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PubMed1993

Ceruletide suppresses rotational behavior in lesioned rats via CCKA receptors.

The effects and pharmacological mechanisms underlying the inhibiting effect of ceruletide, a cholecystokinin (CCK)-related peptide, on apomorphine-induced turning behavior in 6-hydroxydopamine lesioned rats were investigated. For this purpose, selective CCKA and CCKB receptor antagonists were used. Ceruletide (50-400 micrograms/kg, s.c.) dose dependently suppressed apomorphine-induced rotational behavior. The antiapomorphine effect of ceruletide was reversed by the selective CCKA receptor antagonist, devazepide, but not by the selective CCKB receptor antagonist, L-365,260. This suggests that the suppression ceruletide exerts on hyperactive nigrostriatal dopamine neurons is mediated by CCKA receptors.

Animals↗
PubMed1994

The CCKB receptor antagonist, L-365,260, elicits antidepressant-type effects in the forced-swim test in mice.

Selective CCKA and CCKB receptor agonists and antagonists were used to study the involvement of endogenous cholecystokinin in the behavioural changes that occur in mice in the forced-swimming test (Porsolt's test). The CCKB receptor antagonist, L-365,260 ((3R)-(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4- benzodiazepin-3-yl)-3-methylphenylurea), but not the CCKA receptor antagonist, devazepide ((3S)-(-)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin -3-yl)- 1H-indole-2-carboxamide), elicited an antidepressant-type response (a decrease in the duration of immobility) that was suppressed by previous treatment with either CCK-8 (H-Asp-Tyr(OSO3H)-Met-Gly- Trp-Met-Asp-Phe-NH2) or the selective CCKB receptor agonist BC-264 (Boc-Tyr(SO3H)-gNle-mGly-Trp-N(Me)-Nle-Asp-Phe- NH2). The L-365,260 effect was also prevented by the dopamine receptor antagonist, SCH-23,390 (a dopamine D1-selective receptor antagonist: R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl- 2,3,4,5-tetrahydro-1H-3-benzazepine) and sulpiride (a dopamine D2-selective receptor antagonist: (-)-5-(aminosulfonyl)-N-[(1-ethyl-2-pyrrolidinyl) methyl]-2-metoxybenzamide). On the other hand, co-administration of subthreshold doses of L-365,260 and nomifensine (an atypical antidepressant that selectively blocks dopamine re-uptake mechanisms, 1,2,3,4-tetrahydro-2-methyl-4-phenyl-8-isoquinolinamine) led to a potent antidepressant-type response. These results indicate that blocking of CCKB receptors could result in an increase of extracellular dopamine contents in some brain areas involved in depression and suggest a potential use of CCKB receptor antagonists, alone or combined with antidepressants, in the treatment of depressive syndromes.

Amino Acid Sequence↗
PubMed1996

Behavioural evidence for cholecystokinin-dopamine D1 receptor interactions in the rat.

The effects of cholecystokinin (CCK) on behavioural responses to the dopamine D1 receptor agonist (+/- )SKF 38393 ((+/- )-2,3,4,5-tetrahydro-7,8- dihydroxy-1-phenyl-1H-3-benzazepine HCl) were studied in the rat. SKF 38393 (5 mg/kg s.c.) induced stereotyped grooming and vacuous chewing movements. Both responses were inhibited by CCK-8S (10-50 micrograms/kg i.p.), but the preferential CCKB receptor agonist CCK-4 (20-100 micrograms/kg i.p.) attenuated SKF 38393-induced grooming only. Suppression of SKF 38393-induced grooming and vacuous chewing movements by CCK-8S was blocked by the selective CCKA receptor antagonist MK-329 (also known as devazepide or L-364,718) (0.1, 0.3 mg/kg i.p.) but unaffected by the CCKB receptor antagonist L-365,260 (0.1, 0.3 mg/kg i.p.). We conclude that CCK can modify dopamine-mediated behavioural responses, possibly reflecting an action post-synaptic to dopamine terminals. The effect on dopamine D1 receptor agonist-induced vacuous chewing movements is probably mediated by CCKA receptors, while the effect on grooming may reflect an interaction with the CCKA receptor and/or a novel CCKB receptor subtype.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1995

Cholecystokinin-B receptor ligands of the dipeptoid series act as agonists on rat stomach histidine decarboxylase.

