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Involvement of central noradrenergic pathways in the control of intestinal motility in rats
Neuroscience Letters, 90 (1988) 297-301 Elsevier Scientific Publishers Ireland Ltd.
297
NSL 05467
Involvement of central noradrenergic pathways in the control of intestinal motility in rats Marie Jos6 Fargeas, Jean Fioramonti and Lionel Burno Department of Pharmcology, 1NRA, Toulouse (France)
(Received 19 January 1988; Revised version received 30 March 1988; Accepted 13 April 1988) Key words: N-(2-Chloroethyl)-N-ethyl-2-bromobenzylamine; Noradrenergic innervation; Electromyography; Intestine; Rat
Small intestinal motility was monitored in conscious rats chronically fitted with intraparietal electrodes, the third and fourth weeks after intraperitoneal administration of saline (controls) or N-(2-chloro-ethyl)N-ethyl-2-bromobenzylamine (DSP-4, 50 mg/kg), a noradrenergic neurotoxin. Norepinephrine concentrations determined 35 days later in the forebrain and the brainstem were dramatically reduced in DSP-4treated rats. The frequency of intestinal cycles of motor activity observed after 15 h of fast was very irregular and significantly lower in DSP-4-treated rats. The disruption of the cyclic activity induced by feeding was uncomplete on the duodenum and significantly shorter on the jejunum after DSP-4 treatment. These data indicate that the central noradrenergic innervation plays an important role in the control of the small intestinal cyclic activity and its postprandial disruption. There is increasing evidence that the central nervous system plays a role in the control o f gastrointestinal motility and the importance o f ~-2 adrenergic receptors has been recently highlighted [4, 9]. ~t2-Adrenergic binding sites have been identified in the vagal dorsal m o t o r nucleus and the tractus solitarius which contain gastrointestinal afferents and efferents [13]. Clonidine, an ~2-adrenergic selective agonist reported to be a potent antidiarrheal drug [11], has been f o u n d to act centrally to inhibit the gastrointestinal transit in mice [9] and to disrupt the cyclic pattern o f intestinal motility (migrating myoelectric complexes, M M C ) in fasted rats [4]. Stimulation o f ~2-adrenoceptors is k n o w n to inhibit noradrenergic but also serotonergic neurons in brain [15] and consequently no firm conclusion a b o u t the role o f the noradrenergic innervation in the control o f intestinal motility can be d r a w n f r o m experiments performed with clonidine. A n o t h e r experimental a p p r o a c h could be the study o f the changes in intestinal motility occurring after destruction o f the central noradrenergic system. This can be achieved by using the noradrenergic neurotoxic agent DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine) [6, 10, 14]. This com-
Correspondence: M.J. Fargeas, Department of Pharmacology, INRA, 180 chemin de Tournefeuille, 31300 Toulouse, France.
0304-3940/88/$ 03.50 © 1988 Elsevier Scientific Publishers Ireland Ltd.
