Benzodiazepines and anterior pituitary function

Abstract

Benzodiazepines (BDZ) are one of the most prescribed classes of drugs because of their marked anxiolytic, anticonvulsant, muscle relaxant and hypnotic effects. The pharmacological actions of BDZ depend on the activation of 2 specific receptors. The central BDZ receptor, present in several areas of the central nervous system (CNS), is a component of the GABA-A receptor, the activation of which increases GABAergic neurotransmission and is followed by remarkable neuroendocrine effects. The peripheral benzodiazepine receptors (PBR), structurally and functionally different from the GABA-A receptor, have been shown in peripheral tissues but also in the CNS, in both neurones and glial cells, and in the pituitary gland. BDZ receptors bind to a family of natural peptides called endozepines, firstly isolated from neurons and glial cells in the brain and then in several peripheral tissues as well. Endozepines modulate several central and peripheral biological activities, including some neuroendocrine functions and synthetic BDZ are likely to mimic them, at least partially. BZD, especially alprazolam (AL), possess a clear inhibitory influence on the activity of the HPA axis in both animals and humans. This effect seems to be mediated at the hypothalamic and/or suprahypothalamic level via suppression of CRH. The strong negative influence of AL on hypothalamicpituitary-adrenal (HPA) axis agrees with its peculiar efficacy in the treatment of panic disorders and depression. BZD have also been shown to increase GH secretion via mechanisms mediated at the hypothalamic or supra-hypothalamic level, though a pituitary action cannot be ruled out. Besides the impact on HPA and somatotrope function, BDZ also significantly affect the secretion of other pituitary hormones, such as gonadotropins and PRL, probably acting through GABAergic mediation in the hypothalamus and/or in the pituitary gland. In all, BDZ are likely to represent a useful tool to investigate GABAergic activity and clarify its role in the neuroendocrine control of anterior pituitary function; their usefulness probably overrides what had been supposed before.

GABAergic mediation of stress-induced secretion of corticosterone and oxytocin, but not prolactin, by the hypothalamic paraventricular nucleus

“…The inhibitory role for GABA on HPA axis is well established (Herman et al, 2002b;Jones et al, 1984;Arvat et al, 2002). GABA is known to inhibit CRH release from hypothalamic slices in vitro (Calogero et al, 1988;Hillhouse and Milton, 1989).…”

Alprazolam and oxazepam block the cue-induced reinstatement of extinguished cocaine seeking in rats

“…Our current data are similar to those reported previously (Goeders and Clampitt 2002) where we showed that pretreatment with the corticosterone synthesis inhibitor, ketoconazole, and the CRH receptor antagonist, CP-154,526, also reduced cue-induced reinstatement, suggesting a role for the HPA axis in cue-induced cocaine craving. Benzodiazepines (e.g., alprazolam, diazepam) have also been demonstrated to decrease the activity of the HPA axis in both humans and animals (Pivac and Pericic 1993;Arvat et al 2002).…”

Early Evolution of Ionotropic GABA Receptors and Selective Regimes Acting on the Mammalian-Specific Theta and Epsilon Subunits

“…The γ-aminobutyric acid (GABA) is the major inhibitory neurotransmitter found in the vertebrate brain and is involved in CNS development and organization [4], neuroendocrine function [5], and neural processes such as learning and memory [6]. GABA is also present in the nervous system of non-vertebrate taxa, for example, flatworms [7], arthropods [8], [9] and early chordates [10].…”