BACKGROUND & AIMS: The effect of gastrin on the enterochromaffin-like cells in the rat stomach is mediated by cholecystokinin (CCK)-B receptors and manifested as activation of histidine decarboxylase (HDC). The dipeptoids PD 136450, PD 135158, and PD 134308 are thought to be selective CCK-B receptor antagonists. The effects of the dipeptoids and of gastrin-17 and sulfated CCK-8 on rat stomach HDC activity were examined. METHODS: Drugs were infused intravenously or subcutaneously to fasted rats, and the HDC activity was determined. RESULTS: The dipeptoids activated HDC with maximal responses (50%-60% of the maximal response to gastrin) at 1 mumol.kg-1.h-1. Rat gastrin-17 activated HDC maximally at 3 nmol.kg-1.h-1, and sulfated CCK-8 produced maximal response at 20 nmol.kg-1.h-1. The CCK-B receptor antagonist L-365,260 inhibited the HDC activation induced by gastrin, sulfated CCK-8, or the dipeptoids. The dipeptoids did not inhibit the gastrin-induced HDC activation. CONCLUSIONS: Gastrin, sulfated CCK-8, and the dipeptoids activated rat stomach HDC. L-365,260 but not devazepide inhibited the HDC activation. Thus, the dipeptoids, which failed to inhibit the gastrin-induced HDC activation, act as CCK-B receptor agonists and not as antagonists. It is important to recognize this to ensure appropriate interpretation of data obtained with these drugs.

Animals↗
PubMed1994

Evidence that cholecystokinin induces immediate early gene expression in the brainstem, hypothalamus and amygdala of the rat by a CCKA 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 micrograms/kg i.p.). In contrast, levels of c-jun, junB and junD mRNA were unaffected by the peptide. The closely related decapeptide, caerulein (50 micrograms/kg i.p.), induced the same pattern of IEG expression as CCK-8S, whereas the desulphated octapeptide, CCK-8DS (50 micrograms/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 CCKA 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 CCKB receptor antagonist, CI-988 (1 or 10 mg/kg i.p.). In addition, the selective CCKB receptor agonists, CCK-4 (50 micrograms/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 CCKA receptors on vagal afferents to stimulate IEG mRNA expression in the rat CNS.

Amygdala↗
PubMed1993

Cholecystokinin receptors and memory: a radial maze study.

CCK receptor agonists and antagonists have repeatedly been demonstrated to improve and impair, respectively, learning and memory functions. However, all studies to date have exploited avoidance paradigms. In the present study, the effect of some CCK receptor agonists and antagonists on the ability to learn an appetitively motivated task and to influence spatial working memory was investigated. In the first experiment, drugs were given immediately after each training session in the radial maze and the animals were tested, drug-free, during a 2-week period. After the initial treatments with caerulein, an unselective CCK receptor agonist (100 ng/kg SC), the animals were slightly less successful to obtain food pellets during the sessions on the first 2 days; whereas proglumide, an unselective CCK receptor antagonist (1 mg/kg SC) was without any effect. However, on the following days, all the three groups of rats (saline, caerulein, and proglumide) performed in a similar way. In the second experiment, drugs were given before each test session to well-trained animals. Scopolamine (0.15 and 0.3 mg/kg IP), the reference amnestic drug, produced dose-dependent impairment of working memory in the radial maze test. Proglumide (1 and 10 mg/kg SC) and devazepide, (a selective CCK-A receptor antagonist; 0.01 and 1 mg/kg SC), as well as caerulein (0.01, 0.1 and 1 microgram/kg SC) and CCK-4 (a selective CCK-B receptor agonist; 25 and 50 micrograms/kg SC) had no reliable effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

CCKA, but not CCKB, agonists suppress the hyperlocomotion induced by endogenous enkephalins, protected from enzymatic degradation by systemic RB 101.

