Bilateral Subdiaphragmatic Vagotomy Research Articles

Splanchnic and vagal denervation attenuate central Fos but not AVP responses to intragastric salt in rats.

We have recently reported that an acute intragastric hypertonic saline load increases plasma arginine vasopressin (PAVP) and Fos immunoreactivity in several central nuclei, including the supraoptic nucleus (SON), paraventricular nucleus (PVN), nucleus of the solitary tract (NTS), area postrema (AP), and lateral parabrachial nucleus (LPBN). We hypothesized that these responses are mediated by stimulation of peripheral osmoreceptors with splanchnic and/or vagal afferent projections. To test this hypothesis, we examined the effect of bilateral subdiaphragmatic vagotomy and bilateral splanchnic denervation on the PAVP and Fos immunoreactivity responses to intragastric hypertonic saline infusion in awake rats. Compared with responses in sham rats, Fos immunoreactivity responses were significantly reduced in vagotomized rats in the AP, SON, and PVN, whereas normal Fos levels were observed in the LPBN. However, vagotomized rats exhibited a normal increase in PAVP. Splanchnic-denervated rats also exhibited similar changes in PAVP in response to intragastric hypertonic saline compared with sham-denervated rats, and no differences were observed in Fos immunoreactivity in the LPBN, SON, and PVN compared with sham rats. However, splanchnic-denervated rats were observed to have significantly lower Fos staining in the NTS and AP compared with sham rats. The inability of splanchnic or vagal denervation alone to block the PAVP response to intragastric hypertonic saline suggests that either peripheral osmoreceptors project via both splanchnic and vagal afferents to mediate AVP release or that the observed response of PAVP is due to the activation of central osmoreceptors in the absence of measurable changes in plasma osmolality.

Chronic central neuropeptide Y infusion in normal rats: status of the hypothalamo-pituitary-adrenal axis, and vagal mediation of hyperinsulinaemia.

Neuropeptide Y in the hypothalamus is a potent physiological stimulator of feeding, and may contribute to the characteristic metabolic defects of obesity when hypothalamic levels remain chronically elevated. Since corticosterone and insulin are important regulators of fuel metabolism, the longitudinal effects of chronic (6 days) intracerebroventricular infusion of neuropeptide Y in normal rats on the hypothalamo-pituitary-adrenal axis and on insulin secretion were studied. Neuropeptide Y-infused rats were either allowed to eat ad libitum, or were pair-fed with normophagic control rats. Neuropeptide Y increased the basal plasma concentrations of adrenocorticotropic hormone and corticosterone during the first 2 days of its intracerebroventricular infusion and increased cold stress-induced plasma adrenocorticotropic hormone concentrations. After 4-6 days of central neuropeptide Y infusion, however, basal plasma adrenocorticotropic hormone and corticosterone concentrations were no different from control values (except in ad libitum-fed rats in which corticosteronaemia remained elevated), they were unaffected by the stress of cold exposure, and the hypothalamic content of corticotropin-releasing factor immunoreactivity was significantly decreased. A state of hyperinsulinaemia was present throughout the 6 days of intracerebroventricular neuropeptide Y infusion, being more marked in the ad libitum-fed than in the pair-fed group. The proportions of insulin, proinsulin, and conversion intermediates in plasma and pancreas were unchanged. Hyperinsulinaemia of the pair-fed neuropeptide Y-infused rats was accompanied by muscle insulin resistance and white adipose tissue insulin hyperresponsiveness, as assessed by the in vivo uptake of 2-deoxyglucose. Finally, bilateral subdiaphragmatic vagotomy prevented both the basal and the marked glucose-induced hyperinsulinaemia of animals chronically infused with neuropeptide Y, demonstrating that central neuropeptide Y-induced hyperinsulinaemia is mediated by the parasympathetic nervous system.

Increased pancreatic islet blood flow in 48-hour glucose-infused rats: involvement of central and autonomic nervous systems.

