Cholecystokinin, behavioral tolerance and tumor-induced anorexia

Cholecystokinin octapeptide (CCK-8, 5 micrograms/kg, IP) was injected daily, for two 4-day periods, into rats bearing the Walker 256 carcinosarcoma (TB) and non-tumor bearing (NTB) control animals. All animals were on a 20 hr food and water deprivation schedule and monitored for food and water intake and bodyweight for 4 hr daily. Food intake was significantly reduced by the daily administration of CCK. Behavioral tolerance to CCK was not observed in either the NTB or TB rats. These results indicate that the parameters describing the phenomenon of behavioral tolerance to CCK are yet to be clearly defined and that peptides other than CCK may underlie the mechanism primarily responsible for producing anorexia associated with cancer.     

Anorexic effect of peripheral cholecystokinin (CCK) varies with age and body composition (short communication)

Obesity of middle-aged mammals is followed at old age by anorexia and cachexia leading to sarcopenia. Complex age- and body composition-related alterations in the regulation of energy homeostasis may be assumed in the background. We aimed to test the possible contribution of age- and body composition-related changes of satiety responses to catabolic brain-gut-axis peptide cholecystokinin (CCK) to these alterations in energy balance during aging. Male Wistar rats (6-8 animals/group) aged 2 months (juvenile), 3 months (young adult), 6 or 12 months (early or late middle-aged), and 24 months (old) were injected intraperitoneally with 5 μg CCK-8 prior to re-feeding after 48-h food-deprivation. CCK suppressed re-feeding in young adult (26.8%), early middle-aged (35.5%), and old (31.4%) animals, but not in juvenile or late middle-aged rats (one-way ANOVA). CCK-resistance of 12 months old rats was prevented by life-long calorie-restriction: CCK suppressed their re-feeding by 46.8%. Conversely, in highfat diet-induced obese 6 months old rats CCK failed to suppress re-feeding. In conclusion, age-related changes in satiety responsiveness to CCK may contribute to the age-related obesity of middle-aged as well as to the anorexia of old animals. CCK-responsiveness is also influenced by body composition: calorie-restriction prevents the resistance to CCK, pre-existing obesity enhances it.     

Reduced feeding response to neuropeptide Y in senescent Fischer 344 rats

The anorexia of aging syndrome in humans is characterized by spontaneous body weight loss reflecting diminished food intake. We reported previously that old rats undergoing a similar phenomenon of progressive weight loss (i.e., senescent rats) also display altered feeding behavior, including reduced meal size and duration. Here, we tested the hypothesis that blunted responsiveness to neuropeptide Y (NPY), a feeding stimulant, occurs concurrently with senescence-associated anorexia/hypophagia. Young (8 mo old, n = 9) and old (24-30 mo old, n = 11) male Fischer 344 rats received intracerebroventricular NPY or artificial cerbrospinal fluid injections. In response to a maximum effective NPY dose (10 microg), the net increase in size of the first meal after injection was similar in old weight-stable (presenescent) and young rats (10.85 +/- 1.73 and 12.63 +/- 2.52 g/kg body wt (0.67), respectively). In contrast, senescent rats that had spontaneously lost approximately 10% of body weight had significantly lower net increases at their first post-NPY meal (1.33 +/- 0.33 g/kg body wt (0.67)) than before they began losing weight. Thus altered feeding responses to NPY occur in aging rats concomitantly with spontaneous decrements in food intake and body weight near the end of life.     

