CCK Modulation Research Articles

Cholecystokinin selectively activates short axon cells to enhance inhibition of olfactory bulb output neurons.

Cholecystokinin (CCK) via CCK-B receptors significantly enhances the GABAA receptor-mediated synaptic inhibition of principal olfactory bulb (OB) output neurons. This CCK action requires action potentials in presynaptic neurons. The enhanced inhibition of OB output neurons is a result of CCK-elevated inhibitory input from the glomerular circuit. CCK modulation of the glomerular circuit also leads to potentiated presynaptic inhibition of olfactory nerve terminals and postsynaptic inhibition of glomerular neurons. Selective excitation of short axon cells underlies the CCK-potentiated glomerular inhibition. Neuropeptides such as cholecystokinin (CCK) are important for many brain functions, including sensory processing. CCK is predominantly present in a subpopulation of excitatory neurons and activation of CCK receptors is implicated in olfactory signal processing in the olfactory bulb (OB). However, the cellular and circuit mechanisms underlying the actions of CCK in the OB remain elusive. In the present study, we characterized the effects of CCK on synaptic inhibition of the principal OB output neurons mitral/tufted cells (MTCs) followed by mechanistic analyses at both circuit and cellular levels. First, we found that CCK via CCK-B receptors enhances the GABAA receptor-mediated spontaneous IPSCs in MTCs. Second, CCK does not affect the action potential independent miniature IPSCs in MTCs. Third, CCK potentiates glomerular inhibition resulting in increased GABAB receptor-mediated presynaptic inhibition of olfactory nerve terminals and enhanced spontaneous IPSCs in MTCs and glomerular neurons. Fourth, CCK enhances miniature IPSCs in the excitatory external tufted cells, although neither in the inhibitory short axon cells (SACs) nor in periglomerular cells (PGCs). Finally, CCK excites all tested SACs and a very small minority of GABAergic neurons in the granule cell layer or in periglomerular cells, but not in deep SACs. These results demonstrate that CCK selectively activates SACs to engage the SAC-formed interglomerular circuit and thus elevates inhibition broadly in the OB glomerular layer. This modulation may prevent the system from saturating in response to a high concentration of odourants or facilitate the detection of weak stimuli by increasing signal-to-noise ratio.

Vagal afferent-dependent cholecystokinin modulation of visceral pain requires central amygdala NMDA-NR2B receptors in rats.

Cholecystokinin (CCK), a gut hormone that is released during feeding, exerts gastrointestinal effects in part through vagal pathway. It is reported to be a potential trigger for increased postprandial visceral sensitivity in healthy subjects and, especially in patients with irritable bowel syndrome. NR2B-containing N-methyl-d-aspartate (NMDA) receptors in the central amygdala (CeA) participate in pain modulation. Systemically administered CCK activates the CeA-innervating neurons. Here, we investigated whether CCK modulation of visceral sensitivity is mediated through CeA NMDA-NR2B receptors and whether this modulation involves vagal pathway. We first examined the visceromotor response (VMR) to colorectal distention (CRD) following i.p. injection of CCK octapeptide (CCK-8) in a rat model. Next, the NR2B antagonist ifenprodil and the NR2A antagonist NVP-AAM077 were microinjected into the CeA before systemic CCK injection. NR2B phosphorylation was detected by Western blot. To down-regulate NR2B gene expression, NR2B-specific small interfering RNA (siRNA) was delivered into CeA neurons by electroporation. In addition, the effects of functional deafferentation by perivagal application of capsaicin and pretreatment with the CCK1 receptor antagonist devazepide were investigated. CCK-8 increased VMR to CRD in a dose-dependent manner. This effect was blunted by intra-CeA administration of ifenprodil (but not NVP-AAM077) and was accompanied by phosphorylation of NR2B subunits in the CeA. CCK failed to increase VMR to CRD in NR2B siRNA-treated rats. Perivagal capsaicin application and pretreatment with devazepide prevented CCK-induced pronociception and CeA NR2B phosphorylation. The pronociception induced by systemic CCK, which is vagal afferent-dependent, requires activation of CeA NMDA-NR2B receptors.