298 pound systemically administered produces a long-lasting degeneration of noradrenergic nerve terminals in the central nervous system while at the periphery, sympathetic adrenergic nerves recover to a large extent within a couple of weeks after DSP4 administration [2, 6, 14]. Moreover, DSP-4 has a very selective action on noradrenergic neurons leaving dopaminergic and serotonergic neurons unaffected [2]. Therefore we have compared in the present study the patterns of small intestinal motility in control and DSP-4-treated rats. Ten male Wistar rats weighing 300-350 g, individually housed and fed with a laboratory pellet rat diet, were used in these experiments. Five rats received DSP-4 hydrochloride (RBI, Wayland, MA) at a dose of 50 mg/kg, i.p., and 5 control rats received saline, i.p. Two weeks later, nichrome wire electrodes (60 cm in length and 80/tm in diameter) were implanted under halothane anesthesia in the wall of the duodeno-jejunum at 5, 15 and 30 cm from the pylorus. The electrode wires were exteriorized on the back of the neck and protected by a glass tube attached to the skin. Three weeks after DSP-4 or saline administration, the electrodes were connected to an electroencephalograph machine (Mini-Huit, Alvar, Paris) for electromyographic recording of intestinal motility for two weeks. Only bursts of spikes which correspond to intestinal contractions were recorded, using a short time constant (0.03 s). To permit a clear determination of the pattern of intestinal motility 24 h/day, the spiking activity was continuously summated every 20 s by an integrator circuit [12] connected with a potentiometric recorder at a low paper speed (6 cm/h). In each rat the pattern of intestinal motility was analyzed two times after a i 5-h period of fast and 3 times during the postprandial period following a 3-g chow meal given after 15 h of fast. On day 35 after DSP-4 or saline administration, rats were killed by decapitation, the forebrain and brainstem were removed and assayed for norepinephrine determination using a high-performance liquid chromatograph equipped with an electrochemical detector. The norepinephrine concentration was strongly diminished 35 days after DSP-4 administration: 23 ___9 and 42 4- 21 ng/g in forebrain and brainstem of DSP-4-treated rats vs 270 + 12 and 764 + 54 ng/g in control rats. In control rats, after 15 h of fasting, the myoelectric activity of the duodenum was organized as previously described [3], into migrating myoelectric complexes (MMC) recurring at 13.0___3.7 min intervals. Each MMC consisted of irregular spiking activity (phase II) for 4.9 + 0.6 followed by a period of intense and regular activity (phase I I I) lasting 4. i + 0.3 min. These phases of activity were separated by a period of quiescence (phase I). MMC which propelled the intestinal contents were propagated from the duodenum to the jejunum (Table I). In DSP-4-treated rats the time interval between two MMCs and the duration of the phase II were significantly increased (P < 0.001) by comparison with control rats. Similarly the duration of the phase III, on the jejunum but not on the duodenum, was significantly (P<0.001) lengthened after DSP-4 (Table I). Another important modification induced by DSP-4 was a greater variation in the period of MMCs (determined as the time elapsed between the ends of two consecutive phases III) and in the duration of the phases II and III as shown by coefficient of variation values indicated in Table I. Moreover, the variance of values of the 3 parameters (period,
299 TABLE I CHARACTERISTICS OF THE MIGRATING MYOLECTRIC COMPLEXES (MMC) IN CONTROL AND DSP-4-TREATED RATS FASTED FOR i 5 h The values are means+ S.D. in min and bracketed numbers are coefl]cients of variation. Period corresponds to the time elapsed between the ends of two consecutive phases III. MMC parameters
Duodenum
Period Duration of phase II Duration of phase III
Jejunum
Control
DSP-4
Control
DSP-4
13.1__+3.9 (29.6) 4.9+ 1.1 (22.1) 4.0+0.7 (I 7.5)
21.3__+12.4" (58.2) 15.4__+9.0" (58.5) 4.6+__2.0 (43.6)
14.1+3.0 (21.5) 4.3+0.9 (21.6) 3.9+0.6 ( 15.2)
25.7__+!7.1" (66.5) 16.4+ 12.2" (74.3) 5.7+ 1.9" (32.9)
*Significantly different from control (P < 0.001, n = 40, Mann-Whitney U-test).
CONTROL
OUOOEIK~
m i
•
I
i
4 WEEKS AFTER DSP4
__
,
,
j
=
~,,.o,b.h.,i.,IL,L
tMEAL
3g
i d~
~.'~
J,. .
r---1 ~
i
trT~n R
PI~
H
Ih
Fig. 1. Integrated records of small intestinal myoelectric activity in fasted and fed control and DSP-4treated rats. Each vertical deflection corresponds to the electrical spiking activity summated each 20 s through an integrator circuit and its height is proportional to the duration, the amplitude and the frequency of the intestinal spike bursts. The pattern of intestinal motility in fasted control rats consists of the regular succession of migrating myoelectric complexes (MMC) which is disrupted after a meal. The expanded record on the right indicates the 3 successive phases of the MMC and their propagation from the duodenum to the jejunum. Note, in the DSP-4-treated rat, the irregular occurrence of MMCs before the meal, the presence of phase III like activity on the duodenum after the meal, and the shorter postprandial disruption of the MMC pattern on the jejunum.