Experimental dissociation of neural circuits underlying conditioned avoidance and hypophagic responses to lithium chloride

We previously reported that noradrenergic (NA) neurons in the nucleus of the solitary tract (NST) are necessary for exogenous CCK octapeptide to inhibit food intake in rats. To determine whether NST NA neurons also are necessary for lithium chloride (LiCl) to inhibit food intake and/or to support conditioned avoidance behavior, saporin toxin conjugated to an antibody against dopamine beta hydroxylase (DSAP) was microinjected bilaterally into the NST to ablate resident NA neurons. DSAP and sham control rats subsequently were tested for the ability of LiCl (0.15M, 2% body wt) to inhibit food intake and to support conditioned flavor avoidance (CFA). LiCl-induced hypophagia was significantly blunted in DSAP rats, and those with the most extensive loss of NST NA neurons demonstrated the most attenuated LiCl-induced hypophagia. Conversely, LiCl supported a robust CFA that was of similar magnitude in sham control and DSAP rats, including rats with the most extensive NA lesions. A terminal c-Fos study revealed intact LiCl-induced c-Fos expression in the lateral parabrachial nucleus and central amygdala in DSAP rats, despite significant loss of NST NA neurons and attenuated c-Fos activation of corticotropin-releasing hormone-positive neurons in the paraventricular nucleus of the hypothalamus (PVN). Thus, NST NA neurons contribute significantly to LiCl-induced hypophagia and recruitment of stress-responsive PVN neurons but appear to be unnecessary for CFA learning and expression. These findings support the view that distinct central nervous system circuits underlie LiCl-induced inhibition of food intake and conditioned avoidance behavior in rats.     

Role of postnatal androgens in sexual differentiation of the lordosis-inhibiting effect of central injections of cholecystokinin

The neuropeptide cholecystokinin (CCK) inhibits lordosis behavior when infused into the ventromedial nucleus of the hypothalamus (VMN) of female rats and has no effect when infused into the VMN of male rats. To test whether this sex difference develops under the control of perinatal steroids, male rats were castrated or given sham surgeries within 3 h of birth and female rats were injected with either 0 or 100 micrograms testosterone propionate on postnatal day 5. As adults, these rats were castrated as necessary, implanted with unilateral cannulae directed at the VMN, and tested for their ability to display female sexual behavior and to respond to CCK. Neonatal castration of males prevented defeminization of this response. When treated with 5 micrograms estradiol benzoate (EB), neonatally castrated males showed both lordosis behavior and a profound inhibition of that behavior after infusions of CCK. Neonatally castrated males did not display lordosis behavior when treated with 2 micrograms EB. Control males showed no lordosis behavior and, therefore, no response to CCK. Both doses of EB induced lordosis behavior in neonatally androgenized females. Significantly, these neonatally androgenized females were less responsive to CCK's inhibition of lordosis and were also anovulatory. These results imply that androgens alter the development of CCK responsive circuits as well as defeminize cyclic gonadotropin release. Levels of 125I-sCCK-8 binding in the VMN were correlated closely with an individual's ability to respond to sCCK-8. In summary, the inhibition of female sexual behavior caused by exogenously administered CCK in normal adult female rats appears to be controlled at least partially by levels of CCK receptors in the VMN and to differentiate under the control of perinatally present testosterone.     

Facilitation of cancer-associated anorexia by cholecystokinin

Cholecystokinin octapeptide (CCK-8, 5 micrograms/kg) was injected i.p. into male Sprague-Dawley rats bearing the Walker 256-carcinosarcoma, or into non-tumour bearing controls, on a 20-h food deprivation schedule. Food and water intake and body weight maintenance were monitored for 15 days after tumour implantation and compared to that of tumour-bearing animals not injected with CCK-8. Food intake was significantly reduced for the duration of the two 4-day periods of CCK-8 injection, indicating that behavioural tolerance to this peptide did not occur. The severity of anorexia and body weight loss in tumour-bearing animals was significantly greater than that observed in non-tumour bearing controls, for the first 13 days of observation. These results indicate that endogenous peptides, such as CCK, may function in tumour-bearing animals to enhance the anorexia and wasting which typifies the anorexia cachexia syndrome.     

