Neuronal Network of Panic Disorder: The Role of the Neuropeptide Cholecystokinin

Abstract

Panic disorder (PD) is characterized by panic attacks, anticipatory anxiety and avoidance behavior. Its pathogenesis is complex and includes both neurobiological and psychological factors. With regard to neurobiological underpinnings, anxiety in humans seems to be mediated through a neuronal network, which involves several distinct brain regions, neuronal circuits and projections as well as neurotransmitters. A large body of evidence suggests that the neuropeptide cholecystokinin (CCK) might be an important modulator of this neuronal network. Key regions of the fear network, such as amygdala, hypothalamus, peraqueductal grey, or cortical regions seem to be connected by CCKergic pathways. CCK interacts with several anxiety-relevant neurotransmitters such as the serotonergic, GABA-ergic and noradrenergic system as well as with endocannabinoids, NPY and NPS. In humans, administration of CCK-4 reliably provokes panic attacks, which can be blocked by antipanic medication. Also, there is some support for a role of the CCK system in the genetic pathomechanism of PD with particularly strong evidence for the CCK gene itself and the CCK-2R (CCKBR) gene. Thus, it is hypothesized that genetic variants in the CCK system might contribute to the biological basis for the postulated CCK dysfunction in the fear network underlying PD. Taken together, a large body of evidence suggests a possible role for the neuropeptide CCK in PD with regard to neuroanatomical circuits, neurotransmitters and genetic factors. This review article proposes an extended hypothetical model for human PD, which integrates preclinical and clinical findings on CCK in addition to existing theories of the pathogenesis of PD.

Acute Shift in Glutamate Concentrations Following Experimentally Induced Panic with Cholecystokinin Tetrapeptide—A 3T-MRS Study in Healthy Subjects

“…Overall, with regard to behavioral effects observed after CCK-4 administration, the present results are in accordance with the extensive body of literature on the panicogenic effects of CCK-4 (see Zwanzger et al, 2012).…”

“…Among the available panicogenic agents, the neuropeptide cholecystokinin-tetrapeptide (CCK-4) has been shown to induce panic attacks both in patients with PD and in healthy volunteers (Zwanzger et al, 2012). Moreover, panic symptoms elicited by CCK-4 are attenuated after pharmacological treatment: Several studies have shown that treatment with antidepressants, which currently represent first-line treatment for PD, lead to a reduction of panic experimentally induced by CCK-4 (Bradwejn and Koszycki, 1994;Shlik et al, 1997).…”

Acute effects on brain cholecystokinin-like concentration and anxiety-like behaviour in the female rat upon a single injection of 17β-estradiol

“…The involvement of CCK in panic disorders was in fact originally described in humans. Indeed, intravenous administration of CCK-4 was found to induce panic attacks in both healthy volunteers and in patients suffering from panic disorders (Bradwejn et al , 1990, Zwanzger et al , 2012 and sex-differences have been found in these effects which makes them even more interesting. Moreover, of the two types of CCK receptors identified, CCK2-R is most abundant in the brain and also the receptor mainly thought to induce the observed anxiogenic effects.…”

Temporal association of elevated cholecystokininergic tone and adolescent trauma is critical for posttraumatic stress disorder-like behavior in adult mice

“…Indeed, a twin study of Vietnam veterans revealed that about 37.9% of vulnerability to PTSD was genetically related (41). Clinical association studies have identified more than 10 candidate genes for PTSD (5,42), whereas the CCKR-2 gene has been repeatedly associated to panic disorder, another major form of anxiety disorders (10). Moreover, polymorphisms in microRNAs that are associated to panic disorder are also functionally related to the CCKergic system (43).…”

“…Stress may dysregulate various neurotransmitter systems in the brain, among which the CCKergic system, including cholecystokinin (CCK) peptides and their receptors, is of a significant importance, based on its dynamic regulation in response to stress (7,8). Actually, the CCKergic system has long been recognized as an anxiogenic factor (7), and CCK peptides were commonly used to induce anxiety in volunteers (9,10). CCK peptides and CCK receptor-2 (CCKR-2) widely distribute in the brain, with the highest level in the limbic system (11), the areas that are critically involved in cognition and emotion (12).…”