The pancreatic islet blood flow of rats 24 h after a prolonged (48-h) glucose infusion was investigated using a nonradioactive microsphere technique. In the basal state, islet blood flow was significantly increased in previously hyperglycemic rats (HG) compared to that in controls (C). During an i.v. glucose challenge, both plasma insulin and islet blood flow were increased in the two groups, but these increases were significantly higher in HG than in C rats. Although less pronounced, the results were similar when glucose was injected into the carotid artery toward the brain at a dose that did not modify the peripheral glucose level. The effect of this intracarotid injection was abolished after bilateral subdiaphragmatic vagotomy in both C and HG rats. Furthermore, in the latter group, both plasma insulin concentration and islet blood flow returned to values similar to those observed in the basal state in C rats. After pretreatment with the alpha2-adrenoceptor agonist clonidine, the insulin response to the intracarotid glucose load was totally blunted in the two groups of rats. By contrast, whereas such a pretreatment lowered the glucose-induced increase in islet blood flow in C rats, it was without effect in HG rats. These data suggest that a period of hyperglycemia and/or hyperinsulinemia is sufficient to induce a perturbation of pancreatic islet blood flow, which appears to be mainly due to an increased parasympathetic activity, whereas the decrease in sympathetic tone does not play a role. These modifications in autonomic nervous system activity could be due to alterations in some brain areas involved in "glucose sensing."

Role of vagus nerves and gastrin in the gastric phase of acid secretion in male anesthetized rats.

We used the pylorus ligation model to determine the role of vagus nerves and gastrin in acid secretion induced by mechanical and chemical stimulation of the gastric lumen in anesthetized male rats. Gastric distension induced by intragastric instillation of saline resulted in a 17-fold increase in acid secretion over the basal level without an alteration in serum gastrin levels. Distension-stimulated acid secretion was inhibited by bilateral subdiaphragmatic vagotomy but not by CI-988, a gastrin receptor antagonist. Intragastric peptone produced a 71-fold increase in acid secretion over the basal level that was accompanied by a significant increase in serum gastrin levels. Whereas vagotomy almost abolished peptone-stimulated acid secretion, CI-988 inhibited peptone-stimulated acid secretion by only 50%. We conclude that the vagus nerves mediate acid secretion by mechanical and chemical stimulation and that gastrin mediates acid secretion partly by chemical stimulation but not by mechanical stimulation in anesthetized male rats.

Effect of bacterial lipopolysaccharide on gastric emptying of liquids in rats.

The objectives of the present investigation were 1) to study the effect of bacterial lipopolysaccharide (LPS) on rat gastric emptying (GE) and 2) to investigate a possible involvement of the vagus nerve in the gastric action of LPS. Endotoxin from E. coli (strain 055:B5) was administered sc, ip or iv to male Wistar rats (220-280 g body weight) at a maximum dose of 50 micrograms/kg animal weight. Control animals received an equivalent volume of sterile saline solution. At a given time period after LPS administration, GE was evaluated by measuring gastric retention 10 min after the orogastric infusion of a test meal (2 ml/100 g animal weight), which consisted of 0.9% NaCl plus the marker phenol red (6 mg/dl). One group of animals was subjected to bilateral subdiaphragmatic vagotomy or sham operation 15 days before the test. A significant delay in GE of the test meal was observed 5 h after iv administration of the endotoxin at the dose of 50 micrograms/kg animal weight. The LPS-induced delay of GE was detected as early as 30 min and up to 8 h after endotoxin administration. The use of different doses of LPS ranging from 5 to 50 micrograms/kg animal weight showed that the alteration of GE was dose dependent. In addition, vagotomized animals receiving LPS displayed a GE that was not significantly different from that of the sham control group. However, a participation of the vagus nerve in LPS-induced delay in GE could not be clearly demonstrated by these experiments since vagotomy itself induced changes in this gastric parameter. The present study provides a suitable model for identifying the mechanisms underlying the effects of LPS on gastric emptying.

Central vs. peripheral metabolic control of estrous cycles in Syrian hamsters. I. Lipoprivation.