Interactions between CCKergic and enkephalinergic systems were studied in mice using behavioral responses measured in Animex. The hyperlocomotion induced by 5 mg/kg of RB 101, a mixed inhibitor of enkephalin-degrading enzymes able to cross the blood-brain barrier, was previously shown to be mediated by delta-opioid receptor stimulation. The IP administration of a CCKA agonist, Boc-Tyr-Lys-(CONH-o-tolyl)-Asp-Phe-NH2 (0.1, 1, 10 micrograms/kg), suppressed the hyperlocomotion produced by IV injection of 5 mg/kg of RB 101. The effect of the CCKA agonist was suppressed by a selective CCKA antagonist, devazepide, injected IP at doses of 20 and 200 micrograms/kg and was potentiated by the selective delta-opioid antagonist naltrindole at the doses of 0.03 mg/kg. IP injection of the selective CCKB agonist BC 264 (0.1-1 mg/kg) did not modify the RB 101-induced hyperlocomotor effect. These results reinforce the observed physiological antagonism between the endogenous CCK and opioid systems but are at variance with the responses measured in stressful conditions. It is concluded that CCKA, but not CCKB, receptor activation counteracts the opioid-related hyperlocomotion.

Amino Acid Sequence↗
PubMed1996

Type A CCK receptors mediate satiety effects of intestinal nutrients.

Previous work indicates that endogenous CCK mediates suppression of sham feeding by some intraintestinal nutrients. To test whether the mechanism involved is dependent upon action at type A or type B CCK receptors, we examined the ability of CCKA (devazepide) and CCKB (L-365,260) receptor antagonists to attenuate the suppression of sham feeding by intraintestinal oleic acid, maltotriose, or L-phenylalanine. Suppression by oleic acid or maltotriose was dose dependently attenuated by intraperitoneal administration of the CCKA receptor antagonist, as was suppression by exogenous CCK. The CCKB receptor antagonist failed to attenuate the suppression of sham feeding by these nutrients. Neither receptor antagonist attenuated the suppression of sham feeding induced by intraintestinal L-phenylalanine. These results suggest that suppression of sham feeding by intestinally infused oleic acid and maltotriose is mediated by endogenous CCK acting at CCKA receptors.

Animals↗
PubMed1996

Are radioligand antagonist/agonist binding ratios in rat pancreas predictive of functional efficacy of cholecystokinin receptor agonists and antagonists?

Radioligand binding assays have been previously used to predict the relative efficacy of novel ligands. In the present study we have investigated whether for the cholecystokinin CCK-A receptors in the rat pancreas, the ratio of binding affinities for compounds for antagonist and agonist radioligands are predictive of functional activity. A number of classical cholecystokinin agonists, such as CCK-8S, caerulein, CCK-8DS, pentagastrin and CCK-4 had antagonist/agonist binding ratios of 4-fold or greater. All compounds behaved as full agonists in the stimulation of phosphatidylinositol (PI) turnover and increase in amylase secretion in rat pancreas. In contrast, compounds such as the benzodiazepine derivatives devazepide and L-365,260 had binding ratios of less than one and lacked agonist activity in either functional assay. Interestingly, the dipeptide derivative CI-988, which has been described as a selective CCK-B antagonist, was found to have an antagonist/agonist binding ratio of 1.5 for the CCK-A receptors in rat pancreas which was sufficiently high for this compound to behave as a full agonist in the amylase assay, although CI-988 did not exhibit agonist activity in the PI assay. These results suggest that the effective receptor reserve in the amylase assay is greater than that required to stimulate PI turnover, and that the selective peptoid CCK-B antagonist CI-988 has weak agonist activity at CCK-A receptors.

Animals↗
PubMedDate not supplied

MK-329 blocks the inhibition of alcohol intake by CCK-8.

Peripheral administration of sulfated cholecystokinin octapeptide (CCK-8) potently reduces alcohol intake, preference, and blood levels in rats. MK-329 (L-364,718 or Devazepide) acts at peripheral cholecystokinin (CCKA) receptors to antagonize CCK-8's physiological and behavioral effects, such as pancreatic stimulation and inhibition of feeding. We determined whether CCKA receptor blockade would also prevent CCK-8's alcohol satiety effect. Water-deprived female and male rats (n = 7 for each) received randomized combinations of intraperitoneal injections of MK-329 (0, 100, 200, or 400 micrograms/kg) followed by CCK-8 (0 or 4 micrograms/kg). Rats were then given access to 5% w/v ethanol for 30 min, followed by 30-min access to water, with food ad lib. MK-329 at all doses significantly (p < 0.05) reduced the suppression of alcohol intake and food intake by CCK-8. MK-329 alone increased alcohol intake at 400 micrograms/kg, and increased food intake, in females and males at 100 and 200 micrograms/kg, respectively. We concluded that CCK-8's alcohol and food satiation effects depend on specific, peripheral CCKA receptors, and satiation of alcohol consumption and drinking-associated feeding reflect an endogenous functional interaction of CCK-8 with CCKA receptors.

