Cholecyctokinin is a neuropeptide found in the gastrointestinal system and brain. Research has shown that it has various isolated fragments that may influence several important areas of human behavior, such as nociception, satiety and anxiety. Cholecystokinin receptors located in the central nervous system (CNS) are known as CCK-B receptors, and they have high affinity for the tetrapeptide fragment CCK-4. Anxiogenic effect of CKK-4 in humans suggested that it might be involved in pathogenesis of panic disorder, and opened new avenues of research into biological aspects of anxiety. Further research showed increased sensitivity of panic disorder patients to CCK-4 in comparison with normal volunteers.
Next, substances capable of blocking CCK-B receptors (CCK-B antagonists) were synthesized and their action was evaluated. One of such antagonists, L-365,260 proved to be effective in blocking CCK-4 induced panic attacks in panic disorder sufferers. However, a pilot study failed to show the effectiveness of the same antagonist in decreasing the frequency of spontaneous panic attacks in panic disorder patients during the course of six weeks. Though CCK-B antagonists may prove to become great potential anxiolitic agents, more research has to be done in order to understand the mechanism of CCK-4 action as a neurotransmitter and its role in naturally occurring panic attacksEthiology of panic disorder: a brief overviewPanic disorder, (PD) is a recognized psychiatric condition and is identified in DSM-III-R as a condition separate from other anxiety disorders. Its main feature is occurrence of unprovoked panic attacks, which happen at random and cannot be explained by the patients. These attacks of fear are closely associated with an overwhelming subjective feeling of anxiety in connection with unpleasant bodily sensations, such as increased heartbeat/palpitations, hot flushes/chills, abdominal distress, nausea, sweating, trembling/shaking, etc. Along with objectively groundless emotional symptoms, e.
g. fear of losing control, sense of unreality and detachment, even fear of dying they affect PD sufferers, interfering with social and professional aspects oftheir lives. Some PD patients associate panic attacks with certain objects or situations, and therefore phobias, especially agoraphobia , are closely associated with the PD. The ethiology of PD is not clear, and most theories support either a psychological or a neurobiological view.
The most developed psychological explanation is cognitive theory of PD. According to Clark’s model, the panic attack develops as a result of misinterpretation of unpleasant bodily sensations,which leads to increasing feeling of anxiety and progresses to a fully developed panic. This misinterpretation is defined as anxiety sensitivity, and it present in PD patients.
When challenged by panicogenic pharmacological agents, anxiety sensitivity causes a faster and stronger response in PD sufferers than in healthy individuals.2 Biological theories concentrate on implicating pathological disturbances in the neurotransmitter systems, including GABA, serotonin (5HT) and noradrenaline. Recently attention was given to a less known neuropeptide cholecystokinin (CCK). Though it was first discovered in the gastrointestinal tract (it is secreted by the small intestine and stimulates gall bladder contractions), its abundant presence in the mammalian brain indicated on its possible functions as a behavior-regulating neurotransmitter. Various electrophysiological data and animal studies linked CCK to anxiety regulation.
For example, its excitatory role on pyramidal neurons of hippocampal area was first observed in rats after electrophoretic administration of CCK, and increased density of CCK-B receptors was detected in rats with low exploratory activity and with novelty-avoidance behavior.7 The later, also known as novelty stress sensitivity, is often observed in panic disorder patients.. Anxiogenic properties of CCK were demonstrated in various animal models of anxiety, and results of only one of these studies suggested anxiolytic rather than anxiogenic properties of CCK.7 The first human study which demonstrated CCK anxiogenic properties was conducted by De Montigny in 1989. The study did not include a control group and all participants were healthy volunteers. Upon injection of various doles of CCK (20-100 mg) 70% of participants developed panic attack symptoms.
7 This discovery was confirmed a year later by Bradwejn and colleagues, who have contributed heavily to the research on the role of CCK as panicogenic agent. In 1991 they confirmed De Montignys observation with the use of a double-blind experimental design.7 Unlike de Montigny, Bradwejns study included no healthy volunteers, but rather panic disorder patients, who were randomly subjected to injections of either