopolamine. ,, ,/
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Fig. 3. Cat 3.1 kg; vagotomized and laparotomized, with adrenals ligated. A: Fastigial stimulation (50 Hz, 1 ms, 0.2 mA) with and without efferent vagal nerve stimulation (6 Hz, 2 ms, 8 V). Note that gastric responses are only elicited against a background of vagal activity. B: When adrenergic inhibitory discharge is blocked by guanethidine, 4 mg/kg i.v., even low frequency vagal stimulation (4 Hz) induces the same level of gastric excitation that required a combined vagal and fastigial stimulation in A. Moreover, no fastigial effects can now be demonstrated.
and it was then again possible to enhance this motility by fastigial stimulation. Administration of acid (HCI) or alkali (NaOH) also induced a transient intestino-gastric inhibitory reflex, which could be abolished by guanethidine. When gastric tone was reflexly inhibited in this way, fastigial stimulation again induced excitatory gastric responses, evidently mediated by adrenergic mechanisms since they were eliminated by guanethidine (4 laparotomized cats and one injected with acid).
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Fig. 5. Frequency-response curves for fastigial stimulation, compiled from 11 cats comparing blood pressure rise, excitatory and inhibitory gastric responses. The excitations are in these cats due to suppression of the intestinogastric inhibitory reflex while gastric inhibitions are produced by increased adrenergic discharge. Note that all 3 curves follow a similar course. Bars indicate S.E.
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The excitatory gastric responses in laparotomized cats remained after decerebration (3 expts.). The fastigially induced gastric effects were not secondary to baroreceptor reflexes since the motility responses were not influenced by artificially varied carotid sinus pressure in three animals. 3. Fastigial influence on the uago-uagal nonadrenergic gastric relaxatory reflex
Electrical stimulation of the central end of one cut vagal nerve, with the other left intact, regularly induced profound and longlasting gastric relaxations that persisted after both adrenergic and cholinergic blockade (Jansson 1969 a). In 7 out of 9 cats treated with atropine and adrenergic blockade (6 cats treated by guanethidine and 3 by spinal cord section) it was possible to inhibit this vago-vagal gastric relaxation by fastigial stimulation. The range of fastigial inhibition varied from merely changing the speed of the gastric relaxation to almost complete blocking of the reflex (Fig. 4). In this experiment fastigial stimulation per se induced a modest but prolonged gastric relaxation, probably due to adrenal catecholamine release, and if this relaxation is taken into account (third signal in Fig. 4) the fastigial suppression of the vago-vagal reflex seems to be nearly complete. 4. Stimulus-response relationships
The fastigial pressor response displays a gradually rising frequency-response curve from 10 Hz up to 5 0 Hz which in most experiments was the optimal frequency level. When compared with the frequency-response curves for the fastigially induced gastric inhibitions and excitations, respectively, they show a conspicuous congruence in virtually all respects (Fig. 5). No difference in threshold could be observed for these three types of responses if instead current was varied. 5 . Responsive cerebellar structures Almost all gastric responses were elicited from the fastigial pressor area. As seen from Fig. 6, showing three frontal sections; 8 , 8.5 and 9 mm posterior to the interaural line, the signs
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p Im -/
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I.
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I I I
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/
!
Fig. 6. Frontal sections 8, 8.5 and 9 mm posterior to the interaural line. For the sake of clarity the same types of gastric responses are always gathered on the same side of the drawings. Open circles: N o response. Open triangles: Gastric relaxations. Open squares: Suppression of intestinogastric inhibitory reflex. Filled triangles: Gastric excitatory responses. Filled dots: Suppression of the vago-vagal inhibitory reflex. Nf, nucleus fastigius; N.i., Nucleus interpositus; N.d., Nucleus dentatus; V.q., Ventriculus quartus; N . v . ~ . ,Nucleus vestibularis lateralis.
representing effective stimulation points are localized in the rostra1 ventromedial part of the fastigial nucleus and adjacent cerebellar white matter anatomically corresponding to the fastigial pressor area. In only 3 cats clearcut excitatory gastric responses were obtained in the absence of a pressor response, all points localized dorsally to the pressor area. It was not possible demonstrate any anatomic separation between points giving different types of gastric responses, they were all intermingled and, moreover, from the same electrode position both excitatory and inhibitory gastric responses could be elicited in different phases of the experiment, depending on e.g. operative procedures.