Cholecystokinin- and dexfenfluramine-induced anorexia compared using devazepide and c-fos expression in the rat brain

It has been proposed that there might be a link between the anorectic actions of cholecystokinin (CCK) and serotonin (5HT). The present study compared the patterns of c-fos protein-like immunoreactivity (FLI) induced in rat brain by CCK and the indirect 5HT agonist dexfenfluramine (DFEN), as well as the ability for devazepide, a CCK-A receptor antagonist, to antagonize both anorexia and FLI induced by these agents. Devazepide reversed the anorectic effect of CCK but not that of DFEN in food deprived rats. The FLI induced by CCK and DFEN occurred in similar brain regions, but in different subdivisions. Such regions included the bed nucleus of the stria terminalis (BST), the lateral central nucleus of the amygdala (CeL), and the lateral parabrachial nucleus (LPB). Devazepide abolished the FLI induced by CCK most of these brain regions, but had no effect on FLI induced by DFEN. These results suggest that the LPB-CeL/BST pathway might be responsible for the anorectic effects of both CCK and DFEN, but different parts or neuronal populations in these structures might be differentially engaged by CCK and DFEN. The putative interaction between CCK and 5HT might happen along this pathway, rather than in the periphery.     

Differential mechanism and site of action of CCK on the pancreatic secretion and growth in rats

Recent studies demonstrated that cholecystokinin (CCK) at physiological levels stimulates pancreatic enzyme secretion via a capsaicin-sensitive afferent vagal pathway. This study examined whether chemical ablation of afferent vagal fibers influences pancreatic growth and secretion in rats. Bilateral subdiaphragmatic vagal trunks were exposed, and capsaicin solution was applied. Pancreatic wet weight and pancreatic secretion and growth in response to endogenous and exogenous CCK were examined 7 days after capsaicin treatment. Perivagal application of capsaicin increased plasma CCK levels and significantly increased pancreatic wet weight compared with those in the control rats. Oral administration of CCK-1 receptor antagonist loxiglumide prevented the increase in pancreatic wet weight after capsaicin treatment. In addition, continuous intraduodenal infusion of trypsin prevented the increase in plasma CCK levels and pancreatic wet weight after capsaicin treatment. There were no significant differences in the expression levels of CCK-1 receptor mRNA and protein in the pancreas in capsaicin-treated and control rats. Intraduodenal administration of camostat or intravenous infusion of CCK-8 stimulated pancreatic secretion in control rats but not in capsaicin-treated rats. In contrast, repeated oral administrations of camostat or intraperitoneal injections of CCK-8 significantly increased pancreatic wet weight in both capsaicin-treated and control rats. Present results suggest that perivagal application of capsaicin stimulates pancreatic growth via an increase in endogenous CCK and that exogenous and endogenous CCK stimulate pancreatic growth not via vagal afferent fibers but directly in rats.     

Cholecystokinin, vasoactive intestinal peptide and peptide histidine methionine responses to feeding in anorexia nervosa.

Anorexia nervosa (AN) is a syndrome of unknown cause characterized by voluntary starvation. Cholecystokinin has been implicated as a neuroendocrine regulatory factor in control of satiety. Relatively little information is known about gastrointestinal hormone responses to feeding in subjects with anorexia nervosa. In the present studies, we examine fasting and postprandial levels of cholecystokinin (CCK), vasoactive intestinal peptide (VIP) and peptide histidine methionine (PHM) in anorexia nervosa subjects and in control individuals. Results of these studies indicate that plasma CCK response to a liquid meal (Ensure Plus) in untreated AN subjects was distinctly different from that observed in healthy controls, both in terms of temporal pattern of peptide released and the amount of CCK secreted into the circulation. Peak levels of CCK release occurred at 30 min following meal ingestion in AN patients and at 60 min in control subjects. Integrated CCK release in untreated AN patients was approximately twice that measured in control individuals. Renutrition therapy was associated with reversion of the pattern of CCK release to that observed in control subjects. Plasma VIP levels were unchanged following meal ingestion in both control and anorexic subjects. In contrast, PHM levels in AN subjects were significantly greater than that observed in control individuals. The pattern of PHM release following liquid meal ingestion was similar to that observed with plasma CCK; namely, peak release of peptide was observed at 30 min which was significantly greater than corresponding control values (P less than 0.05). In conclusion, these results demonstrate distinctive differences in plasma CCK and PHM levels in response to feeding in AN subjects when compared to control individuals. These findings suggest that the earlier and greater rise in plasma CCK levels in AN subjects following meal ingestion may contribute to the abnormal sensation of satiety in this condition.     