Suppression of cAMP-dependent gene expression by cholecystokinin in the hippocampus

Our previous study suggests that "the neuropeptidergic system" might promote a diversity of the mechanisms that regulate signal transmission in the hippocampus. Cholecystokinin (CCK) is the mostly expressed neuropeptide gene in the hippocampus. Here, we investigated whether CCK regulates immediate-early genes (Egr1/zif268 and Fos), critical indicators of cortical neuronal activity. We showed that CCK increased Egr1/zif268 promoter activity in a neuronal cell line, which is transfected with CCK(B) receptor. Unexpectedly, in living hippocampal slices, CCK significantly suppressed cAMP-induced expression of Egr1/zif268 and Fos through CCK(B) receptor activation. This suppression was involved in activating GABA(B) and cannabinoid 1 receptors. In addition to transient CCK modulation of action potentials on hippocampal principal neurons, we suggest that release of endogenous CCK might indirectly produce the suppression of cAMP-dependent gene expression in the hippocampus.

Application of Convolution Code in CCK Modulation Technology

Adopted by IEEE802.11b standard as the high speed expanding scheme, CCK modulation technology performs well in error probability with high signal noise ratio. However, the CCK system’s error probability soars when SNR is comparably low or the number of users in the same channel increases suddenly. Based on CCK algorithm and convolution code’s structure, this paper analyzed code parameters’ influence on error probability and proposed a channel coding scheme suitable for CCK modulation: convolution code （2,1,7）with 3bit soft decision decoding. Simulation Results demonstrated that system performance is greatly improved when SNR is upon 1.3dB and 2dB’s additional coding gain is attained compared with hard decision decoding.

Properties and performance of the IEEE 802.11b complementary-code-key signal sets

We describe similarities and differences between complementary-code-key (CCK) modulation and modulation that is derived from biorthogonal signals, and we present performance results and other information that may be useful to those who have applications for CCK modulation that do not require IEEE 802.11b compliance. The properties and performance of the highrate IEEE CCK 802.11b modulation formats are investigated and compared with the properties and performance of alternative modulation formats that are based on biorthogonal signals. Several complementary properties are derived for the full-rate (11 Mb/s) CCK signal set, the half-rate (5.5 Mb/s) CCK signal set, a full-rate signal set obtained from biorthogonal signals, and a half-rate biorthogonal signal set. Each signal set is a complementary set, but each also has stronger complementary properties. We evaluate the performance of IEEE 802.11b standard CCK modulation, CCK with certain modifications that depart from the IEEE standard, and modulation that is derived from biorthogonal signals. Performance comparisons are presented for additive white Gaussian noise (AWGN) channels and for channels with specular multipath. In particular, for AWGN channels, we provide an accurate analytical approximation for the frame error probability for full-rate CCK modulation.

Brain regional neuropeptide changes resulting from social defeat.

Past work has demonstrated robust brain changes in cholecystokinin (CCK-8) following social defeat. Here the authors analyzed brain regional, CCK-8, substance P, corticotropin releasing factor (CRF), and neuropeptide Y levels in adult male Long-Evans rats defeated in a resident-intruder social aggression paradigm, as indexed by elevated bites received, freezing, and emission of 20-kHz calls. Brains harvested 6 hr after social defeat were dissected into 12 regions (olfactory bulbs, 3 cortical regions [frontal cortex, cortex above the basal ganglia, cortex above the diencephalon], caudate-putamen, basal forebrain, hypothalamus, hippocampus, thalamus, tectum, tegmentum, and lower brain stem). Neuropeptide radioimmunoassays demonstrated the following statistically significant regional changes in defeated rats as compared with nondefeated rats: CCK-8 was reduced in frontal cortex and cortex overlying diencephalon, the olfactory bulbs, caudate-putamen, hippocampus, tectum, and lower brainstem. Neuropeptide Y was elevated in the caudate-putamen. Substance P was elevated in the cortex over the basal ganglia and decreased in basal forebrain. CRF was diminished in the hippocampus. The results highlight more robust CCK modulation by social defeat as compared with 3 other neuropeptide systems involved in brain emotional regulation.