Metabolic energy availability has profound effects on reproduction in a wide variety of species. We have been studying the effects of fasting on estrous cycles in Syrian hamsters as a model system for metabolic control of reproduction. In previous experiments, a 48-h period of fasting inhibited estrous cycles in lean, but not fat, hamsters. In fat hamsters the effects of fasting may have been offset by the presence of high circulating levels of free fatty acids mobilized from lipids in adipose tissue. Consistent with this idea fat hamsters treated with the inhibitor of fatty acid oxidation methyl palmoxirate (MP) showed fasting-induced anestrus. Experiment 1 was designed to examine whether vagally transmitted signals are critical for the inhibitory effects of fasting and MP treatment. Lean or fat hamsters that had received bilateral subdiaphragmatic vagotomy or sham surgery were fasted and treated with MP or vehicle. In vagotomized and sham-operated hamsters, estrous cycles were inhibited in lean fasted hamsters and in fat fasted hamsters treated with MP, but not in fat fasted hamsters treated with vehicle. Thus the results of experiment 1 indicated that vagally transmitted signals about peripheral fatty acid availability are not critical for the effects of these particular metabolic challenges on estrous cycles in Syrian hamsters. In experiment 2, hamsters without food were allowed to ingest pure glucose or fructose solutions or vegetable shortening. One-half of each group was treated with an inhibitor of glucose utilization, 2-deoxy-D-glucose (2-DG), or vehicle. If ingestion of fructose or shortening, but not glucose, had protected hamsters from 2-DG-induced anestrus, this might have indicated that peripheral fuel availability is critical for anestrus. On the contrary, 2-DG treatment induced anestrus regardless of the type of fuel ingested. Neither experiment yielded results that implicated changes in peripheral fuel availability as a critical signal in metabolic control of estrous cycles.

Subdiaphragmatic vagotomy does not attenuate c-Fos induction in the nucleus of the solitary tract after conditioned taste aversion expression

After acquisition of a conditioned taste aversion (CTA) against sucrose, intraoral infusions of sucrose induce c-Fos-like immunoreactivity (c-FLI) in the medial intermediate nucleus of the solitary tract (iNTS) of the rat. In order to determine if c-FLI expression in the iNTS depends on subdiaphragmatic vagal afferent input to the NTS secondary to gastrointestinal symptoms during CTA expression (e.g. diarrhea), we quantified the induction of c-FLI in the iNTS by sucrose infusions after total subdiaphragmatic vagotomy in rats with a previously acquired CTA against sucrose. Rats were conditioned against intraoral infusions of sucrose by pairing sucrose infusions with toxic LiCl injections. After CTA acquisition, rats underwent bilateral subdiaphragmatic vagotomy or were sham-vagotomized. One week after surgery, rats received an intraoral infusion of sucrose. One hour after the test infusion, rats were perfused and processed for c-FLI. Vagotomy had no apparent effect on the behavioral expression of the previously acquired CTA, because both vagotomized and sham-vagotomized rats rejected all of the test intraoral infusion of sucrose. There was also no significant difference between vagotomized and sham-vagotomized rats in the number of c-FLI-positive cells in the iNTS after CTA expression. We conclude that c-FLI induction correlated with CTA expression is not dependent on subdiaphragmatic vagal efferent output or afferent input.

Vagotomy blocks responses to vaginocervical stimulation after genitospinal neurectomy in rats

To ascertain whether any effects of vaginocervical stimulation (VS) are mediated by the vagus nerve, all known afferent nerves from the reproductive tract to the spinal cord were transected and the rats were tested for residual responses to VS. After combined bilateral transection of the pelvic, hypogastric, and pudendal nerves (NX), the following responses to VS were greatly reduced or abolished: lordosis to flank-perineum palpation, leg extension, immobilization, and blockage of both tail withdrawal to radiant heat and leg withdrawal to foot pinch. However, after these nerve cuts, the following persisted as significant residual responses to VS: 1) analgesia [measured as increase in vocalization threshold (VOCT) to tailshock], 2) pupil dilatation (PD), and 3) increase in heart rate (HR). Subsequent bilateral subdiaphragmatic vagotomy (VX) significantly reduced the magnitude of PD and abolished the analgesia. By contrast, VX produced no significant effect on the HR increase to VS. The above findings provide evidence that brain-mediated responses to vaginocervical stimulation can be elicited via the vagus nerves.