300 duration of phase II and phase III) were significantly different ( P < 0.002) between control and DSP-4-treated rats. A recent study [5] has shown that peripheral sympathectomy using 6-hydroxydopamine in guinea pigs did not abolish the MMCs but induced a decrease in their frequency associated with an increase in the duration of the phase II. These data and our results indicate that both peripheral and central noradrenergic innervation plays an important role in the regular occurrence of the MMCs. The second major change induced by DSP-4 on intestinal motility was observed in the postprandial period. In control rats, as previously described [3], a 3-g laboratory chow meal disrupted the MMC pattern which was replaced by a continuous presence of a phase II-iike activity for 172_+ 19 and 158_+ 12 min on the duodenum and the jejunum, respectively. As indicated in Fig. 1, phase III-like activities persisted on the duodenum after the meal in DSP-4-treated rats. The duration of the postprandial disruption of MMC was significantly reduced (P<0.001, n = 15) at the jejunal level, the first phase III appearing 94 + 23 min after the meal. These results indicate that the central noradrenergic innervation is involved in the postprandial changes in intestinal motility. However, an involvement of peripheral sympathetic neurons cannot be excluded since noradrenaline concentration has not been determined in peripheral tissue. Since a recovery of noradrenaline in peripheral organs has been described a few weeks after DSP-4 application in three different studies [2, 6, 14] performed in rats, it is very likely that the changes in postprandial intestinal motility observed after DSP-4 administration are of central origin. Previous data [4] indicate that intracerebroventricular administration of an ~2antagonist performed 1 h after a meal was able to restore a MMC pattern typical of the fasted state, suggesting that central ~2-adrenergic receptor stimulation is involved in the postprandial changes of the small intestinal motility. This result can be correlated with the important increase of the ~2-binding in the hypothalamus at the onset of the night, a time at which rats dramatically increase feeding [8]. Moreover food deprivation is known to reduce the population of ~2-receptors [7]. Our results showing a reduction of the intestinal motor response to eating in DSP-4treated rats may be explained by an alteration of ~2-receptors within the brain. On the other hand, it has been shown that the depletion of central norepinephrine induced by DSP-4 lead to an ~2-adrenergic receptor supersensitivity [2]. In this case, the postprandial motor response may be enhanced rather than shortened. Therefore our results lead to suppose an impaired response of central ~2-receptors rather than an ~2-receptor supersensitivity. Such an hypothesis is in agreement with another work [1] concluding to a functional subsensitivity of ~2-adrenoceptors in DSP-4-treated rats. Finally, our results indicate that the central noradrenergic innervation plays an important role in the regular occurrence of the small intestinal cyclic activity in the fasted state and in the postprandial changes of this activity. We thank Dr. R. Samanin from the Mario Negri Institute (Milan, Italy) for norepinephrine determination.
301 t Barbeito, L., Fernandez, C., Silveira, R. and Dajas, F., Evidences for a sympatho-adrenal dysfunction after lesion of the central noradrenergic pathways in rats, J. Neural Transm., 67 (1986) 205-214. 2 Dooley, D.J., Bittiger, U., Hauser, K.L., Bischoff, S.F. and Waldmeier, P.C., Alteration of central alpha 2 and beta adrenergic receptors in the rat after DSP-4, a selective noradrenergic neurotoxin, Neuroscience, 9 (1983) 889-898. 3 Fargeas, M.J., Fioramonti, J. and Bueno, L., Prostaglandin E2: a neuromodulator in the central control of gastrointestinal motility and feeding behavior by calcitonin, Science, 225 (1984) 1050-1052. 4 Fargeas, M.J., Fioramonti, J. and Bueno, L., Central ~2-adrenergic control of the pattern of small intestinal motility in rats, Gastroenterology, 91 (1986), 1470-1475. 5 Galligan, J.J., Furness, J.B. and Costa, M., Effects of cholinergic blockade, adrenergic blockade and sympathetic denervation on gastrointestinal myoelectric activity in guinea pig, J. Pharmacol. Exp. Ther., 228 (1986) 1114-1125. 6 Jaim-Etcheverry, G. and Zieher, L.M., DSP-4: a novel compound with neurotoxic effects on noradrenergic neurons of adult and developing rats, Brain Res., 128 (1980) 513-523. 