Psychopharmacology (1998) 135 : 342352 © Springer-Verlag 1998
ORIGINAL INVESTIGATION
B.O. Ward · D.N. Stephens
Sensitisation of withdrawal signs following repeated withdrawal
from a benzodiazepine: differences between measures
of anxiety and seizure sensitivity
Received : 13 April 1997 / Final version : 14 August 1997
Abstract Three experiments examined the e¤ect of
either withdrawal from diazepam, or repeated treat-
ment with the convulsant, pentylenetetrazol (PTZ), on
behaviour and seizure threshold. The behaviours mea-
sured were on the elevated plus maze and in the four-
plate test; seizure threshold was measured as dose of
PTZ infused via the tail vein to the Þrst clonic twitch.
In experiment 1, we examined the e¤ect of either sin-
gle or repeated withdrawal from diazepam using a pro-
cedure in which the drug was administered SC in a
slow release depot. Three cycles of withdrawal from
diazepam were compared to a single withdrawal expe-
rience. A single withdrawal from diazepam following
chronic treatment gave rise, 72 h following the last dos-
ing, to behavioural changes, suggestive of anxiety, in
both tests, but did not result in a reduced convulsant
threshold. In contrast, repeated withdrawal resulted in
a reduction in sensitivity in several measures of anxi-
ety, but sensitised the mice to the convulsive e¤ects of
the PTZ. The unexpected failure to Þnd an increased
sensitivity to a convulsive agent following a single with-
drawal from SC diazepam was examined in experiment
2. The seizure threshold following a single withdrawal
of mice which had received diazepam chronically IP in
aqueous vehicle was signiÞcantly reduced relative to
vehicle-treated controls, whereas that of animals receiv-
ing the same dose SC in oil, was not. It is argued that
the di¤erence may arise from the animals treated
repeatedly with IP diazepam unintentionally experi-
encing repeated withdrawal, since the half-life of the
drug by this route is short. In experiment 3, repeated
sub-convulsant PTZ treatment reduced the convulsant
threshold (the dose of PTZ required to give rise to the
Þrst clonic twitch), but had no signiÞcant e¤ect on the
behavioural measures of anxiety compared to a single
dose of PTZ or vehicle controls. The results suggest
that repeated withdrawal from chronic treatments with
diazepam sensitises mice to convulsant stimuli in a
manner resembling the e¤ects of repeated administra-
tion of sub-convulsant doses of PTZ, but that neither
repeated PTZ nor repeated diazepam withdrawal
results in increased sensitivity to anxiogenic stimuli;
rather, repeated withdrawal from diazepam may reduce
the susceptibility of mice to behavioural measures of
anxiety.
Key words Conßict · Diazepam · Pentylenetetrazole ·
Mice · Plus maze · Four plate · Repeated withdrawal ·
Kindling · Dependence · Anxiety
Introduction
Long-term treatment with sedative-hypnotic drugs
including alcohol, barbiturates and benzodiazepines
may lead to dependence, manifested as a syndrome of
abstinence signs and symptoms following drug with-
drawal. In the case of alcohol, a number of clinical and
experimental reports suggest that previous experience
of withdrawal increases the severity of subsequent with-
drawal episodes. Thus patients undergoing alcohol
withdrawal are more likely to experience seizures if they
have undergone previous episodes of detoxi Þcation
(Mendelson et al. 1966; Baker and Cannon 1979;
Brown et al. 1988; Lechtenberg and Worner 1991;
Booth and Blow 1993). Analogous Þndings have also
been reported from animal experiments which showed
that the severity of the withdrawal intensity increased
following several withdrawal episodes (Branchey et al.
1971; Walker and Zornetzer 1974; Baker and Cannon
1979; Clemmesen and Hemmingsen 1984; Maier and
Pohoreky 1989; Becker and Hale 1993; Kokka et al.
B.O. Ward · D.N. Stephens (*)
Laboratory of Experimental Psychology, University of Sussex,
Falmer, Brighton BN1 9QG, UK
Fax (+44) 1273-678611, e-mail:dns@biols.susx.ac.uk