CCK-evoked hyperemia in rat gastric mucosa involves neural mechanisms and nitric oxide

This study was performed to identify the possible neural mechanisms and mediators that underlie the gastric mucosal hyperemia evoked by cholecystokinin octapeptide (CCK-8). Gastric mucosal blood flow in anesthetized rats was assessed by the clearance of hydrogen and gastric acid secretion determined in the luminally perfused stomach. The gastric mucosal hyperemic effect of a low dose of CCK-8 (0.04 nmol/min iv infusion for 7 min) was abolished by inhibition of nitric oxide synthesis with NG-nitro-L-arginine methyl ester (15 mg/kg iv) and significantly blunted by defunctionalization of afferent neurons with a neurotoxic dose of capsaicin (125 mg/kg sc). The hyperemic reaction to a high dose of CCK-8 (0.2 nmol/min) was not significantly affected by these pharmacological maneuvers. The vasodilator response to low-dose CCK-8 (0.04 nmol/min) was further analyzed and found to be inhibited by acute bilateral subdiaphragmatic vagotomy, atropine (1 mumol/kg ip), and the antagonistic calcitonin gene-related peptide (CGRP) fragment CGRP-(8-37) (6 nmol/ min ia). Cyclooxygenase inhibition with indomethacin (10 mg/kg ip) was ineffective. The CCK-8-induced increment of gastric acid secretion was not significantly altered by any of these procedures. These results indicate that the gastric vasodilator effect of submaximal doses of CCK-8 is brought about by a vagovagal reflex that involves acetylcholine, CGRP or a related peptide, and nitric oxide as vasodilator messengers.

Changes of the total water content and magnetic relaxation characteristics of the liver and small intestine in vagotomy

Bilateral subdiaphragmatic truncal vagotomy in rats results in a disturbance of water metabolism in the liver and small intestine which manifests itself in an increase of the total water content, prolongation of the spin-lattice and spin-spin relaxation, and in a distortion of the correlation between them. The dynamics of water metabolism is of a onepeak nature in the liver with a maximum after 7 days, whereas in the small intestine it is of a dual-peak type with peaks at 7 and 30 days. Near-normalization of the water balance in the digestive organs occurs 220 days later.

Microinjection of TRH analogue into the dorsal vagal complex stimulates pancreatic secretion in rats.

Thyrotropin-releasing hormone (TRH) stimulates pancreatic exocrine secretion through the vagus nerve when injected into rat cerebrospinal fluid. However, little is known about the exact site of action of TRH in the brain to stimulate pancreatic secretion. Recent neuroimmunochemical and neurophysiological studies suggest that TRH could be a neurotransmitter in the dorsal vagal complex, which sends fibers to the pancreas through the vagus nerve. We therefore hypothesized that TRH may act centrally in the dorsal vagal complex to stimulate pancreatic exocrine secretion. To address this question, a TRH analogue, [1-methyl-(S)-4,5-dihydroorotyl]-L-histidyl-L-prolinamide- NH2, was microinjected into the dorsal vagal complex, and basal pancreatic fluid flow and protein secretion were measured in urethan-anesthetized rats. Microinjection of TRH analogue (0.2-2 ng/site) into the dorsal vagal complex significantly stimulated pancreatic flow and protein output in a dose-dependent manner. As a control, microinjection of the TRH analogue into the brain stem outside the vagal complex failed to stimulate pancreatic secretion. Either bilateral subdiaphragmatic vagotomy or atropine abolished the ability of the TRH analogue to stimulate pancreatic secretion. Our data suggest that TRH acts in the dorsal vagal complex to stimulate pancreatic secretion through vagus-dependent and cholinergic pathways. The dorsal vagal complex may play an important role as a central site for control of the exocrine pancreas.

