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

Abstract

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...

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

“…The well-accepted mechanism of CCK-induced gastroinhibition suggests that CCK-8s activates C-type vagal afferent fibers via a paracrine mechanism, since capsaicin attenuates, or even abolishes, the effects of systemic CCK-8s (34,50,61). Several studies, however, have reported direct effects of CCK-8s on brain stem circuits (4,6,7,13,48,79). Our data imply that at least some of the effects of CCK-8s on gastric tone and the modulation of the esophageal-gastric reflex may be due to a direct effect of CCK-8s on brain stem neurocircuitry.…”

“…Behavioral, biochemical, and electrophysiological studies have shown that a relevant portion of the gastrointestinal effects of sulfated CCK (CCK-8s) are due to direct actions at the level of brain stem vagal circuits. In fact, CCK-8s acts on vagal afferent fibers that synapse on NTS neurons as well as at the level of subpopulations of NTS and DMV neurons (4,6,7,9,12,13,48,51,71,74,75,79). These studies suggest that functional CCK-A receptors are present on the membrane of subgroups of NTS and gastric-projecting DMV neurons.…”

Ongoing ingestive behavior is rapidly suppressed by a preabsorptive, intestinal “bitter taste” cue

“…Interestingly, however, as mentioned previously, application of DB to GI cells stimulates the release of CCK (8,18). While CCK is generally considered a satiety hormone that exerts its effects through both vagal and nonvagal (humoral) routes at various peripheral and central targets (3,27,34), it is also believed to convey stimulusspecific information in a paracrine fashion at local sensory afferent terminals (15,36). If CCK is involved as a critical chemosensory signaling component, then pretreatment with devazepide, a CCK-1R antagonist, should abolish the early response to intraduodenal DB, compared with pretreatment with its vehicle.…”

Presynaptic Melanocortin-4 Receptors on Vagal Afferent Fibers Modulate the Excitability of Rat Nucleus Tractus Solitarius Neurons

“…Surgical vagal deafferentation was achieved by sectioning the vagal afferent nerve rootlets (supranodose afferent rhizotomy) in six rats using a technique described previously Baptista et al, 2007). Rats were anesthetized with an intramuscular injection of a mixture of ketamine/xylazine/acepromazine (80, 1.6, 5 mg/ml/kg Ϫ1 , respectively) and placed in a stereotaxic frame.…”

“…Furthermore, the classical satiety hormone cholecystokinin (CCK) and the longer-lasting ␣MSH synthetic analog melanotan II (MTII) use the cAMP-ERK (extracellular signal-regulated kinase)-cAMP response elementbinding protein cascade in NTS circuits as a common pathway to integrate satiety signals from the gut and adiposity signals from the hypothalamus in the control of meal size and food intake (Sutton et al, 2005). We have also shown that CCK modulates NTScentralis neurons via an increase of glutamatergic synaptic inputs (Baptista et al, 2005a(Baptista et al, , 2007, an effect that occurs also in POMC neurons of the caudal NTS (Appleyard et al, 2005).…”