Cholecystokinin-induced excitation in the substantia nigra: evidence for peripheral and central components

Hommer, Daniel W.; Palkovits, M; Crawley, Jacqueline N.; Paul, Steven M.; Skirboll, L.R.

doi:10.1523/jneurosci.05-06-01387.1985

Cited by 80 publications

(21 citation statements)

References 19 publications

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“…In support of our findings, peripherally administered caerulein has been reported to reduce endogenous dopamine release in the striatum (Hamamura et al 1989). Hommer et al (1985) have reported that CCK has an excitatory action on neural firing rate in the substantia nigra following peripheral administration. This opposite effect of caerulein and CCK on nigral dopaminergic neurons may be ascribed to the difference in drugs, experimental conditions and methodology.…”

Section: Discussionsupporting

confidence: 89%

“…Peripheral administration of cholecystokinin evokes a number of behavioral effects, including satiety, decrease in exploratory behavior, sedation, and analgesia. Cholecystokinin octapeptide (CCK-8) decreases cerebral glucose metabolism in a characteristic pattern (Lucignani et al 1984) and has an excitatory action on neural firing rate in the mesencephalon following systemic administration (Skirboll et al 1981;Hommer et al 1985). Clinically, cholecystokinin (CCK) has been implicated in the etiology and treatment of schizophrenia.…”

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confidence: 99%

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Changes in GABA content and turnover in discrete regions of rat brain after systemic administration of caerulein

Nakamura¹,

Matsumoto

Hirano

et al. 1990

Psychopharmacology

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The effects of systemically injected caerulein, a cholecystokinin octapeptide analogue, on GABA content and turnover have been studied in various regions of rat brain. Caerulein decreased GABA levels in the nucleus accumbens, tuberculum olfactorium and substantia nigra and diminished GABA turnover rates in the striatum, nucleus accumbens and substantia nigra, as estimated from the rate of GABA accumulation after inhibition of GABA transaminase by aminooxyacetic acid (AOAA). These results indicate the effect of caerulein on the utilization of GABA in specific cerebral regions and suggest that the GABAergic system is involved in the mechanism of action of peripherally administered caerulein.

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Section: Discussionsupporting

confidence: 89%

mentioning

confidence: 99%

Changes in GABA content and turnover in discrete regions of rat brain after systemic administration of caerulein

Nakamura¹,

Matsumoto

Hirano

et al. 1990

Psychopharmacology

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“…Portions of the DVC, however, have a "leaky" blood-brain barrier (2,5,25,28), and several groups have provided functional evidence of a possible hormonal action of CCK to affect vagal neurons directly. More specifically, Hommer and colleagues (35) showed that sys- temic administration of CCK activates a NTS-nigral pathway, which is interrupted by lesion of the medulla but not of vagal afferent pathways. Similarly, the short-term satiety effects of CCK are antagonized by the blood-brain barrier-permeant CCK-A antagonist devazepide, but not by A-70104, a selective CCK-A antagonist that does not cross the blood-brain barrier (52).…”

Section: Discussionmentioning

confidence: 99%

Effects of brain stem cholecystokinin-8s on gastric tone and esophageal-gastric reflex

Holmes¹,

Tong²,

Travagli³

2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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Holmes GM, Tong M, Travagli RA. Effects of brain stem cholecystokinin-8s on gastric tone and esophageal-gastric reflex. Am J Physiol Gastrointest Liver Physiol 296: G621-G631, 2009. First published January 8, 2009 doi:10.1152/ajpgi.90567.2008.-The actions of cholecystokinin (CCK) on gastrointestinal functions occur mainly via paracrine effects on peripheral sensory vagal fibers, which engage vago-vagal brain stem circuits to convey effector responses back to the gastrointestinal tract. Recent evidence suggests, however, that CCK also affects brain stem structures directly. Many electrophysiological studies, including our own, have shown that brain stem vagal circuits are excited by sulfated CCK (CCK-8s) directly, and we have further demonstrated that CCK-8s induces a remarkable degree of plasticity in GABAergic brain stem synapses. In the present study, we used fasted, anesthetized Sprague-Dawley rats to investigate the effects of brain stem administration of CCK-8s on gastric tone before and after activation of the esophageal-gastric reflex. CCK-8s microinjected in the dorsal vagal complex (DVC) or applied on the floor of the fourth ventricle induced an immediate and transient decrease in gastric tone. Upon recovery of gastric tone to baseline values, the gastric relaxation induced by esophageal distension was attenuated or even reversed. The effects of CCK-8s were antagonized by vagotomy or fourth ventricular, but not intravenous, administration of the CCK-A antagonist lorglumide, suggesting a central, not peripheral, site of action. The gastric relaxation induced by DVC microinjection of CCK-8s was unaffected by pretreatment with systemic bethanecol but was completely blocked by N G -nitro-L-arginine methyl ester, suggesting a nitrergic mechanism of action. These data suggest that 1) brain stem application of CCK-8s induces a vagally mediated gastric relaxation; 2) the CCK-8s-induced gastric relaxation is mediated via activation of nonadrenergic, noncholinergic pathways; and 3) CCK-8s reverses the esophageal-gastric reflex transiently.vago-vagal reflexes; gastric reflexes ESOPHAGEAL DISTENSION has long been recognized to elicit a robust and reflexive gastric relaxation (21). Early models of gastrointestinal vago-vagal reflexes presented a framework to explain many of the features of the brain stem circuits devoted to gastric reflex control, whereby stimulation of sensory vagal afferent fibers activates second-order neurons of the nucleus tractus solitarii (NTS). Subsequently, these second-order neurons modulate the output of preganglionic neurons in the dorsal motor nucleus of the vagus (DMV) that, in turn, control gastric functions to complete the vago-vagal loop (reviewed in Ref. 72).The esophageal-gastric reflex (or receptive relaxation) decreases gastric tone and allows swallowed food to be transported to the stomach with a minimal increase in intragastric pressure. Neurophysiological studies by Jean first showed the association of neurons of the caudal brain stem with esophageal function (reviewed in Re...