Alcohol Drinking↗
PubMed1996

Several roles of CCKA and CCKB receptor subtypes in CCK-8-induced and LiCl-induced taste aversion conditioning.

Administration of a relatively large IP dose of sulfated cholecystokinin (26-33) (CCK-8; 1.0 mumol/kg) consistently induced moderate taste aversion conditioning (TAC) using a 20-min, one-bottle test in Long-Evans rats. Because CCK-8 has affinity for both CCKA and CCKB receptor subtypes, we wanted to determine the subtype involved in CCK-8-induced TAC. Pretreatment with the selective CCKA antagonist MK-329 (L-364, 718 or devazepide), at doses of 0.1, 1.0, or 10.0 mumol/kg, markedly antagonized (> 70%) CCK-8-induced TAC. Pretreatment with the selective CCKB antagonist L-365,260, at doses of 0.1 or 1.0 mumol/kg, partially antagonized (approximately 50%) CCK-8-induced TAC, although the highest dose of L-365,260. 10.0 mumol/kg, did not. These partial antagonistic effects of L-365,260 on CCK-8-induced TAC were replicated in our second study. In our third study, we observed that another CCKB antagonist, the dipeptoid CI-988, also partially antagonized CCK-8-induced TAC at a dose of 0.1, but not 1.0 or 10.0, mumol/kg. In our final study, pretreatments with a single dose (i.e., 10.0, but not 0.1 or 1.0, mumol/kg) of either MK-329 or L-365,260 were also shown to partially antagonize the formation of moderate TAC induced by treatment with LiCl at 708 mumol/kg. Marked antagonism of LiCl-induced TAC was also observed following pretreatment with the known anxiolytic chlordiazepoxide HCl at 7.4 mumol/kg. Considering the existing data on the induction of TAC by various CCK analogues, we consider an action of CCK-8 on peripheral CCKA, but not CCKB, receptors necessary for the induction of TAC. Our results of partial antagonism of CCK-8- and LiCl-induced TAC by L-365,260, CI-988, or MK-329 suggest, but do not prove, that both CCKA and CCKB mechanisms may be operative during TAC. Because the CCK antagonists affected TAC like chlordiazepoxide, blockade of CCKA and CCKB mechanisms may produce a mild anxiolytic effect.

Animals↗
PubMed1996

Individual differences in the feeding response to CCKB antagonists: role of the nucleus accumbens.

Cholecystokinin (CCK) decreases food intake in a variety of species when administered systemically or centrally. Moreover, both CCKA and CCKB receptor mechanisms have been implicated in CCK's effects on feeding. Previous work done in our laboratory has shown that rats exhibit significant individual differences in the consumption of sugar. Moreover, intra-nucleus accumbens (Acc) administration of CCK reduced sugar consumption in rats with high baseline sugar intake (High) but did not affect sugar consumption in rats with low baseline sugar intake (Low). Thus, CCK mechanisms may contribute to individual differences in sugar intake observed in rats. The present study examined the involvement of endogenous CCK mechanisms in the regulation of sugar intake in Low and High rats. In Experiment 1, male Wistar rats were administered either the CCKA antagonist devazepide (0.001, 0.01, 0.1 mg/kg) or the CCKB antagonist L,365-260 (0.01, 0.1, 0.5 mg/kg) IP, and their intake of sugar and powdered lab chow recorded for 1 h. Experiment 2 was identical to Experiment 1 with the exception that rats received intra-Acc administrations of the selective CCKB antagonist PD-135158 (3, 10, 30 micrograms). Results showed that blockade of CCKB, but not CCKA receptors produced an increase in sugar consumption in Low rats and a decrease in sugar consumption in High rats. These effects were obtained with both systemic and intra-Acc administrations of a selective CCKB antagonist. These results suggest that endogenous CCK contributes to the mechanism regulating sugar consumption in Low and High rats through its actions on CCKB receptors in the Acc.

