Pharmacological Properties

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Physiology

CCK peptides belong to a family of neuroendocrine pep-tides. CCK was discovered in extracts of the small intestine as a substance that elicits the hormonal gallbladder contracting effect and that can stimulate pancreatic secretion. That these two effects are mediated by the same substance was revealed in 1961 by Viktor Mutt, who also identified its chemical identity (Reeve et al. 1994). CCK also acts as a growth factor for the pancreas and as a neurotransmitter.

Only one CCK mRNA molecule is produced from the CCK gene, and its translational product, preproCCK, consists of 115 amino acid residues. This product is the source of all CCKs. The bioactive CCK peptides include those with 83, 58, 39, 33, 22, and 8 amino acid residues and these are produced in a cell-specific manner. CCK peptides share a common C-terminal sequence with another peptide, gastrin, which has recently also been found in multiple molecular forms (Rehfeld et al. 2007). Modification of this tetrapeptide amide sequence strongly reduces biological activity.

CCK peptides bind to CCKA and CCKB (alternatively, CCK1 and CCK2, respectively) receptors that are both coupled to G proteins. As ligands, CCKA receptors require CCKs that are amidated at the C-terminal, and sulfated on a tyrosine in the seventh position from the terminal. These receptors mediate contraction of gallbladder and relaxation of the sphincter of Oddi, and pancreatic growth and enzyme secretion. These receptors are also expressed in the peripheral nervous system and in the anterior pituitary; expression in the brain is less prevalent than of the CCKB receptors. The latter are identical to the gastrin receptor, and besides brain, are abundantly expressed on gastric ECL-cells and parietal cells, and in the pancreas. CCKB receptors also bind non-sulfated CCK, CCK-5, and CCK-4 with high affinity. Importantly, the peripheral physiological responses mediated via CCKB receptors are elicited by gastrin, because the plasma levels of gastrin are much higher than those of CCK (Rehfeld et al. 2007). In brain, CCKB receptors are expressed with the highest density in the striatum, cerebral cortex, and the olfactory nuclei; moderate levels have been found in the ► hippocampus, substantia nigra, periaqueductal grey matter, and pontine nuclei.

CCK in circulation originates mainly from the intestinal endocrine cells that release the peptide in response to food rich in protein and fat. Since the satiety-inducing ability of CCK was discovered in 1973, many studies on animals and humans have shown it to serve as an endogenous satiety factor (Reeve et al. 1994). This satiety signal appears to be mainly mediated by the vagus nerve and subsequently the nucleus tractus solitarius and area postrema to the hypothalamus. CCK also inhibits gastric acid secretion, directly via CCKB receptors and indirectly via CCKA receptors stimulating ► somatostatin release.

Neuronal CCK

Neurons mainly synthesize and release CCK-8. At variance with many ► neuropeptides, expression of CCK is highest in the neocortex. Other brain regions enriched with CCK are caudate-putamen, hippocampus, and ► amygdala, and significant levels are present in thalamus, hypothalamus, olfactory bulb, ventral tegmental area and periaqueductal grey matter. CCK-8 release is, characteristically to neurotransmitters, evoked by potassium-induced depolarization and dependent upon calcium. CCK has been shown to elicit both excitatory and inhibitory postsynaptic potentials. CCK interacts with several other neurotransmitter systems, most notably ► dopa-mine, ► GABA, ► endogenous opioids and endocannabi-noids (Harro 2006).

For both CCK receptors, a plethora of selective ligands of distinct chemical classes have been synthesized (Berna et al. 2007). This has strongly facilitated detailed studies on physiology of the CCK systems. Several of the drugs are chemically not peptides and are active when administered via enteral route.

Panicogenic Properties

Intravenous administration of CCK C-terminal tetra-peptide (CCK-4) or pentapeptide (CCK-5 or pentagas-trin) elicits ► panic attacks in patients with panic disorder and in healthy volunteers. This effect is dose dependent. The most common symptoms in response to a bolus injection of CCK-4 are dyspnea, palpitations, chest pain or discomfort, faintness, dizziness, paresthesia, hot flushes or cold chills, nausea or abdominal distress, anxiety or fear or apprehension, and fear of losing control. In panic disorder patients the attacks are not distinguishable to them from their spontaneous panic attacks. The panic disorder patients are more sensitive to the CCK-4 challenge than healthy subjects, but patients with other anxiety disorders do not differ in this regard from healthy volunteers. In panic disorder patients, a few alterations in CCK levels or cellular responses to CCK have been reported, but all findings remain waiting for independent replication. CCK-4-induced anxiety is accompanied by a robust activation in a broad cerebral network including anterior cingulate cortex, middle and superior frontal gyrus, precuneus, middle and superior temporal gyrus, occipital lobe, sublobar areas, cerebellum and brainstem (Dieler et al. 2008).

