Behavioural Brain Research 144 (2003) 111–117
Research report
Impact of environmental housing conditions on the emotional responses
of mice deficient for nociceptin/orphanin FQ peptide precursor gene
A.-M. Ouagazzal
a,∗
, J.-L. Moreau
b
, M. Pauly-Evers
b
, F. Jenck
c
a
Inst. de Genetique et de Biologie Moleculaire et Cellulaire (IGBMC), 1 rue Laurent Fries, BP 10142, 67404 Illkirch, France
b
Roche, Pharma Division, CNS Research Department, CH 4070 Basel, Switzerland
c
Actelion Pharmaceuticals, CH 4123 Allschwil, Switzerland
Received 9 August 2002; received in revised form 17 February 2003; accepted 17 February 2003
Abstract
Nociceptin/orphanin FQ (N/OFQ) is a newly discovered neuropeptide that has been implicated in the neurobiological regulation of the
behavioral responses to stress and fear. To investigate the role of this peptide in the expression of stress/anxiety-related behaviors in mice, a
gene targetingapproach to disrupt N/OFQ in the pre-proN/OFQ gene was used. The impact of environmental housing conditions (single and
social housing) was assessed on N/OFQ-knockout male and female mice in different experimental paradigms known to trigger distinctive
types of stress and anxiety states. Neurological examination of homozygous mutant adult animals indicated that basic neurological functions
(vision, audition, olfaction, tactile and pain sensitivity, motor performances) were normal. When housed individually, N/OFQ-knockout
animals displayed responses similar to control animals in behavioral tests of emotional reactivity (behavioral despair, locomotor activity,
light–dark preference, and acoustic startle tests). In contrast, increased emotional responses were detected when individually housed mice
were crowded together (five per cage) under conditions of competitive access to food, water, space, and social contacts. Under those
conditions, male mice deficient for N/OFQ developed greater home–cage aggression and increased fear/anxiety-like behaviors in the
light–dark and acoustic startle tests, when compared to their wild-type littermates. Group-housed female mutants also showed higher level
of anxiety in the acoustic startle test, but needed additional restrain stress to express detectable levels of anxiety in the light–dark test.
These data indicate a clear environment-induced rise in fear reactions of N/OFQ-knockout mice. They further suggest that N/OFQ system
is essential for development of adequate coping strategies to acute and chronic stress.
© 2003 Elsevier Science B.V. All rights reserved.
Keywords: Anxiety; Stress; N/OFQ; Mice
1. Introduction
Nociceptin/orphanin FQ (N/OFQ) is a 17-amino acid
neuropeptide that has been identified as naturally occurring
agonist of an opioid-like receptor (NOP) [1,2]. Despite the
fact that N/OFQ and its receptor show structural similarities
to the peptides and receptors of the opioid family, they are
pharmacologically distinct from the opioids [2,3]. As such,
N/OFQ and its receptors appear to constitute a novel neuro-
modulatory system. N/OFQ is widely distributed through the
central nervous system and is predominantly expressed in
several brain regions known to be associated with cognitive
and emotional functions such as the hippocampus, amyg-
dala, and central gray regions [4,5]. The distinctive pattern of
∗
Corresponding author. Tel.: +33-388-65-56-64;
fax: +33-388-65-32-01.
E-mail address: abdel@igbmc.u-strasbg.fr (A.-M. Ouagazzal).
N/OFQ distribution in the brain has generated considerable
excitement regarding possible physiological and behavioral
functions mediated by this new neuropeptide. Recent studies
have implicated N/OFQ in the control of a variety of behav-
iors including locomotor activity, learning processes, feeding
and sensory responses to stress, such as analgesia [2,4,6–8].
N/OFQ was also reported to play an important role in adap-
tative responses to stress. Intracerebroventricular infusion of
N/OFQ produced anxiolytic-like effects in a variety of anx-
iety tests including the elevated plus-maze, light–dark and
operant conflict tests [9,10]. N/OFQ was also reported to
reduce the defense behaviors of mice confronted with nat-
ural threatful stimuli and suppress the vocalizations elicited
by electrical stimulation of cingular cortex in guinea pig
[11,12]. Furthermore, systemic administration of synthetic
N/OFQ receptor agonist, Ro 64-6198, was shown to produce
anxiolytic effects across various tests of anxiety and to re-
verse stress- and CRF-induced anorexia in rats [13,14].An
0166-4328/$ – see front matter © 2003 Elsevier Science B.V. All rights reserved.
doi:10.1016/S0166-4328(03)00066-4