Medullary thyrotropin-releasing hormone mediates vagal-dependent adaptive gastric protection induced by mild acid in rats

Background & Aims : Adaptive gastric protection is dependent on vagal pathways in rats. It is hypothesized that medullary thyrotropin-releasing hormone (TRH), known to regulate vagal function, is part of the brain mechanisms mediating adaptive gastric protection. Methods : Urethane-anesthetized rats were pretreated with either acute bilateral subdiaphragmatic vagotomy, sham operation, or intracisternal injection of purified control, TRH, or peptide YY antibody. Gastric lesions were assessed 75 minutes after orogastric administration of 1 mL of either vehicle or 0.35N HCI followed 15 minutes later by 0.6N or 1.0N HCI. Results : Injection of 0.6N and 1.0N HCI induced gastric lesions covering 23.1% ± 2.7% and 37.8% ± 3.3% of the corpus mucosa, respectively. Pretreatment with 0.35N HCI resulted in 67.3% and 50.5% reductions in gastric lesions induced by 0.6N and 1.0N HCI, respectively. Subdiaphragmatic vagotomy or intracisternal injection of TRH antibody increased gastric lesions induced by 0.6N HCI to 32.2% ± 2.2% and 42.9% ± 5.6%, respectively, and completely abolished the protective effect of 0.35N HCI pretreatment. Control or peptide YY antibody injected intracisternally did not alter the gastric protection induced by mild acid. Conclusions : These results indicate that medullary TRH plays a role in the vagally mediated adaptive gastric protection induced by mild acid.

Neuronal regulation of the release and action of secretin-releasing peptide and secretin

The acid-stimulated release of secretin is mediated by a secretin-releasing peptide (SRP) in rats. In the present study we investigated to determine whether a neural mechanism(s) is involved in the regulation of release and action of SRP in anesthetized rats. A concentrated acid perfusate (CAP) containing SRP was obtained from donor rats. CAP administered to recipient rats significantly increased pancreatic flow volume (81.6 +/- 18.3%), bicarbonate output (188.7 +/- 15.6%), and plasma secretin level (from 0.9 +/- 0.2 to 4.4 +/- 0.5 pM). However, this effect was attenuated by CAP from donor rats pretreated with tetrodotoxin (TTX), propranolol, bilateral subdiaphragmatic vagotomy (BSV), or systemic and topical administration of capsaicin. In contrast, CAP from donor rats pretreated with phentolamine, atropine, or hexamethonium did not alter the increase in plasma secretin concentration and pancreatic secretion. Moreover, the action of CAP on secretin release was significantly inhibited in the recipient rats pretreated with TTX, BSV, and topical applications of capsaicin but was not suppressed in the recipient rats pretreated with atropine, hexamethonium, or propranolol. Furthermore, perivagal and duodenojejunal mucosal application of capsaicin abolished the pancreatic secretory response to secretin at 5 pmol.kg-1.h-1. In conclusion, the release and action of both SRP and secretin are mediated by a vagal afferent pathway. beta-Adrenergic receptors also play a significant role in the release of SRP.

Effects of vagotomy on cholecystokinin- and dexfenfluramine-induced fos-like immunoreactivity in the rat brain

This study compared the effects of bilateral subdiaphragmatic vagotomy on the Fos-like immunoreactivity (FLI), a marker of neuronal activation, in rat brain induced by two anorectic agents, cholecystokinin (CCK) and the serotonin agonist, dexfenfluramine (DFEN). In the nonvagotomized rats, both CCK (5 μg/kg, IP) and DFEN (2 mg/kg, IP) Induced FU in the nucleus of the solitary tract (MST), the external subdivision of the lateral parabrachial nuclei (LPBE), the lateral subdivision of the central amygdeloid nucleus (CeL), and the bed nucleus of the stria terminallis (BST). However, subregional distribution of the FLI induced by the two agents was different in most of these regions. Additionally, the area postrema and the medial subdivision of the hypothalamic paraventricular nucleus were preferentially activated by CCK but not DFEN, while the caudate-putemen was activated by DFEM but not CCK. Bilateral subdiaphragmatic vagotomy completely abolished CCK-induced FLI in all the brain regions but did not attenuate DFEN-Induced FLI in any of these regions, including the NST. The results of the present study suggest that DFEN-activation of the NST-LPBE-CeL/BST neuraxis is not mediated by the vague nerve. On the other hand, and consistent with a variety of other data, activation of various parts of the brain by peripherally administered CCK depends on a vagal pathway. These data are discussed in relation to a previously proposed interaction between CCK and serotonin in mediating satiety.