Effect of exogenous and endogenous insulin on the secretory response of the pancreas to the octapeptide of cholecystokinin (CCK8) in normal rats

The author studied the effect of insulin on CCK8-stimulated secretion by the pancreas. CCK8 (0.6 nmol.kg-1) was administered to normal anaesthetized rats 30 min after the intravenous injection of insulin (10 U.kg-1), glucose (2 g.kg-1) or NaCl (controls). Pancreatic juice was collected from the intubated common bile duct. In rats given exogenous insulin, there were no statistically significant differences in total protein, amylase and trypsinogen output after CCK8 compared with the controls. In rats in which endogenous insulin secretion was stimulated with glucose, the amylase response to CCK8 was not significantly different from the control animals, but the trypsinogen response was significantly lower. The results show that insulin, in some still unknown manner, inhibits the trypsinogen secretory response to CCK8. In addition, they confirm data claiming that the synthesis and secretion of pancreatic amylase require a given critical ratio of insulin to glucose, or of insulin to the factor stimulating pancreatic secretion.     

Interaction of apolipoprotein AIV with cholecystokinin on the control of food intake

Apolipoprotein AIV (apo AIV) and cholecystokinin (CCK) are peptides that act both peripherally and centrally to reduce food intake by decreasing meal size. The present study examined the effects of intraperitoneally administered bolus doses of recombinant apo AIV, CCK-8, and a combination of subthreshold doses of apo AIV and CCK on 4-h food intake in rats that were fasted overnight. Apo AIV at 100 microg/kg reduced food intake significantly relative to the saline control for 1 h, as did doses of CCK-8 at or above 0.125 microg/kg. Doses of apo AIV (50 microg/kg) or CCK (0.06 microg/kg) alone had no effect on food intake. However, when these subthreshold doses of apo AIV and CCK were administered together, the combination produced a significant inhibition of food intake relative to saline controls (P < 0.001), and the duration of the effect was longer than that caused by the administration of either apo AIV or CCK alone. The satiation effect produced by CCK-8 + apo AIV was attenuated by lorglumide, a CCK1 receptor antagonist. We conclude that, whereas the intraperitoneal administration of doses of either recombinant apo AIV or CCK at or above threshold levels reduces food intake, the coadministration of subthreshold doses of the two peptides is highly satiating and works via CCK1 receptor.     

Significance of Ca2+, Rb+ fluxes, of cAMP and cGMP for the CCK8-modulated insulin release

In rat pancreatic islets the effects of cholecystokinin-8 (CCK8) on glucose-mediated insulin release, 45Ca2+ net uptake, 45Ca2+ efflux, 86Rb+ efflux, cAMP- and cGMP levels were studied. In the presence of a substimulatory glucose concentration (3 mM) CCK8 concentrations of up to 1 microM had no effect on insulin release, but CCK8 at 10 nM potentiated the stimulatory effect of glucose (11.1 mM). 10 nM CCK8 enhanced glucose-stimulated 45Ca2+ net uptake but was ineffective at substimulatory glucose levels. CCK8 had no effect on cAMP and cGMP levels in the presence of 11.1 mM glucose, CCK8 increased 86Rb+ (a measure of K+) in the presence of both 3 and 11.1 mM glucose. This effect was abolished when Ca2+ was omitted from the perifusion medium. CCK8 did not alter glucose (11.1 mM)-stimulated 45Ca2+ efflux rate. These data indicate that (1) CCK8 potentiates glucose-stimulated insulin secretion possibly via an effect on Ca2+ uptake, 2) by affecting Ca2+ uptake, CCK8 enhances K+ efflux, and 3) CCK8 does not mediate its effect via cAMP or cGMP. With respect to 86Rb+ efflux the mechanism of CCK8 action appears to be different from that of glucose. When the mechanism of CCK action on islets is compared with that on exocrine pancreas (data from others) there are similarities (importance of Ca2+ uptake and non-importance of cAMP and cGMP).     