7 Jhanwar-Uniyal, M. and Leibowitz, S.F., Impact of food deprivation on ~1- and ~2-noradrenergic receptors in the paraventricular nucleus and other hypothalamic areas, Brain Res., Bull., 17 (1986) 889-896. 8 Jhanwar-Uniyal, M., Roland, C.R. and Leibowitz, S.F., Diurnal rhythm of ~2-noradrenergic receptors in the paraventricular nucleus and other brain areas: relation to circulating corticosterone and feeding behavior, Life Sci., 38 (1986) 473-482. 9 Jiang, Q., Sheldon, R.J. and Porreca, F., Clonidine inhibits gastrointestinal transit primarily through central sites in the mouse, Gastroenterology, 92 (1987) 1454 (abstract). 10 Jonsson, G., Hallman, H., Ponzio, F. and Ross, S., DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine) - a useful denervation tool for central and peripheral noradrenaline neurons, Eur. J. Pharmacol., 72 (1981) 173-188. 11 Lal, H., Shearman, G.T. and Ursillo, R.C., Nonnarcotic antidiarrheal action of clonidine and lofexidine in the rat, J. Clin. Pharmacol., 21 (t981) 16-19. 12 Latour, A., Un dispositif simple d'analyse quantitative de l'61ectromyogramme intestinal chronique, Ann. Rech. Vet., 4 (1973) 347-353. 13 Robertson, H.A. and Leslie, R.A., Noradrenergic alpha 2 binding sites in vagal dorsal motor nucleus and nucleus tractus solitarius: autoradiographic localization, Can. J. Physiol. Pharmacol., 63 (1985) 1190-I 194. 14 Ross, S.B., Long-term effects of N-2-chloroethyl-N-ethyl-2-bromobenzylamine hydrochloride on noradrenergic neurones in the rat brain heart, Br. J. Pharmacol., 58 (1976) 521-257. 15 Svensson, T.H., Bunney, B.S. and Aghajanian, G.K., Inhibition of both noradrenergic and serotonergic neurons in brain by the atpha-adrenergic agonist clonidine, Brain Res., 92 (1975) 291-306.
297
NSL 05467
Involvement of central noradrenergic pathways in the control of intestinal motility in rats Marie Jos6 Fargeas, Jean Fioramonti and Lionel Burno Department of Pharmcology, 1NRA, Toulouse (France)
(Received 19 January 1988; Revised version received 30 March 1988; Accepted 13 April 1988) Key words: N-(2-Chloroethyl)-N-ethyl-2-bromobenzylamine; Noradrenergic innervation; Electromyography; Intestine; Rat
Small intestinal motility was monitored in conscious rats chronically fitted with intraparietal electrodes, the third and fourth weeks after intraperitoneal administration of saline (controls) or N-(2-chloro-ethyl)N-ethyl-2-bromobenzylamine (DSP-4, 50 mg/kg), a noradrenergic neurotoxin. Norepinephrine concentrations determined 35 days later in the forebrain and the brainstem were dramatically reduced in DSP-4treated rats. The frequency of intestinal cycles of motor activity observed after 15 h of fast was very irregular and significantly lower in DSP-4-treated rats. The disruption of the cyclic activity induced by feeding was uncomplete on the duodenum and significantly shorter on the jejunum after DSP-4 treatment. These data indicate that the central noradrenergic innervation plays an important role in the control of the small intestinal cyclic activity and its postprandial disruption. There is increasing evidence that the central nervous system plays a role in the control o f gastrointestinal motility and the importance o f ~-2 adrenergic receptors has been recently highlighted [4, 9]. ~t2-Adrenergic binding sites have been identified in the vagal dorsal m o t o r nucleus and the tractus solitarius which contain gastrointestinal afferents and efferents [13]. Clonidine, an ~2-adrenergic selective agonist reported to be a potent antidiarrheal drug [11], has been f o u n d to act centrally to inhibit the gastrointestinal transit in mice [9] and to disrupt the cyclic pattern o f intestinal motility (migrating myoelectric complexes, M M C ) in fasted rats [4]. Stimulation o f ~2-adrenoceptors is k n o w n to inhibit noradrenergic but also serotonergic neurons in brain [15] and consequently no firm conclusion a b o u t the role o f the noradrenergic innervation in the control o f intestinal motility can be d r a w n f r o m experiments performed with clonidine. A n o t h e r experimental a p p r o a c h could be the study o f the changes in intestinal motility occurring after destruction o f the central noradrenergic system. This can be achieved by using the noradrenergic neurotoxic agent DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine) [6, 10, 14]. This com-
Correspondence: M.J. Fargeas, Department of Pharmacology, INRA, 180 chemin de Tournefeuille, 31300 Toulouse, France.
