Duration of treatment and activation of α1-containing GABAA receptors variably affect the level of anxiety and seizure susceptibility after diazepam withdrawal in rats

Abstract

Long-term use of benzodiazepine-type drugs may lead to physical dependence, manifested by withdrawal syndrome after abrupt cessation of treatment. The aim of the present study was to investigate the influence of duration of treatment, as well as the role of α1-containing GABAA receptors, in development of physical dependence to diazepam, assessed through the level of anxiety and susceptibility to pentylenetetrazole (PTZ)-induced seizures, 24 h after withdrawal from protracted treatment in rats. Withdrawal of 2 mg/kg diazepam after 28, but not after 14 or 21 days of administration led to an anxiety-like behavior in the elevated plus maze. Antagonism of the diazepam effects at α1-containing GABAA receptors, achieved by daily administration of the neutral modulator βCCt (5 mg/kg), did not affect the anxiety level during withdrawal. An increased susceptibility to PTZ-induced seizures was observed during diazepam withdrawal after 21 and 28 days of treatment. Daily co-administration of βCCt further decreased the PTZ-seizure threshold after 21 days of treatment, whilst it prevented the diazepam withdrawal-elicited decrease of the PTZ threshold after 28 days of treatment. In conclusion, the current study suggests that the role of α1-containing GABAA receptors in mediating the development of physical dependence may vary based on the effect being studied and duration of protracted treatment. Moreover, the present data supports previous findings that the lack of activity at α1-containing GABAA receptors is not sufficient to eliminate physical dependence liability of ligands of the benzodiazepine type.

Prefrontal excitatory/inhibitory balance in stress and emotional disorders: Evidence for over-inhibition

“…A previous study found that withdrawal from 2 mg/kg of chronic diazepam treatment over 14 days did not increase anxiety-like behavior in male rats (Kovačević et al, 2014).…”

Behavioural interaction of pyrazoloquinolinone positive allosteric modulators at α6GABAA receptors and diazepam in rats: Anti‐diazepam‐induced ataxia action as a structure‐dependent feature

“…15 The threshold dose of pentylenetetrazole (mg/kg) required to provoke seizures was calculated from the recorded volume of infusion (ml), concentration of pentylenetetrazole (mg/ml) and body-weight (kg), using the formula: volume of pentylenetetrazole (ml) Â concentration of pentylenetetrazole (mg/ml)/body-weight (kg). In accordance with our previous data, 16 parameters of the infusion (pentylenetetrazole concentration and infusion rate) were optimized such that convulsive events appear in less than 1 min in control rats.…”

Synthesis of aza and carbocyclic β-carbolines for the treatment of alcohol abuse. Regiospecific solution to the problem of 3,6-disubstituted β- and aza-β-carboline specificity

“…18,[26][27][28] Therefore, in addition to their use to study the molecular basis of alcohol reinforcement, α1 Bz β-carboline ligands which display mixed pharmacological antagonistagonist activity in alcohol P and HAD rats may be capable of reducing alcohol intake while eliminating or greatly reducing the anxiety associated with habitual alcohol, abstinence or detoxification. 18,[28][29][30] Consequently, these types of ligands may be ideal clinical agents for the treatment of alcohol dependent individuals.…”