Effect of gastrointestinal peptides on ingestion in old and young mice

Early satiety may play a role in the anorexia of aging. The effects of the peripheral satiety agents cholecystokinin (CCK), bombesin, glucagon, and calcitonin were studied in 8 and 25 month old mice. During normal feeding behavior, the older mice consumed more than their younger counterparts, however, when food deprived, the younger consumed more. All peptides inhibited food intake over the first hour after administration in young and old mice. CCK, bombesin, and calcitonin suppressed feeding in 25 month old mice to a greater extent than in 8 month old mice. However, CCK demonstrated the greatest age-related suppression of food intake. CCK has a potential role to play in the pathogenesis of the anorexia of aging.     

Endogenous cholecystokinin reduces food intake and increases Fos-like immunoreactivity in the dorsal vagal complex but not in the myenteric plexus by CCK1 receptor in the adult rat

We hypothesized that endogenous CCK reduces food intake by activating the dorsal vagal complex (DVC) and the myenteric neurons of the gut. To test this hypothesis, adult rats were given camostat mesilate; a nonnutrient releaser of endogenous CCK, by orogastric gavage, and Fos-like immunoreactivity (Fos-LI) was quantified in the DVC and the myenteric plexus. The results for endogenous CCK were compared with those for exogenous CCK-8. Exogenous CCK-8 reduced food intake and stimulated Fos-LI in the DVC and in myenteric neurons of the duodenum and jejunum. In comparison, endogenous CCK reduced food intake and increased DVC Fos-LI but did not increase Fos-LI in the myenteric plexus. Similar to CCK-8, devazepide, a specific CCK(1) receptor antagonist, and not L365,260, a specific CCK(2) receptor antagonist, attenuated the reduction of food intake by camostat. In addition, Fos-LI in the DVC in response to both exogenous CCK-8 and camostat administration was significantly attenuated by vagotomy, as well as by blocking CCK(1) receptors. These results demonstrate for the first time that reduction of food intake in adult rats by endogenous CCK released by a nonnutrient mechanism requires CCK(1) receptors, the vagus nerve, and activation of the DVC, but not the myenteric plexus.     

Anti-inflammatory effects of leptin and cholecystokinin on acetic acid-induced colitis in rats: role of capsaicin-sensitive vagal afferent fibers

Leptin and cholecystokinin (CCK) have a synergistic interaction in the suppression of food intake, and afford similar gastroprotective activity. The present study was designed to investigate the putative protective effects of CCK and leptin on acute colonic inflammation. Leptin or CCK-8s was injected to rats intraperitoneally immediately before and 6 h after the induction of colitis with acetic acid. CCK-A receptor antagonist (L-364,718) or CCK-B receptor antagonist (L-365,260) was injected intraperitoneally 15 min before leptin or CCK treatments. In a group of rats, vagal afferent fibers were denervated by topical application of capsaicin on the cervical vagi. Rats were decapitated at 24 h, and the distal 8 cm of the colon were removed for macroscopic scoring, determination of tissue wet weight index (WWI), histologic assessment and tissue myeloperoxidase (MPO) activity. All inflammation parameters were increased by acetic acid-induced colitis compared to control group. Leptin or CCK-8s treatment reduced these parameters in a similar manner, while co-administration of leptin and CCK was found to be more effective in reducing the macroscopic score and WWI. CCK-8s-induced reduction in the score and WWI was prevented by CCK-A, but not by CCK-B receptor antagonist, whereas neither antagonist altered the inhibitory effect of leptin on colitis-induced injury. On the other hand, perivagal capsaicin prevented the protective effects of both CCK-8s and leptin on colitis. Our results indicate that leptin and CCK have anti-inflammatory effects on acetic acid-induced colitis in rats, which appear to be mediated by capsaicin-sensitive vagal afferent fibers involving the reduction in colonic neutrophil infiltration.     