Discussion Gastric motility was found to be influenced by the fastigial pressor area in a most complex way. Thus, in the anesthetized but otherwise intact animals, either increases or decreases in gastric tone could be elicited and biphasic responses were often seen, with an initial suppression followed by excitation. Concerning the excitatory gastric responses to fastigial stimulation seen in these intact animals they were, at least in part, mediated via the vagi and of cholinergic nature, since they were eliminated, or greatly reduced, by vagotomy or anticholinergic agents, but not by spinal cord section. The neurogenic sympathetic inhibitory influence on gastric motility is predominantly exerted by means of inhibitory connections with the intramural cholinergic excitatory neurons (e.g. Jansson and Martinson 1966). This was taken into account when the inhibitory gastric responses to fastigial stimulation were analysed. They were abolished by cholinergic
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blockade, or by vagotomy but reappeared if the peripheral ends of the cut vagi were stimulated simultaneously with the fastigial pressor area. After guanethidine the inhibitory responses were either abolished or reduced. In the latter case they appeared with a delay of about 20 s, indicating a hormonal mechanism, in all likelihood adrenal catecholamine release. It is known that guanethidine does not prevent adrenal catecholamine release whose peripheral effects are instead potentiated (Abercrornbie and Davies 1963). These findings clearly indicate that the relaxations from fastigial pressor area stimulation in intact animals were adrenergically mediated. Laparofomy profoundly changed the gastric responses to fastigial pressor area stirnulation. Noxious stimuli to the abdominal cavity, including laparotomy, intestinal distension etc. induce a marked, adrenergically mediated depression of gastric motility via intestino-gastric inhibitory reflexes. Independent of the direction of fastigially induced gastric responses seen before laparotomy, the animal always displayed excitatory gastric responses after this procedure. Such excitatory gastric responses might be explained either by increased activity in vagal cholinergic fibres, by an inhibition of adrenergic discharge or by a suppression of prevailing activity in the vagal relaxatory fibres (Martinson 1965). Again, the gastricexcitatory responses were abolished by vagotomy, or in some cases reduced. In the laparotomized cats, it was possible to increase gastric tone by fastigial stimulation even after bilateral vagotomy, provided that the distal ends of the vagal nerves were simultaneously stimulated but these gastric excitatory responses were abolished by guanethidine. This indicates that the excitatory responses seen in the laparotomized cats were due to fastigial suppression of a prevailing sympathetic influence on the stomach. This situation should be compared to that before laparotomy, where fastigial stimulation led to an increased sympathetic activity to the stomach in about half the animals. Evidently laparotomy caused an activation of the intestino-gastric inhibitory reflex and this reflex is inhibited from the fastigial pressor area. Further, when transient intestino-gastric inhibitory reflexes were induced by intraabdominal injections of irritant solutions, fastigial stimulation led to a gastric motility increase by suppressing this transient reflex, while the same fastigial stimulation produced motility inhibition as long as basal gastric motility was present. It is known that the intestinointestinal inhibitory reflex can be suppressed from supraspinal levels, e.g. from the medullary “depressor area” (Johansson, Jonsson and Ljung 1965, 1968). The arterial baroreceptors were, on the other hand, of no importance for the excitatory gastric responses induced by fastigial stimulation in laparotomized animals, even though they are activated along with the fastigial pressor response. The cerebellum has been found to influence also hypothalamically induced autonomic responses (Lisander and Martner 1971, 1973), and diencephalic lesions (Sawyer, Hilliard and Ban 1961) or precollicular decerebration (Ban et aZ. 1956) abolish some autonomic responses elicited from the cerebellum. On the other hand, the fastigial pressor response persists after midbrain transection (Miura and Reis 1969, Achari and Downman 1970) while fastigially induced effects on intravesical pressure were changed (Manchanda and Bhattarai 1972). In the present study, the fastigial inhibition of the intestino-gastric inhibitory reflex persisted after intercollicular decerebration indicating that the effects were not