A method for selective section of vagal afferent or efferent axons in the rat.

Although normally a mixed nerve, intracranially the vagus separates into dorsal rootlets that contain afferent axons and ventral rootlets that contain efferents. Surgical procedures are described for exposing the ventral surface of the occipital bone at the level where the vagus passes through the posterior lacerated foramen. When the foramen is expanded medially and the dura lanced, the intracranial course of the vagus can be observed by use of an operating microscope. Under these conditions, either the efferent or the afferent rootlets can be severed selectively. When the dorsal rootlets are divided and the contralateral trunk is cut below the diaphragm, a selective bilateral subdiaphragmatic afferent vagotomy is produced with unilateral sparing of the efferents. Cutting the efferents intracranially has the converse effect.

Changes in islet blood flow in rats with NIDDM.

Islet blood flow was quantified in NIDDM rats either of the GK strain on after neonatal injection of STZ (n0-STZ), using the non-radioactive microsphere technique. In the basal state, there was a good correlation between plasma insulin level and islet blood flow, i.e. both were increased or decreased in comparison to those of control rats in GK and n0-STZ rats, respectively. The increased islet blood flow and plasma insulin levels observed in the GK rats were abolished by bilateral subdiaphragmatic vagotomy. During a glucose challenge, whereas plasma insulin and islet blood flow were doubled in control rats, these parameters were not modified in the diabetic rats. These data demonstrate an alteration in the islet blood flow of diabetic rats during a glucose challenge which could participate in the abnormal glucose-induced insulin secretion previously described in these two models.

Evidence that cholecystokinin induces immediate early gene expression in the brainstem, hypothalamus and amygdala of the rat by a CCK A receptor mechanism

The effect of sulphated cholecystokinin octapeptide (CCK-8S) on immediate early gene expression in the rat CNS was investigated using the technique of in situ hybridization. A rapid and transient induction of c- fos, NGFI-A and NGFI-B (nerve growth factor-induced genes A and B) mRNA was demonstrated in the nucleus tractus solitarius (NTS), area postrema (AP), hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei, and central nucleus of the amygdala, following peripheral administration of CCK-8S (1–100 μg/kg i.p.). In contrast, levels of c-jun, jun B and jun D mRNA were unaffected by the peptide. The closely related decapeptide, caerulein (50 mg/kg i.p.), induced the same pattern of IEG expression as CCK-8S, whereas the desulphated octapeptide, CCK-8DS (50 mg/kg i.p.), had no effect on levels of mRNA for any IEG studied. Expression of IEG mRNA in these areas was suppressed by bilateral subdiaphragmatic vagotomy, and by pretreatment with the selective CCK A receptor antagonist, devazepide (0.1 and 1 mg/kg i.p.). In contrast, CCK-8S induction of IEG mRNA was not blocked by pretreatment with the selective CCK B receptor antagonist, CI-988 (1 or 10 mg/kg i.p.). In addition, the selective CCK B receptor agonists, CCK-4 (50 μg/kg i.p.) or pentagastrin (2 mg/kg i.p.), failed to induce IEG expression in any of the areas studied. These results suggest that systemic CCK-8S primarily acts via CCK A receptors on vagal afferents to stimulate IEG mRNA expression in the rat CNS.