Effect of meta-chlorophenylpiperazine and cholecystokinin on food intake of Osborne-Mendel and S5B/P1 rats

Objective: To investigate whether there is a difference in sensitivity to a serotonin agonist, meta‐chlorophenylpiperazine (mCPP), or cholecystokinin (CCK‐8), an intestinal hormone that inhibits food intake, between the Osborne‐Mendel (OM) rat, which becomes obese eating a high‐fat diet, and the S5B/Pl (S5B) rat, which is resistant to dietary‐induced obesity. Research Methods and Procedures: OM and S5B rats were adapted to either a high‐saturated‐fat diet (56% energy as fat) or a low‐fat diet (10% energy as fat) or to both for 14 days and then treated with several doses of mCPP or CCK‐8. Results: Treatment with mCPP reduced food intake in both strains of rats. The dose‐response curve showed that the OM rats had an increased sensitivity to the serotonergic agonist. Animals eating the high‐fat diet had less response to mCPP; and in the S5B rats, the response was significantly reduced. After treatment with CCK‐8, there was a similar dose‐related suppression of food intake in both the OM and S5B rats. Discussion: These data are consistent with the hypothesis that the serotonin system in the S5B rat has a greater activity that could act to inhibit fat intake. The response to CCK was not significantly affected by strain or diet.     

Intestinal metabolism and absorption of cholecystokinin analogs in rats

Intestinal metabolism and poor permeability were known to be major barriers for oral absorption of large peptide drugs. Dimensionless wall permeability values of C-terminal octa- and tetra-peptides cholecystokinin analogs (CCK8 and CCK4) were estimated and found out to be greater than 1, suggesting no permeability-limited absorption for CCK analogs. Thus, a strategy employing enzyme inhibitors and a specific delivery site to improve the absorption was developed and tested with CCK8, followed by identification of metabolites of the analogs and their participating enzymes in rabbit brush-border membrane vesicles. Thiorphan and amastatin, a specific enzyme inhibitor for enkephalinase and aminopeptidase, respectively, in pH 4 buffer solution were coadministered with CCK8 to the ileum in fistulated rats. The absolute bioavailability (F) of CCK8 was 5.4% and increased to 19% in the presence of the enzyme inhibitors, while the F values following oral administration were close to zero. These results indicate that peptide oral delivery is possible.     

Leptin receptor-deficient obese Zucker rats reduce their food intake in response to hypobaric hypoxia

Exposure to hypoxia induces anorexia in humans and rodents, but the role of leptin remains under discussion and that of orexigenic and anorexigenic hypothalamic neuropeptides remains unknown. The present study was designed to address this issue by using obese (Lepr(fa)/Lepr(fa)) Zucker rats, a rat model of genetic leptin receptor deficiency. Homozygous lean (Lepr(FA)/Lepr(FA)) and obese (Lepr(fa)/Lepr(fa)) rats were randomly assigned to two groups, either kept at ambient pressure or exposed to hypobaric hypoxia for 1, 2, or 4 days (barometric pressure, 505 hPa). Food intake and body weight were recorded throughout the experiment. The expression of leptin and vascular endothelial growth factor (VEGF) genes was studied in adipose tissue with real-time quantitative PCR and that of selected orexigenic and anorexigenic neuropeptides was measured in the hypothalamus. Lean and obese rats exhibited a similar hypophagia (38 and 67% of initial values at day 1, respectively, P < 0.01) and initial decrease in body weight during hypoxia exposure. Hypoxia led to increased plasma leptin levels only in obese rats. This resulted from increased leptin gene expression in adipose tissue in response to hypoxia, in association with enhanced VEGF gene expression. Increased hypothalamic neuropeptide Y levels in lean rats 2 days after hypoxia exposure contributed to accounting for the enhanced food consumption. No significant changes occurred in the expression of other hypothalamic neuropeptides involved in the control of food intake. This study demonstrates unequivocally that altitude-induced anorexia cannot be ascribed to anorectic signals triggered by enhanced leptin production or alterations of hypothalamic neuropeptides involved in anabolic or catabolic pathways.     

