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

Abstract

We investigated the influence of a representative classical benzodiazepine on the regulation of the hypothalamic-pituitary-adrenocortical (HPA) axis activity both under basal conditions and stress. Adult male Wistar rats were intravenously administered with temazepam (0.5, 1, and 3 mg/kg body weight) and plasma concentrations of corticotropin (ACTH) and vasopressin (AVP) were measured in blood samples collected via chronically implanted jugular venous catheters. Simultaneously, the release of AVP within the hypothalamic paraventricular nucleus (PVN) was monitored via microdialysis. Plasma AVP levels remained unaffected by the different treatment conditions. Temazepam blunted the stressor exposure-induced secretion of ACTH in a dose-dependent manner. Concurrently, and also in a dose-dependent manner temazepam enhanced the intra-PVN release of AVP, known to originate from magnocellular neurons of the hypothalamic neurohypophyseal system. Furthermore, temazepam did not affect the in vitro secretion of ACTH from the adenohypophyseal cells. Taken together, the results of this study suggest that temazepam modulates the central nervous regulation of the HPA axis by altering intra-PVN AVP release. An increasingly released AVP of magnocellular origin seems to provide a negative tonus on ACTH secretion most probably via inhibiting the release of ACTH secretagogues from the median eminence into hypophyseal portal blood.

Long-term anxiolytic and antidepressant-like behavioural effects of tiagabine, a selective GABA transporter-1 (GAT-1) inhibitor, coincide with a decrease in HPA system activity in C57BL/6 mice

“…Thus far, these results generally indicate an attenuation of HPA system activity and/or a shift toward lower setpoints by GAT-1 inhibition. In general, the inhibitory role of GABA in HPA system regulation is well established (e.g., Herman, et al, 2003;Welt, et al, 2006). Our results are, thus, in line with several preclinical and clinical data showing a reduction of stress hormone system activity in GAT-1 knock-out animals (Liu, et al, 2007) or after treatment with benzodiazepines and vigabatrin, a GABA transaminase inhibitor (Tran, et al, 1999;Zwanzger, et al, 2001b;2003a).…”

GABA Regulates the Rat Hypothalamic‐Pituitary‐Adrenocortical Axis via Different GABA‐A Receptor α‐Subtypes

“…Notably, administration of the GABA‐A receptor antagonist bicuculine to organotypic cultures upregulated CRH and vasopressin gene expression, 33 suggesting that intrinsic GABAergic neurons in the slice exert powerful control on the CRH neurons that are distinct from more remote inputs. Electrophysiological data have confirmed a local origin of GABAergic inputs to the parvocellular neurons, 34,35 and local release of vasopressin within the PVN may also play a role 36 . Parvocellular neurons in the medial PVN subdivision receive synaptic inputs from neurons in the lateral and dorsal hypothalamus and the suprachiasmatic nucleus, all of which are considered to be GABAergic 30,37,38 .…”

Anxiolytic Treatment Impairs Helping Behavior in Rats

“…In addition to serving as powerful anxiolytics, benzodiazepines are sedating; they reduce exploratory motor behavior and at high enough doses can serve as hypnotics (sleep-inducing drugs). Benzodiazepines can also reduce oxytocin transmission ( Yagi and Onaka, 1996 ; Welt et al, 2006 ), which may be expected to impair social behavior ( Anacker and Beery, 2013 ; Febo and Ferris, 2014 ). Other studies show that benzodiazepines promote approach and reduce aggression in rats ( Christmas and Maxwell, 1970 ; Weerts et al, 1993 ).…”