The effects of central cholecystokinin receptor blockade on hypothalamic-pituitary-adrenal and symptomatic responses to overnight withdrawal from alprazolam

Abstract

Abrupt withdrawal from benzodiazepines (BZs) produces anxiety and potently activates the hypothalamic-pituitary-adrenal (HPA) axis in animals (Eisenberg 1987; Owens et al 1991). Alcohol withdrawal similarly activates the HPA axis in humans (Adinoff et al 1991; yon Bardeleben et al 1989). The human HPA response to BZ withdrawal has been little studied (Adam et al 1984), but the animal and human alcohol data predict activation. Abrupt BZ withdrawal also produces increases in hippocampal and cortical cholecystokinin (CCK) receptor number (Harro et al 1990) and in pre-proCCK mRNA (Rattray et al 1993). CCK agonists can induce anxiety and activate hippocampal neurons; both of these effects are antagonized by BZs (Bradwejn and de Montigny 1984; de Montigny 1989). CCK also activates the HPA axis (Abelson et al 1991), whereas BZs inhibit it (Owens et al 1991). CCK and BZs thus appear to interact antagonistically in modulating anxiety and the stress axis, raising the possibility that BZ withdrawal-induced anxiety and HPA axis activation could be me-