0304-3940/88/$ 03.50 © 1988 Elsevier Scientific Publishers Ireland Ltd.
298 pound systemically administered produces a long-lasting degeneration of noradrenergic nerve terminals in the central nervous system while at the periphery, sympathetic adrenergic nerves recover to a large extent within a couple of weeks after DSP4 administration [2, 6, 14]. Moreover, DSP-4 has a very selective action on noradrenergic neurons leaving dopaminergic and serotonergic neurons unaffected [2]. Therefore we have compared in the present study the patterns of small intestinal motility in control and DSP-4-treated rats. Ten male Wistar rats weighing 300-350 g, individually housed and fed with a laboratory pellet rat diet, were used in these experiments. Five rats received DSP-4 hydrochloride (RBI, Wayland, MA) at a dose of 50 mg/kg, i.p., and 5 control rats received saline, i.p. Two weeks later, nichrome wire electrodes (60 cm in length and 80/tm in diameter) were implanted under halothane anesthesia in the wall of the duodeno-jejunum at 5, 15 and 30 cm from the pylorus. The electrode wires were exteriorized on the back of the neck and protected by a glass tube attached to the skin. Three weeks after DSP-4 or saline administration, the electrodes were connected to an electroencephalograph machine (Mini-Huit, Alvar, Paris) for electromyographic recording of intestinal motility for two weeks. Only bursts of spikes which correspond to intestinal contractions were recorded, using a short time constant (0.03 s). To permit a clear determination of the pattern of intestinal motility 24 h/day, the spiking activity was continuously summated every 20 s by an integrator circuit [12] connected with a potentiometric recorder at a low paper speed (6 cm/h). In each rat the pattern of intestinal motility was analyzed two times after a i 5-h period of fast and 3 times during the postprandial period following a 3-g chow meal given after 15 h of fast. On day 35 after DSP-4 or saline administration, rats were killed by decapitation, the forebrain and brainstem were removed and assayed for norepinephrine determination using a high-performance liquid chromatograph equipped with an electrochemical detector. The norepinephrine concentration was strongly diminished 35 days after DSP-4 administration: 23 ___9 and 42 4- 21 ng/g in forebrain and brainstem of DSP-4-treated rats vs 270 + 12 and 764 + 54 ng/g in control rats. In control rats, after 15 h of fasting, the myoelectric activity of the duodenum was organized as previously described [3], into migrating myoelectric complexes (MMC) recurring at 13.0___3.7 min intervals. Each MMC consisted of irregular spiking activity (phase II) for 4.9 + 0.6 followed by a period of intense and regular activity (phase I I I) lasting 4. i + 0.3 min. These phases of activity were separated by a period of quiescence (phase I). MMC which propelled the intestinal contents were propagated from the duodenum to the jejunum (Table I). In DSP-4-treated rats the time interval between two MMCs and the duration of the phase II were significantly increased (P < 0.001) by comparison with control rats. Similarly the duration of the phase III, on the jejunum but not on the duodenum, was significantly (P<0.001) lengthened after DSP-4 (Table I). Another important modification induced by DSP-4 was a greater variation in the period of MMCs (determined as the time elapsed between the ends of two consecutive phases III) and in the duration of the phases II and III as shown by coefficient of variation values indicated in Table I. Moreover, the variance of values of the 3 parameters (period,
299 TABLE I CHARACTERISTICS OF THE MIGRATING MYOLECTRIC COMPLEXES (MMC) IN CONTROL AND DSP-4-TREATED RATS FASTED FOR i 5 h The values are means+ S.D. in min and bracketed numbers are coefl]cients of variation. Period corresponds to the time elapsed between the ends of two consecutive phases III. MMC parameters
Duodenum
Period Duration of phase II Duration of phase III
Jejunum
Control
DSP-4
Control
DSP-4
13.1__+3.9 (29.6) 4.9+ 1.1 (22.1) 4.0+0.7 (I 7.5)
21.3__+12.4" (58.2) 15.4__+9.0" (58.5) 4.6+__2.0 (43.6)
14.1+3.0 (21.5) 4.3+0.9 (21.6) 3.9+0.6 ( 15.2)
25.7__+!7.1" (66.5) 16.4+ 12.2" (74.3) 5.7+ 1.9" (32.9)
*Significantly different from control (P < 0.001, n = 40, Mann-Whitney U-test).