Urocortins and Cholecystokinin-8 Act Synergistically to Increase Satiation in Lean But Not Obese Mice: Involvement of Corticotropin-Releasing Factor Receptor-2 Pathway

Interactions between gastrointestinal signals are a part of integrated systems regulating food intake (FI). We investigated whether cholecystokinin (CCK)-8 and urocortin systems potentiate each other to inhibit FI and gastric emptying (GE) in fasted mice. Urocortin 1 and urocortin 2 (1 microg/kg) were injected ip alone or with CCK (3 microg/kg) in lean, diet-induced obese (DIO) or corticotropin-releasing factor receptor-2 (CRF(2))-deficient mice. Gastric vagal afferent activity was recorded from a rat stomach-vagus in vitro preparation. When injected separately, urocortin 1, urocortin 2, or CCK did not modify the 4-h cumulative FI in lean mice. However, CCK plus urocortin 1 or CCK plus urocortin 2 decreased significantly the 4-h FI by 39 and 27%, respectively, compared with the vehicle + vehicle group in lean mice but not in DIO mice. Likewise, CCK-urocortin-1 delayed GE in lean but not DIO mice, whereas either peptide injected alone at the same dose had no effect. CCK-urocortin 2 suppression of FI was observed in wild-type but not CRF(2)-deficient mice. Gastric vagal afferent activity was increased by intragastric artery injection of urocortin 2 after CCK at a subthreshold dose, and the response was reversed by devazepide. These data establish a peripheral synergistic interaction between CCK and urocortin 1 or urocortin 2 to suppress FI and GE through CRF(2) receptor in lean mice that may involve CCK modulation of gastric vagal afferent responsiveness to urocortin 2. Such synergy is lost in DIO mice, suggesting a resistance to the satiety signaling that may contribute to maintain obesity.

Cholecystokinin as a factor in the enhanced potency of spinal morphine following carrageenin inflammation

1. Cholecystokinin (CCK) has been shown to diminish opioid analgesia. Here we investigate whether changes in the physiological levels of spinal CCK are responsible for the enhanced potency of spinal morphine in animals following carrageenin inflammation, as compared with normal animals. 2. Single dorsal horn nociceptive neurones were recorded in intact halothane-anaesthetized rats in the presence and absence of carrageenin-induced inflammation and comparisons were made between the two groups of animals. Inflammation was induced by the injection of 100 microliters of 2% lambda-carrageenin into the hind paw. 3. The inhibitory effect of intrathecal morphine on the C-fibre-evoked responses of the neurones was enhanced in the carrageenin-treated animals such that the effects of 0.25 microgram and 10 micrograms of morphine in normal animals were comparable to those of 0.01 microgram and 2.5 micrograms in the carrageenin animals. The effect of 0.2 mg kg-1 of the CCKB antagonist, L-365,260, on the antinociceptive potency of intrathecal morphine was examined in both groups of animals. In normal animals, L-365,260 produced a significant enhancement in the effect of morphine indicating a tonic CCK modulation in these animals, but it had no effect on the inhibitions produced by either dose of morphine in the carrageenin animals. 4. The inhibition of the C-fibre-evoked response produced by intrathecal morphine in the presence of 1 microgram of CCK was examined in both groups of animals. CCK attenuated the effects of morphine only in animals with carrageenin inflammation, having no effect on the action of morphine in normal animals. 5. The effects of both CCK and L-365,260 were therefore dependent on the inflammatory state of the animal, with each drug being active in opposite situations.6. We propose that in normal animals, morphine may produce a maximal stimulation of the release of CCK such that exogenous CCK is unable to reduce further the analgesic effects under these conditions.However, the differential effects of the agonist and antagonist in the normal and inflamed rats points to a role of CCK in the enhanced opiate actions. This enhancement of the potency of spinal morphine in inflammation is best explained by a reduction in spinal CCK release by morphine in this state.

CCK modulation of cerebellar afferents: Dopaminergic involvement

1. Dopamine agonists and dopamine releasers act at the level of the striatum to activate a mossy fiber pathway which in turn increases cerebellar cGMP in the rodent. 2. CCK acts to both decrease basal cerebellar cGMP levels as well as to antagonize increases in cerebellar cGMP elicited by dopaminergic agonists and releasers. 3. This CCK action involves a “central-type” CCK receptor population which resides outside of the cerebellum. 4. These data are consistent with the pharmacology for CCK inhibition of dopamine release in the striatum; suggesting that CCK effects on cerebellar cGMP may be mediated by antidopaminergic actions within the striatum.