Sulfated cholecystokinin octapeptide in the rat: pontomedullary distribution and modulation of the respiratory pattern.

We performed anatomical and physiological studies to determine the site and actions of sulfated cholecystokinin octapeptide (CCK8-S) on breathing. Peptide locations were determined by combined immunodetection of CCK8-S- containing synaptic varicosities and retrograde labeling of medullary neurons projecting to the ventral respiratory group. Retrogradely labeled neurons and CCK8-S immunolabeled varicosities overlapped within the nuclei of the solitary tract, ventral respiratory group, and the Kolliker-Fuse nucleus. Additional CCK8-S immunoreactive terminals were located in the rostroventrolateral medullary reticular nucleus, lateral paragigantocellular reticular nucleus, and the caudal pontine reticular nucleus. The respiratory effects of CCK8-S, which binds to CCK(A) and CCK(B) receptors, were examined by intravenous injection in adult rats and by bath application in the in vitro neonatal rat brainstem - spinal cord preparation. CCK8-S produced an increase in the mean amplitude of diaphragmatic electromyogram (EMG) of 28 +/- 35% (SD) and a decrease in mean respiratory interval of 13 +/- 4% in vivo. In vitro, CCK8-S significantly increased inspiratory duration and decreased respiratory interval, primarily by shortening expiratory duration. CCK8-unsulfated, a specific agonist for CCK(B) receptors, did not produce these effects. CCK8-S effects in the in vitro preparation were partially blocked by the CCK receptor antagonist lorglumide (final bath concentration 600 nM). These results suggest that CCK8-S modulates the respiratory rhythm via CCK(A) receptors within one or more medullary or pontine respiratory groups in both neonatal and adult rats.     

CCK-8 modulation of mesolimbic dopamine: Antagonism of amphetamine-stimulated behaviors

Rats (N=15) were implanted with cannulae above the dopaminergic A10 ventral tegmental area (VTA). Two weeks later, four measures of open field behavior were quantified for 10 minutes commencing 30 minutes after parenteral d-amphetamine (1.5 mg/kg) and directly after bilateral infusion of 1.5 μl of: (a) artificial CSF only (VEH), (b) 1.25 μg desulfated CCK (DS-CCK), or (c) 1.25 μg sulfated CCK (CCK). Additional rats with bilateral cannulae directed toward the A10 terminal zones of nucleus accumbens were similarly tested with either VEH (N=2) or sulfated CCK (N=2). With VTA infusions, both the number of occurrences and duration of rearing were significantly reduced in CCK rats, while neither the number of square crossings nor duration of forward locomotion were significantly modified from controls. With nuclei accumbens septi (NAS) infusions, CCK-8 reduced rearing behavior more than ambulatory behavior in this preliminary testing. With either VTA or NAS infusions, no significant differences from controls were found upon two derived measures of motoric performance, namely, “velocity” (number of squares crossed per second in locomotion) and “vertical stability” (seconds per rear). These results suggest a modulation of dopaminergically-mediated behavior by (sulfated) CCK-8 at the cell body region and terminal fields of the mesolimbic (A10) dopamine system.