CONTROL
OUOOEIK~
m i
•
I
i
4 WEEKS AFTER DSP4
__
,
,
j
=
~,,.o,b.h.,i.,IL,L
tMEAL
3g
i d~
~.'~
J,. .
r---1 ~
i
trT~n R
PI~
H
Ih
Fig. 1. Integrated records of small intestinal myoelectric activity in fasted and fed control and DSP-4treated rats. Each vertical deflection corresponds to the electrical spiking activity summated each 20 s through an integrator circuit and its height is proportional to the duration, the amplitude and the frequency of the intestinal spike bursts. The pattern of intestinal motility in fasted control rats consists of the regular succession of migrating myoelectric complexes (MMC) which is disrupted after a meal. The expanded record on the right indicates the 3 successive phases of the MMC and their propagation from the duodenum to the jejunum. Note, in the DSP-4-treated rat, the irregular occurrence of MMCs before the meal, the presence of phase III like activity on the duodenum after the meal, and the shorter postprandial disruption of the MMC pattern on the jejunum.
300 duration of phase II and phase III) were significantly different ( P < 0.002) between control and DSP-4-treated rats. A recent study [5] has shown that peripheral sympathectomy using 6-hydroxydopamine in guinea pigs did not abolish the MMCs but induced a decrease in their frequency associated with an increase in the duration of the phase II. These data and our results indicate that both peripheral and central noradrenergic innervation plays an important role in the regular occurrence of the MMCs. The second major change induced by DSP-4 on intestinal motility was observed in the postprandial period. In control rats, as previously described [3], a 3-g laboratory chow meal disrupted the MMC pattern which was replaced by a continuous presence of a phase II-iike activity for 172_+ 19 and 158_+ 12 min on the duodenum and the jejunum, respectively. As indicated in Fig. 1, phase III-like activities persisted on the duodenum after the meal in DSP-4-treated rats. The duration of the postprandial disruption of MMC was significantly reduced (P<0.001, n = 15) at the jejunal level, the first phase III appearing 94 + 23 min after the meal. These results indicate that the central noradrenergic innervation is involved in the postprandial changes in intestinal motility. However, an involvement of peripheral sympathetic neurons cannot be excluded since noradrenaline concentration has not been determined in peripheral tissue. Since a recovery of noradrenaline in peripheral organs has been described a few weeks after DSP-4 application in three different studies [2, 6, 14] performed in rats, it is very likely that the changes in postprandial intestinal motility observed after DSP-4 administration are of central origin. Previous data [4] indicate that intracerebroventricular administration of an ~2antagonist performed 1 h after a meal was able to restore a MMC pattern typical of the fasted state, suggesting that central ~2-adrenergic receptor stimulation is involved in the postprandial changes of the small intestinal motility. This result can be correlated with the important increase of the ~2-binding in the hypothalamus at the onset of the night, a time at which rats dramatically increase feeding [8]. Moreover food deprivation is known to reduce the population of ~2-receptors [7]. Our results showing a reduction of the intestinal motor response to eating in DSP-4treated rats may be explained by an alteration of ~2-receptors within the brain. On the other hand, it has been shown that the depletion of central norepinephrine induced by DSP-4 lead to an ~2-adrenergic receptor supersensitivity [2]. In this case, the postprandial motor response may be enhanced rather than shortened. Therefore our results lead to suppose an impaired response of central ~2-receptors rather than an ~2-receptor supersensitivity. Such an hypothesis is in agreement with another work [1] concluding to a functional subsensitivity of ~2-adrenoceptors in DSP-4-treated rats. Finally, our results indicate that the central noradrenergic innervation plays an important role in the regular occurrence of the small intestinal cyclic activity in the fasted state and in the postprandial changes of this activity. We thank Dr. R. Samanin from the Mario Negri Institute (Milan, Italy) for norepinephrine determination.