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mediated v i a structures cranial to the midbrain. It is possible that the fastigial inhibition is mediated v i a the medullary “depressor area”, which, as mentioned, can suppress the spinally conveyed intestino-intestinal (gastric) reflexes. The possibility that the fastigial nucleus might increase gastric tone also by suppressing the discharge in the vagal relaxatory fibres was investigated in connection with their activation in vago-vagal reflexes. It was clearly demonstrated that this reflex could be inhibited by fastigial stimulation. This suppression was not exerted at the effector level by e.g. adrenergic or cholinergic mechanisms since the inhibition was still present after combined cholinergic (atropine) and adrenergic blockade (guanethidine or spinal cord transection). The vago-vagal relaxatory reflex is relayed in the lower brainstem since it is unaffected both by intercollicular decerebration and spinal cord transection at CI-C, (Jansson 1969 b). Evidence for a relay center for this reflex close to the obex has been presented by Nakazato and Ohga (1971) and the fastigial influence is likely to be exerted at this bulbar level. Histological examination revealed that the cerebellar area from which gastric responses could be elicited was quite restricted (Fig. 6). Although the intention was primarily to investigate the fastigial pressor area, considerable parts of the fastigial nucleus and adjacent cerebellar areas were stimulated before the pressor area was identified. However, it was a regular finding that the gastric effects were almost exclusively obtained from the fastigial pressor area. There were no signs of any gross anatomical differentiation between the points causing different types of gastric responses. The technique utilized, however, does not allow for a more detailed analysis of the neuron pools involved due to current spread, etc. The frequency-response curves (Fig. 5 ) representing the fastigially induced blood pressure rise, the gastric relaxation in intact animals and the suppression of the intestino-gastric inhibitory reflex all follow a similar course, suggesting that the neuron pools responsible for these effects operate through functionally similar mechanisms. The results indicate that the fastigial pressor area can induce gastric relaxation by increased adrenergic sympathetic discharge, and also by adrenal catecholamine release. Increased gastric tone can, on the other hand, be elicited via inhibition of the sympathetic intestino-gastric inhibitory reflex, by increasing vagal excitatory cholinergic discharge and also by inhibition of reflexly induced activity in the vagal relaxatory fibres. Neurogenic control of the stomach is most complex and exerted at several levels. Thus, intramural neurons give rise to a basic activity which is modified by intramural ganglionic, by spinal sympathetic and by bulbar vagal reflexes. Several parts of the central nervous system, not the least hypothalamic and cortical sections, are able to influence gastric motor activity. The question arises whether these higher autonomic “centres” exert their effects mainly, or only, by modifying the activity in reflexes affecting stomach motility. In the present experiments evidence was obtained indicating that the cerebellar fastigial nucleus is able to suppress two autonomic reflexes inhibiting the stomach. Further, if gastric motor activity was high, as in intact animals, the fastigial nucleus often lowered this basal (cholinergic) activity by inducing an increased sympathetic activity, perhaps by modulation of spinal sympathetic reflex arcs. In any case, the present study reveals that the cerebellum tends to increase gastric tone when it is low and decrease it when it is high. The results thus also stress the importance of the prevailing experimental conditions during explorations of central nervous control of autonomic mechanisms,
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This study has been sponsored by grants from the Swedish Medical Research Council(No. B74-14X-16-10C), from Svenska Sallskapet for Medicinsk Forskning and from the Faculty of Medicine, University of Goteborg.