Animals↗
PubMed1994

Different modifications of the dopamine metabolism in the core and shell parts of the nucleus accumbens following CCK-A receptor stimulation in the shell region.

After the injection of CCK8 into the posterior N. Acc. of rats DA, DOPAC HVA contents were determined from punches of the anterior and posterior N. Acc. and VTA. CCK8 (20 pmol/side) modified these levels only in the posterior N. Acc. and these responses were inhibited by the CCK-A antagonist devazepide. Five min after treatment, DA, DOPAC and HVA were increased in the N. Acc.shell and 10 min later they were decreased in the N. Acc.core. These data suggest that in these regions CCK8 could both abolish the influence of DA from the core on the transmission of motor information and favor that of DA from the shell on emotional-like responses.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1995

Changes in hypothalamic cholecystokininA and cholecystokininB receptor subtypes and associated neuropeptide expression in response to salt-stress in the rat and mouse.

This study demonstrates cholecystokinin receptor plasticity in response to salt-loading in the rat and mouse hypothalamus. It identifies, for the first time, the cholecystokinin receptor subtypes involved, firstly by receptor autoradiography and secondly by in situ hybridization. Both species showed increases in hypothalamic [125I]Bolton Hunter-cholecystokinin-8 binding. Co-incubation with the specific cholecystokininA and cholecystokininB antagonists, devazepide and CI-988, indicated that in the rat cholecystokininB receptor binding markedly increased, with a small increase in cholecystokininA receptor binding. In the mouse the response was comprised solely of cholecystokininA receptors. In situ hybridization studies were carried out on a range of peptide messenger ribonucleic acids after salt-loading. In the rat large increases in hypothalamic gene expression were detected for oxytocin, vasopressin, corticotrophin-releasing factor and preprocholecystokinin. In the mouse only vasopressin messenger ribonucleic acid increased, whilst hypothalamic oxytocin, preprocholecystokinin and corticotropin-releasing factor remained unchanged. However, corticotrophin-releasing factor messenger ribonucleic acid increased in the mouse amygdala. In situ hybridization was performed using oligonucleotide probes specific for either the cholecystokininA or cholecystokininB receptor messenger ribonucleic acid, and this showed good agreement with the receptor autoradiography. CholecystokininB receptor expression was upregulated in the rat hypothalamus along with a small but significant increase in cholecystokininA receptors. In the mouse only cholecystokininA receptor expression was increased. In addition to these molecular changes rats lost about 25% of their body weight during six days of salt-challenge, whilst mice continued to grow in line with controls. This work demonstrates differential changes in cholecystokinin receptor subtype binding between the rat and the mouse. It represents the first report of differential changes in cholecystokininA and cholecystokininB receptor messenger ribonucleic acids within the brain, and shows that cholecystokinin receptors within the rodent hypothalamus are capable of plastic responses to chronic osmotic stress.

Animals↗
PubMed1992

Molecular modelling of asperlicin derived cholecystokinin A receptor antagonists.

The C3-substituted benzodiazepines derived from asperlicin, e.g. devazepide (L-364,718, MK-329), constitute the most potent class of cholecystokinin A-type (CCKA) receptor antagonists. In order to gain insight into the prerequisites for binding, we examined the conformational properties of both potent and weak representatives of this class with computer assisted molecular modelling (CAMM) techniques. The CAMM results indicate that the binding site for the C3-substituents is a planar slot on the CCKA receptor surface and, in addition, allow the proposal of a model which describes the relative binding mode of the less potent R isomers versus that of the S isomers. The latter model illustrates the unique spatial properties of the benzodiazepine moiety, which we suggest functions primarily as an invertible core which assures an optimal arrangement of attached substituents.

Benzodiazepinones↗
PubMed1994

Characterisation of CCKB receptors on GH3 pituitary cells: receptor activation is linked to Ca2+ mobilisation.