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“…These morphological characteristics raise the possibility that NTS neuronal activity can be modulated by circulating molecules, including CCK. In fact, there is functional evidence that CCK can cross the BBB to activate a solitarius-nigral pathway (27), to phosphorylate CCK-A receptors in the DVC (65) and to induce short-term satiety (10).…”

Section: Discussionmentioning

confidence: 99%

Effects of cholecystokinin-8s in the nucleus tractus solitarius of vagally deafferented rats

Baptista¹,

Browning²,

Travagli³

2007

American Journal of Physiology-Regulatory, Integrative and Comp

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Baptista V, Browning KN, Travagli RA. Effects of cholecystokinin-8s in the nucleus tractus solitarius of vagally deafferented rats. Am J Physiol Regul Integr Comp Physiol 292: R1092-R1100, 2007. First published November 22, 2006; doi:10.1152/ajpregu.00517.2006.-We have shown recently that cholecystokinin octapeptide (CCK-8s) increases glutamate release from nerve terminals onto neurons of the nucleus tractus solitarius pars centralis (cNTS). The effects of CCK on gastrointestinal-related functions have, however, been attributed almost exclusively to its paracrine action on vagal afferent fibers. Because it has been reported that systemic or perivagal capsaicin pretreatment abolishes the effects of CCK, the aim of the present work was to investigate the response of cNTS neurons to CCK-8s in vagally deafferented rats. In surgically deafferented rats, intraperitoneal administration of 1 or 3 g/kg CCK-8s increased c-Fos expression in cNTS neurons (139 and 251% of control, respectively), suggesting that CCK-8s' effects are partially independent of vagal afferent fibers. Using whole cell patch-clamp techniques in thin brain stem slices, we observed that CCK-8s increased the frequency of spontaneous and miniature excitatory postsynaptic currents in 43% of the cNTS neurons via a presynaptic mechanism. In slices from deafferented rats, the percentage of cNTS neurons receiving glutamatergic inputs responding to CCK-8s decreased by ϳ50%, further suggesting that central terminals of vagal afferent fibers are not the sole site for the action of CCK-8s in the brain stem. Taken together, our data suggest that the sites of action of CCK-8s include the brain stem, and in cNTS, the actions of CCK-8s are not restricted to vagal central terminals but that nonvagal synapses are also involved. brain stem; electrophysiology; c-fos CHOLECYSTOKININ, WHICH IS released from intestinal cells following ingestion of nutrients (34,37,47), has profound effects on gastrointestinal functions. In fact, it is well known that cholecystokinin, and, in particular, the cleaved octapeptide cholecystokinin-8s (CCK-8s), induces vagally mediated gastric relaxation, increases pancreatic exocrine secretion, and induces short-term satiety (36,38,41,42,48,62).Many studies have proposed that the vagally mediated effects of CCK-8s are almost exclusively due to a paracrine action of CCK-8s on peripheral, capsaicin-sensitive vagal afferent fibers (8,14,41). This postulate stems mainly from the observations that C-fiber ablation induced by perivagal capsaicin treatment greatly attenuates, or abolishes altogether, the effects of systemic administration of CCK-8s on gastric motility, gastric acid secretion, and pancreatic exocrine secretion (32,33,41,58). One must keep in mind, however, that the localized perineural application involves the use of very high concentrations of capsaicin, usually 33 mM (i.e., 1% solution) (9,23,25,41,56,63,67). Such a high concentration of capsaicin raises the possibility that its observed effects are due to the toxic effects of massiv...

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Cholecystokinin-induced excitation in the substantia nigra: evidence for peripheral and central components

Cited by 80 publications

References 19 publications

Changes in GABA content and turnover in discrete regions of rat brain after systemic administration of caerulein

Changes in GABA content and turnover in discrete regions of rat brain after systemic administration of caerulein

Effects of brain stem cholecystokinin-8s on gastric tone and esophageal-gastric reflex

Effects of cholecystokinin-8s in the nucleus tractus solitarius of vagally deafferented rats

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