References ABERCROMBIE, G. F. and B. N. DAVIES,The action of guanethidine with particular reference to the sympathetic nervous system. Brit. J. Pharmacol. 1963. 20. 171-177. Autonomic responses evoked by stimulation of fastigial nuclei ACHARI,N. K. and C. B. B. DOWNMAN, in the anaesthetized cat. J. Physiol. (Lond.) 1969. 204. 130P. Autonomic effector responses to stimulation of nucleus fastigius. ACHARI,N. K. and C. B. B. DOWNMAN, J. Physiol. (Lond.) 1970. 210. 637-650. BAN, T., K. INOUE,S. OZAKIand T. KUROTSU,Interrelation between anterior lobe of cerebellum and hypothalamus in rabbit. Med. J. Osaka Uniu. 1956. 7. 101-115. R. S. SNIDER,V. B. MOUNTCASTLE and R. B. BROMILEY, Delimitation of central BARD,P., C. N. WOOLSEY, nervous mechanisms involved in motion sickness. Fed. Proc. 1947. 6. 72. G., Vago-vagal reflex relaxation of the stomach in the cat. Actaphysiol. scand. 1969 a. 75.245-252. JANSSON, JANSSON, G., Extrinsic nervous control of gastric motility. An experimental study in the cat. Acta physiol. scand. 1969 b. Suppl. 326. JANSSON,G . and B. LISANDER, On adrenergic influence on gastric motility in chronically vagotomized cats. Acta physiol. scand. 1969. 76. 463471. Studies o n the ganglionic site of action of sympathetic outflow to the JANSSON,G. and J. MARTINSON, stomach. Acta physiol, scand. 1966. 68. 184-192. and B. LJUNG, Supraspinal control of the intestino-intestinal inhibitory reflex. JOHANSSON, B., 0. JONSSON Acta physiol. scand. 1965. 63. 442-449. JOHANSSON, B., 0. JONSSON and B. LIUNG, Tonic supraspinal mechanisms influencing the intestinointestinal inhibitory reflex. Acta physiol. scand. 1968. 72. 200-204. LISANDER, B. and J. MARTNER, Cerebellar suppression of the autonomic components of the defence reaction. Acta physiol. scand. 1971. 81. 84-95. LISANDER, B. and J. MARTNER, Interaction between the fastigial pressor response and the defence reaction. Acta physiol. scand. 1973. 87. 359-367. LISANDER, B. and J. MARTNER, Influences on gastrointestinal and bladder motility by the fastigial nucleus. Acta physiol. scand. 1914. 90. 792-794. S. K. and R. BHATTARAI, Autonomic responses to stimulation of paleocerebellum-effects MANCHANDA, of intercollicular section. Indian J. Physiol. Pharmacol. 1972. 14. 329-338. S.K., 0. P. TANDON and I. S.ANEJA,Role of the cerebellum in the control of gastro-intestinal MANCHANDA, motility. J. Neural Transmission 1972. 33. 195-209. J., Studies on the efferent vagal control of the stomach. Actaphysiol. scand. 1965. 65. Suppl. MARTINSON, 255. MARTNER, J., Influences o n colonic and small intestinal motility by the cerebellar fastigial nucleus. Acta physiol. scand. 1975 a. 94. 82-94. MARTNER, J., Influences o n the defecation and micturition reflexes by the cerebellar fastigial nucleus. Acra physiol. scand. 1975 b. 94. 95-104. MIURA,M. and D. J. REIS, Cerebellum: A pressor response elicited from the fastigial nucleus and its efferent pathway in brainstem. Brain. Res. 1969. 13. 595-599. NAKAZATO, Y. and A. OHGA,Intramedullary pathways of the vago-vagal reflexes with special reference to those evoked by stimulation of the abdominal vagus. Jap. J. Physiol. 1971. 21. 175-188. J. F. and E. J. VAN LIERE,Studies on the visceral nervous system. XVII. Reflexes from thecolon. PEARCY, I. Reflexes to the stomach. Amer. J. Physiol. 1926. 78. 64-73. and T. BAN,Autonomic and EEG responses to cerebellar stimulation in rabbits. SAWYER, C . H., J. HILLIARD Amer. J. Physiol. 1961. 200. 405-412. THOMAS, J. E. and M. V. BALDWIN,Pathways and mechanisms of regulation of gastric motility. In: Handbook of Physiology. Sect. 6. Vol. 4. Washington. American Physiological Society. 1968. WOLFE,J. W., Chronic gastric ulceration associated with experimentally induced posterior cerebellar vermal lesions. Physiol. Behao. 1969. 4. 101 1-1013. W. J., Innervation of the gastro-intestinal tract. In: Handbook of Physiology. Sect. 6 . Vol. 4. YOUMANS, Washington. American Physiological Society. 1968.
