Dose Response of Arginine Vasopressin to the CCK-B Agonist Pentagastrin

Abstract

Cholecystokinin (CCK) is a peptide neurotransmitter that modulates hypothalamic-pituitary-adrenal (HPA) axis activity and may be involved in fear or anxiety states. Arginine vasopressin (AVP) also modulates HPA axis activity and may play a role in fear conditioning. Few human studies have examined interactions between CCK and AVP systems. To explore relationships between CCK-B receptor activation, the HPA axis response, and AVP release, a dose-response study using the CCK-B receptor agonist pentagastrin was conducted. Adrenocorticotropin (ACTH) and cortisol results have been previously reportedand AVP data is presented here. Thirty-five healthy subjects were randomly assigned to receive placebo, or 0.2, 0.4, 0.6, or 0.8 Cholecystokinin (CCK) is a peptide neurotransmitter that is widely distributed in brain areas involved with cognitive or emotional aspects of behavior, such as prefrontal cortex, cingulate, hippocampus, amygdala, and the locus coeruleus (Lindefors et al. 1993;Saito et al. 1980). Some evidence suggests it may modulate stress responsiveness, functioning as a neuromodulator of the hypothalamicpituitary-adrenal (HPA) axis (Abelson and Liberzon 1999). CCK-B agonists, such as pentagastrin, activate the HPA axis in humans, stimulating release of adrenocorticotropin (ACTH) and cortisol (Abelson and Liberzon 1999;de Montigny 1989;Degli Uberti et al. 1983;Späth-Schwalbe et al. 1988).Levels of CCK and corticotropin-releasing hormone (CRH) were found to be correlated in human cerebrospinal fluid, suggesting that central regulation of these two neuropeptides may be linked in humans; and this linkage may be tighter under conditions of stress (Geracioti et al. 1999). Animal work also demonstrates substantial interaction between CCK and the HPA axis. The axis is directly sensitive to CCK activation (Kamilaris et al. 1992;Matsumura et al. 1983;Mezey et al. 1986;Reisine and Jensen 1986); and CCK peptide is colocalized with other HPA axis secretagogues (Kiss et al. 1984;Larsson and Rehfeld 1981;Mezey et al. 1986; Mill- ington et al. 1992;Rehfeld 1978;Rehfeld and Larsson 1981;Rehfeld et al. 1987;Vanderhaeghen et al. 1985). Central CCK systems are stress and glucocorticoid sensitive (Mezey et al. 1986;Siegel et al. 1987); and peripheral CCK can regulate activity in central components of the HPA axis (Chen et al. 1993).Though CCK-HPA axis interactions are well established, the mechanisms by which they interact remain uncertain. Central regulation of the HPA axis is exerted primarily through corticotropin-releasing hormone (CRH), arginine vasopressin (AVP), and negative glucocorticoid inhibition (Aguilera 1994). Animal work suggests that both CRH (Biró et al. 1993;Kamilaris et al. 1992) and AVP (Bondy et al. 1989;DeBold et al. 1984;Mezey et al. 1986;Verbalis et al. 1987) could mediate CCK effects on the HPA axis. However, due to substantial cross species variation in CCK function (Hinks et al. 1995;Woodruff et al. 1991), human studies will be needed to clarify these mechanisms in humans. CCK-induced release of ACTH...

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“…Studies in healthy volunteers do suggest that alteration in AVP release may be linked to emotional and behavioural responses. For example, exposure to the cholecystokinin-B receptor agonist, pentagastrin induces anxiety symptoms which correlate with plasma AVP concentrations [82]. However, further investigations are needed to confirm this correlation and the mechanisms underlying this effect.…”

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“…AVP is linked to the activation of the HPA axis, and the expression level of AVP in the paraventricular nucleus is increased by both acute and repeated stress (Berkenbosch et al ., ; Aguilera and Rabadan‐Diehl, ). Moreover, clinically, both the plasma AVP levels and the level of AVP immunoreactivity in the paraventricular nucleus are elevated in patients with MDD, compared with healthy controls (Purba et al ., ; van Londen et al ., ), and AVP release is significantly correlated with anxiety symptom responses in healthy subjects challenged with an anxiogenic cholecystokinin‐B agonist (Abelson et al ., ). Thus, AVP seems to be a key component in stress‐related disorders, such as depression and anxiety (for reviews, see Scott and Dinan, ; Zelena, ).…”