Effects of systematically administered ceruletide on the in vivo release and metabolism of dopamine in the medial prefrontal cortex of awake, freely moving rats: an in vivo microdialysis study

The effects of the cholecystokinin octapeptide-related peptide, ceruletide (CER), on the in vivo release and metabolism of dopamine (DA) in the medial prefrontal cortex were examined in awake, freely moving rats, using in vivo microdialysis. Subcutaneously administered CER (200 μg/kg) increased extracellular levels of DA, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA), indicating that extracellular levels of DOPAC and HVA may reflect DA release in the medial prefrontal cortex. Bilateral subdiaphragmatic vagotomy markedly attenuated the CER-induced effect, but did not abolish it completely. CER (10 −7 and 10 −10 M), applied locally via the dialysis tube, had no effect on the extracellular levels of either DOPAC or HVA. The CCK-A receptor antagonist, L-364,718 (3 mg/kg, i.p.), completely prevented CER-induced increases in the extracellular levels of DOPAC and HVA. The CCK-B antagonist, L-365,260 (3 mg/kg, i.p.), however, given 1 h before the CER treatment, slightly attenuated the CER-induced increase in the extracellular levels of DOPAC, but not the CER-induced increase in HVA, 60–180 min after the treatment. These findings indicate that systematically administered CER modulates the in vivo release and metabolism of DA in the medial prefrontal cortex. We suggest that systemically administered CER exerts its action on both vagal afferent nerves and the area postrema via CCK-A receptors, thus enhancing the in vivo release and metabolism of DA in the medial prefrontal cortex.

CCK-A and CCK-B receptors enhance olfactory recognition via distinct neuronal pathways.

We have previously reported that CCK-A receptor agonists and CCK-B receptor antagonists both enhance memory in an olfactory recognition test. Here, we report that the memory-enhancing effect of the CCK-B receptor antagonist L-365,260 (1 mg/kg i.p.), but not that of the CCK-A receptor agonist caerulein (0.03 mg/kg i.p.), was dramatically decreased following a bilateral transection of the perforant path, a principal source of input to the hippocampal formation. We further confirmed that a significant memory deficit occurred subsequent to this deafferentation of the hippocampus in untreated animals. In contrast, the effect of caerulein, but not that of L-365,260, was abolished following a bilateral subdiaphragmatic vagotomy. These results demonstrate that the hippocampal system plays a role in olfactory recognition and indicate that distinct neuronal pathways underlie the memory-enhancing effects of CCK-A and CCK-B drugs observed in the olfactory recognition test. The former effects (CCK-A) appear to involve a peripheral relay to the brain via the vagus nerve, whereas the latter (CCK-B) are directly central and involve, at least in part, the hippocampal system.

Neuroleptic-induced chewing movements in the rat are suppressed by peripherally but not centrally administered CCK and abolished by bilateral subdiaphragmatic vagotomy

We have previously demonstrated that intraperitoneal cholecystokinin (CCK-8S) suppresses the vacuous chewing mouth movements (VCM's) elicited by chronic neuroleptic administration in the rat, a possible model of tardive dyskinesia (TD) in humans. The studies described here were undertaken in order to better determine whether this effect is mediated centrally or peripherally. In the first set of experiments, CCK-8S (10, 30 or 50 ng, i.c.v.) was found to have no effect on VCM's elicited by 20 weeks treatment with fluphenazine decanoate (25 mg/kg, i.m., every 3 weeks). A second set of experiments was then performed to determine if the previously observed effects of intraperitoneal CCK-8S were vagally mediated. As previously described, CCK-8S (10, 30 or 60 μg/kg, i.p.) suppressed neuroleptic-induced VCM's in sham-operated animals without affecting the baseline VCM rate. Bilateral subdiaphragmatic vagotomy alone unexpectedly suppressed neuroleptic-induced VCM's to control levels and CCK-8S had no further effect. Vagotomy also prevented the suppressive effects of peripherally administered CCK-8S on rearing and grooming. We conclude that neuroleptic-induced VCM's may depend upon tonic activity in the vagus nerve and/or its central projections and that the effects of CCK-8S on this behavioural response are likely to be peripherally mediated.