The Ventilatory Response to Cholecystokinin Tetrapeptide in Healthy Volunteers

Abstract

The cholecystokinin (CCK) system, which has been shown to interact with both the panicogenic and respiratory systems, provides an interesting mechanism to further evaluate the central chemoreceptor and its effect on panic attack sensitivity. Intravenous CCK, a naturally occurring neuropeptide in the brain, has been found to induce the emotional and somatic symptoms of panic in both Panic Disorder (PD) and Normal Control (NC) subjects in a dose-dependent and reproducible fashion. To induce these effects, lower doses of intravenous CCK are required in the PD patients, relative to the NC subjects potentially suggesting that endogenous alterations in the CCK system may be contributing to the development of PD.Intravenous administration of CCK-4 in association with panic also results in subjective dyspnea, that is, diminution in vital capacity without an effect on the respiratory resistance. CCK-4 also causes a significant increase in tidal volume and minute ventilation but has no effect on breathing frequency. These observations suggest that a CCK-B receptor agonist may be acting as a respiratory stimulant, exerting its effect on anxiety through a direct effect on respiration.This study represents an examination of the specific effects of CCK-4 on the central chemoreceptor response.The study used a modified rebreathing technique, which accurately measures the ventilatory response to carbon dioxide in terms of both threshold and sensitivity. This technique requires the subject to rebreathe from a bag containing a hyperoxic and hypercapnic gas mixture resulting in rapid equilibration between alveolar gas and arterial blood. Use of a hyperoxic gas allows for the preferential examination of the central chemoreflexes (sensitive to CO2) with little if any effect of the peripheral (oxygen sensitive) chemoreflexes.After significant training, 15 healthy control subjects were assigned via a double blind procedure to receive an intravenous injection of placebo or CCK-4, using a between-subjects design. A between-subjects comparison was undertaken for the injection run (run #3) between subjects receiving the CCK-4 injection and those receiving the placebo injection. As well, a within-subject comparison was undertaken to compare the results of the run following the injection (run #3) vs. the previous run when no injection took place (run #2).No significant differences were noted between subjects who received CCK-4 as compared with placebo for: basal or sub-threshold ventilation, threshold CO2 resulting in a change in ventilation, or sensitivity of the central chemoreflex, regardless of whether a panic attack did or did not take place. In addition, within the group receiving the CCK-4 challenge, no significant differences were noted during run #3 (received the CCK-4 injection) and a prior run where no injection took place (run #2).We conclude that CCK-4 does not act to induce panic by altering the central (CO2 sensitive) chemoreceptor.