The panicogenic effect of administered CCK-4 can be prevented by treatment with ► benzodiazepines or CCKB receptor antagonists, or chronic administration of tri-cyclics. However, attempts to cure panic disorder or generalized anxiety disorder with non-peptide CCKB antagonists of different chemical classes have been unsuccessful. It has been proposed that the failure of attempts to prevent panic attacks in panic disorder with CCKB antagonists used in published studies is due to limitations of these treatments (poor bioavailability and/or insufficient brain penetration of the compounds), but while such a suggestion is not entirely in contradiction with the efficacy of these drugs against CCK-induced panic in humans, it is certainly weakened by this evidence (Harro 2006).

CCK Receptor Agonists and Antagonists in Animal Models of Anxiety

Both systemic and intracerebral administration of CCK peptides has been found to elicit anxiogenic-like effects in ► animal models of anxiety, including ► elevated plus-maze and ► open field test, and several others. These effects are usually antagonized by CCKB but not CCKA receptor antagonists. It should be noted that the efficacy of low, non-sedating doses of CCK peptides is not universally reproduced across laboratories and may require presence of unknown environmental factors. CCKB receptor antagonists as a single treatment have been reported to possess anxiolytic properties, but several thorough studies have not supported such a claim and it seems possible that the anxiolytic-like effect is mimicked by enhancement of locomotor activation by these drugs (Harro 2006).

Behavioral tests that are most sensitive to anxiety-related effects of CCK receptor ligands include potentiated startle, and particularly those that are based on exploratory activity. Effects of CCK receptor ligands on defensive behavior are weak and on social behavior rather contradictory. Conflict tests based on ► punishment procedures are not sensitive to CCK, and when exploratory behavior is punished as in the four plate test, CCK antagonists fail to show anxiolytic-like action.

Neurobiology of CCK in Animal and Human Anxiety

Studies that have examined levels of CCK or CCK receptors in anxiety have not found consistent alterations in CCK expression, but increases in CCKB ► receptor binding have been described in animal models of anxiety and in human postmortem studies. CCKB receptor binding sites are upre-gulated in cerebral cortex and cerebellum of persistently anxious or stressed rats, and in transgenic mice that overexpress CCKB receptors anxiety levels are higher, this increase being sensitive to ► benzodiazepine anxiolytics. CCK receptor binding has been found increased in frontal and cingulate cortex of human ► suicide victims, and by measuring mRNA levels with quantitative PCR this has been confirmed and attributed to CCKB subtype.

Brain regions in which neuronal CCK appears to play a role in anxiety-related behavior include cortex, amygdala (particularly basolateral), periaqueductal grey matter, cerebellum, septum, hippocampus (particularly areas CA1 and CA2), and paraventricular thalamus (Harro 2006). In some brain regions the anxiety-related effects of CCK are known to occur with some specificity: CCK in amygdala prevents ► extinction learning, and CCK-mediated activation of periaqueductal grey by anticipatory anxiety elicits hyperalgesia. In several brain regions such as cortex, hippocampus and amygdala, anxiety-related effects of CCK may interact with changes in GABA-ergic activity. In several brain regions ► GABA and CCK coexist in a population of interneurons that also express ► endocan-nabinoid CB1 receptors. Serotonin, noradrenaline, and opioids also modulate the anxiety-related effects of CCK. The anxiogenic effect of CCK-4 can be blocked with a ► CRF receptor antagonist. This suggests that CCK-elicited anxiety is dependent upon the activation of the HPA stress axis.

Stressful events have been associated with changes in CCK levels and CCK mRNA expression. Direct examination of extracellular levels of CCK after a stressful event as measured using in vivo ► microdialysis has suggested increased release of the peptide in the frontal cortex (Becker et al. 2001). Importantly, such an increase was observed in rats that had repeatedly been submitted to social defeat in the form of being placed first into a protected smaller environment within an aggressive resident's cage and subsequently allowed a physical contact, but not in animals that could after initial protected exposure explore the whole cage as the resident had been removed. Because ► microdialysis was conducted after protected exposure to the resident, the findings suggest that either in frontal cortex CCK is released only after sensitization by severe stressors or that learning of safety can prevent cortical CCK release. Adaptive or maladaptive changes in brain that underlie such differential reactions to threat may also cause the individual to react to drugs dependent upon stressfulness of the situation, as this has been reported for the effects of administered CCK peptides (► Stress: Influence on drug action). Several other studies also suggest that the role of CCK release in adapting with environmental signals depends upon the previous experiences of the subject, and these may determine whether the net effect of CCK release is anxiety, panic, or instead, perceived safety (Harro 2006).

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