Cholecystokinin receptors on GH3 rat anterior pituitary cells have been characterised using radioligand binding and Ca2+ mobilisation. [125I]Bolton Hunter CCK-8s (BHCCK) bound dose dependently to GH3 cells (Kd 85 pM, Bmax 23 fmol/mg protein). Competition curves with CCK-8s (IC50 2.4 nM), pentagastrin (IC50 25 nM) and devazepide (IC50 820 nM), were consistent with a population predominantly of CCKB receptors. Binding of [125I]BHCCK to lysed cells was inhibited by 10 microM GTP-gamma-S and 10 microM GppNHp, suggesting the receptor was linked to a guanine nucleotide binding protein. Intracellular Ca2+ mobilisation was a functional consequence of CCKB receptor activation in GH3 cells using the fluorescent dye fura-2. CCK-8s (0.1 nM-1 microM) and the selective CCKB receptor agonist, pentagastrin, (0.1 nM-100 microM) dose dependently increased intracellular Ca2+ with a similar maximal increase of 2.85-fold and 2.77-fold respectively. Response to a submaximal dose of the CCKB receptor agonist pentagastrin (100 nM) was dose dependently blocked by the CCKB receptor antagonist L-365,260. GH3 cells may therefore provide a useful model to study CCKB receptor coupling in a pituitary cell line.

Animals↗
PubMed2004

Structure-activity function for binding and signaling in CHO-K1 and COS-7 cells expressing the cholecystokinin A receptor.

Key amino acids of the cholecystokinin (CCK) peptide for receptor binding are sulfated Y27, W30, D32, and F33-NH(2). Three-dimensional modeling showed that the CCK-A receptor (CCK-AR) antagonist devazepide penetrated into the transmembrane (TM) domains, whereas CCK was placed on the surface of the CCK-AR. Four types of rat CCK-AR cDNAs were transfected into CHO-K1 and COS-7 cells: normal CCK-AR cDNA transfected cells (wild type, WT); K120 substituted with V; K130V; and R352V. Binding of [3H]CCK-8 was observed in WT and K130V, but not in K120V and R352V. CCK caused Ca(2+) spiking in WT and K130V, whereas K120V and R352V had no effect. Three chimeras including the CCK-AR/3ibeta2 adrenergic receptor (beta2AR), 3Nibeta2AR, and 3Cibeta2AR were constructed. Two groups of point mutations in the CCK-AR3i were also made: Y252V, S274V, S281V, and S289V (non-phospho-acceptor Y or S); S260V, S264V, S271V, and S275V (phospho-acceptor S). WT and CCK-AR/3Cibeta2AR increased [Ca(2+)](i) in response to CCK; 3Nibeta2AR was vice versa. CCK failed to increase [IP(3)] in phospho-acceptor S to V without affecting binding. Non-phospho-acceptor S or Y to V showed normal response. Thus, Lys120 outside the TM2 and Arg352 outside the TM6 of the CCK-AR are amino acids interacting with Tyr[SO(3)H]27 and Asp32 of the CCK peptide for binding. Phospho-acceptor Ser groups in the CCK-AR 3Ni are amino acids for initiating cell signaling.

Amino Acid Sequence↗
PubMed2006

Very low levels of cholecystokinin octapeptide activate Na-pump in the cerebral cortex of CCK2 receptor-deficient mice.

This study provides the first evidence that CCK-8 (0.01 pM to 0.1 mM) stimulates Na,K-ATPase in the cortical membranes of wild-type and CCK(2) receptor-deficient mice. In each genotype, the maximal stimulation was about 40%. Homozygous mice revealed substantially lower EC50 (4 pM) than heterozygous (37 pM) or wild-type animals (682 pM). In homozygous CCK2 receptor-deficient mice, the expression of CCK1 receptor gene was 5-fold higher than in wild-type animals. CCK1 receptor antagonist devazepide counteracted effect of CCK-8 in all three genotypes, whereas CCK2 receptor antagonist L-365, 260 showed significant antagonism in wild-type and heterozygous mice. The cooperativity of Na,K-ATPase for Na+, but not for K+, was lost in homozygous mice. Altogether, very low concentrations of CCK-8 via CCK1 and CCK2 receptors stimulate Na,K-ATPase in the cerebral cortex. CCK2 receptor-deficiency leads to the altered functionality of Na,K-ATPase that might be compensated by CCK1 receptor mediated influence of CCK (and its agonists) on the enzyme.

Animals↗