301 t Barbeito, L., Fernandez, C., Silveira, R. and Dajas, F., Evidences for a sympatho-adrenal dysfunction after lesion of the central noradrenergic pathways in rats, J. Neural Transm., 67 (1986) 205-214. 2 Dooley, D.J., Bittiger, U., Hauser, K.L., Bischoff, S.F. and Waldmeier, P.C., Alteration of central alpha 2 and beta adrenergic receptors in the rat after DSP-4, a selective noradrenergic neurotoxin, Neuroscience, 9 (1983) 889-898. 3 Fargeas, M.J., Fioramonti, J. and Bueno, L., Prostaglandin E2: a neuromodulator in the central control of gastrointestinal motility and feeding behavior by calcitonin, Science, 225 (1984) 1050-1052. 4 Fargeas, M.J., Fioramonti, J. and Bueno, L., Central ~2-adrenergic control of the pattern of small intestinal motility in rats, Gastroenterology, 91 (1986), 1470-1475. 5 Galligan, J.J., Furness, J.B. and Costa, M., Effects of cholinergic blockade, adrenergic blockade and sympathetic denervation on gastrointestinal myoelectric activity in guinea pig, J. Pharmacol. Exp. Ther., 228 (1986) 1114-1125. 6 Jaim-Etcheverry, G. and Zieher, L.M., DSP-4: a novel compound with neurotoxic effects on noradrenergic neurons of adult and developing rats, Brain Res., 128 (1980) 513-523. 7 Jhanwar-Uniyal, M. and Leibowitz, S.F., Impact of food deprivation on ~1- and ~2-noradrenergic receptors in the paraventricular nucleus and other hypothalamic areas, Brain Res., Bull., 17 (1986) 889-896. 8 Jhanwar-Uniyal, M., Roland, C.R. and Leibowitz, S.F., Diurnal rhythm of ~2-noradrenergic receptors in the paraventricular nucleus and other brain areas: relation to circulating corticosterone and feeding behavior, Life Sci., 38 (1986) 473-482. 9 Jiang, Q., Sheldon, R.J. and Porreca, F., Clonidine inhibits gastrointestinal transit primarily through central sites in the mouse, Gastroenterology, 92 (1987) 1454 (abstract). 10 Jonsson, G., Hallman, H., Ponzio, F. and Ross, S., DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine) - a useful denervation tool for central and peripheral noradrenaline neurons, Eur. J. Pharmacol., 72 (1981) 173-188. 11 Lal, H., Shearman, G.T. and Ursillo, R.C., Nonnarcotic antidiarrheal action of clonidine and lofexidine in the rat, J. Clin. Pharmacol., 21 (t981) 16-19. 12 Latour, A., Un dispositif simple d'analyse quantitative de l'61ectromyogramme intestinal chronique, Ann. Rech. Vet., 4 (1973) 347-353. 13 Robertson, H.A. and Leslie, R.A., Noradrenergic alpha 2 binding sites in vagal dorsal motor nucleus and nucleus tractus solitarius: autoradiographic localization, Can. J. Physiol. Pharmacol., 63 (1985) 1190-I 194. 14 Ross, S.B., Long-term effects of N-2-chloroethyl-N-ethyl-2-bromobenzylamine hydrochloride on noradrenergic neurones in the rat brain heart, Br. J. Pharmacol., 58 (1976) 521-257. 15 Svensson, T.H., Bunney, B.S. and Aghajanian, G.K., Inhibition of both noradrenergic and serotonergic neurons in brain by the atpha-adrenergic agonist clonidine, Brain Res., 92 (1975) 291-306.