In Vitroandin VivoEffects of the Triazolobenzodiazepine Alprazolam on Hypothalamic Pituitary-Adrenal Function: Pharmacological and Clinical Implications*

Abstract

We report here a study of the effects of alprazolam on in vivo pituitary-adrenal function in jacketed nonrestrained nonhuman primates and on in vitro CRH release from rat hypothalami and ACTH release from rat dispersed anterior pituicytes. We undertook this study because alprazolam is the only benzodiazepine effective in treating both major depressive and anxiety disorders, and recent data suggest that the hypercortisolism of major depression reflects hypersecretion of CRH. Moreover, the intracerebroventricular administration of CRH can reproduce many of the components of the symptom complex of major depression, including not only hypercortisolism, but also hypothalamic hypogonadism, decreased libido, anorexia, and intense anxiety. As a comparison, we also assessed the effects of diazepam on in vitro CRH release, because in contrast to alprazolam, diazepam is effective in anxiety states but not in depression. Alprazolam (0.01-0.3 mg/kg, iv) produced a dose-dependent inhibition of both plasma ACTH and cortisol secretion in non-restrained adult male rhesus monkeys. Our in vitro studies showed that alprazolam significantly inhibited serotonin (5HT)-induced CRH release in a dose-dependent fashion (10(-10)-10(-5) M). Diazepam also inhibited 5HT-induced CRH release, but was 40 times less potent than alprazolam. Alprazolam was ineffective in blocking basal or CRH-induced ACTH release from rat dispersed anterior pituicytes, suggesting that its in vivo effects are through inhibition of CRH secretion. As expected, the inactive benzodiazepine ligand Ro 15-1788 inhibited the effects of alprazolam on 5HT-induced CRH release, but this occurred only at doses below 10(-7) M. Interestingly, when incubated alone in higher doses with our rat hypothalamic organ culture, Ro 15-1788, like alprazolam, produced a dose-dependent inhibition of 5HT-induced CRH release (10(-7)-10(-5) M), suggesting an agonistic action of Ro 15-1788 at the benzodiazepine receptor at higher concentrations. We conclude that alprazolam is capable of suppressing the primate pituitary-adrenal axis, and that this suppression most likely reflects suppression of the CRH neuron rather than of the pituitary corticotroph cell. We speculate that the enhanced capacity of alprazolam to suppress the CRH neuron relative to other benzodiazepines may contribute to its unique efficacy among this class of drugs in the treatment of major depression. The capacity of Ro 15-1788 to reverse alprazolam-induced suppression of the CRH neuron indicates that the effects of alprazolam are mediated at least in part via its interaction with the benzodiazepine component of the gamma-aminobutyric acidA macromolecular complex.

Temazepam Triggers the Release of Vasopressin into the Rat Hypothalamic Paraventricular Nucleus: Novel Insight into Benzodiazepine Action on Hypothalamic–Pituitary–Adrenocortical System Activity During Stress

“…This is in line with previous studies which were predominantly based on the analysis of plasma corticosterone concentrations (Bruni et al, 1980;Schürmeyer et al, 1988;Owens et al, 1989Owens et al, , 1993Kalogeras et al, 1990;Breier et al, 1991Breier et al, , 1992Schuckit et al, 1992;Torpy et al, 1993Torpy et al, , 1994Rohrer et al, 1994;Korbonits et al, 1995;Arvat et al, 1998Arvat et al, , 1999Skelton et al, 2000). However, in contrast to corticosterone, changes in plasma ACTH can be directly linked to the secretory activity of the parvocellular neurons of the PVN: AVP and CRH are secreted as releasing hormones from these neurons into the pituitary portal blood to synergistically stimulate the secretion of ACTH from the anterior pituitary (Aguilera and Rabadan-Diehl, 2000;Aguilera et al, 2001).…”

“…We, therefore, tested the possibility whether or not temazepam might directly act at the level of the anterior pituitary. In our hands, drug administration failed to alter ACTH secretion in vitro (Kalogeras et al, 1990). Thus, there is good evidence that the observed changes in ACTH release induced by temazepam after stressor exposure are due to an action of the benzodiazepine at the brain level.…”

Inferior petrosal sinus sampling in healthy subjects reveals a unilateral corticotropin-releasing hormone-induced arginine vasopressin release associated with ipsilateral adrenocorticotropin secretion.

“…Furthermore, AVP by itself is a weak ACTH secretagogue and requires CRH to exert a potent effect on the release of ACTH. Even though inferior petrosal sinus cannulation is regarded as a stressful procedure, endogenous CRH levels in both petrosal sinuses were found to be below the detection limit of our assay, probably due to the pretreatment of our subjects with fentanyl and diazepam, both of which are known to inhibit hypothalamic CRH secretion (50,51). Therefore, low CRH secretion during baseline sampling and a diminished synergistic effect with AVP probably account for the absence of a correlation between the ACTH and the AVP ISG.…”

L-tryptophan implicated in human eosinophilia-myalgia syndrome causes fasciitis and perimyositis in the Lewis rat.

“…Implicated L-TRP-treated rats showed significantly lower hypothalamic corticotropin releasing hormone mRNA and hippocampal mineralocorticoid receptor mRNA levels, as well as a trend to lower plasma corticosterone levels, compared to the other groups of rats. A contaminant(s) structurally related to L-TRP with serotonin antagonist or benzodiazepine agonist activity could theoretically suppress the HPA axis (27)(28)(29)(30). In light of our previously proposed hypothesis that enhanced susceptibility to inflammatory disease in the LEW/N rat is related to their deficient HPA axis-related counter-regulation of the inflammatory response (2, 10-12), a contaminant(s), with suppressive effects on the HPA axis, could amplify its own or other contaminant(s)' proinflammatory effects.…”