Behavioural Brain Research 121 (2001) 199–205
Research report
Nitric oxide involvement in the anxiogenic-like effect of
substance P
I.P. Baretta
a
, J. Assreuy
b
, T.C.M. De Lima
b,
*
a
Department of Pharmacology, Uni6ersidade Paranaense, Umuarama PR, Brazil
b
Department of Pharmacology, Biological Sciences Center, Uni6ersidade Federal de Santa Catarina, Rua Ferreira Lima,
82
—
Centro-
88015
-
420
-SC, Floriano´polis, Brazil
Received 2 October 2000; received in revised form 8 January 2001; accepted 8 January 2001
Abstract
This study investigates whether nitric oxide (NO) is involved in the anxiogenic profile of action of substance P (SP) in mice in
the elevated plus-maze (EPM). Adult Swiss mice were injected with NOS inhibitors such as
L
-NOARG (20 nmol/kg) i.p.,
L
-NAME (3 nmol per site), 7-NI (0.25 nmol per site) i.c.v. or vehicle (NaCl 0.9% i.p. or PBS i.c.v.). About 30 min (i.p.
pretreatment) or 5 min later (i.c.v. pretreatment), the animals received i.c.v. injections of SP (10 pmol) or phosphate buffered
saline (PBS) (2 ml). Afterwards, they were observed in the EPM. SP per se reduced the time spent on open arms, an anxiogenic-like
effect. This effect was reverted by different NOS inhibitors and the NO donor. NOS inhibitors had no influence on the EPM
parameters but the NO-releasing compound SNAP, as well as its parent thiol NAP, increased the animals’ locomotor activity.
8-Br-cGMP (20 nmol), a permeable cGMP analog, promoted an anxiogenic-like effect per se and enhanced the SP effect on the
EPM. Altogether, these results suggest a putative NO role in the mediation of the anxiogenic-like effect of SP. © 2001 Elsevier
Science B.V. All rights reserved.
Keywords
:
Nitric oxide; Substance P; NOS inhibitors; NO donor; cGMP; Anxiety
www.elsevier.com/locate/bbr
1. Introduction
Nitric oxide (NO) has emerged as a simple and
unique molecule that can readily diffuse through cell
membranes to exert several biological actions in mam-
malian cells. Various studies have shown that NO has a
significant role in neurotransmission, neurotoxicity and
plasticity processes, regulation of cerebral blood flow,
vasodilation, inhibition of platelet aggregation and in
the antiproliferative action of some cytokines [20,38]. It
is synthesized from
L
-arginine through the action of
three isoforms of the enzyme NO synthase (NOS)
[3,4,27,37], all of them dependent on NADPH The use
of NOS inhibitors strongly supports a role for NO as a
neurotransmitter in the central nervous system (CNS)
[18,19,34,36].
Several biological actions of NO are mediated
through the activation of soluble guanylate cyclase
(GC) that converts GTP in cGMP [49]. Thus, the
action of different neurotransmitters such as acetyl-
choline, glutamate and glycine, that increased cGMP
levels, is presumed to be mediated via NO [37]. How-
ever, the list of NO effects, which are independent of
cyclic GMP is also growing at a rapid rate [39].
In the CNS, neuronal NOS is widely distributed in
brain areas of mammals [3,4], such as the amygdala, the
hypothalamus and the dorsal periaqueductal grey
(DPAG) [52]. The region of locus coeruleus, the main
noradrenergic nucleus in the brain, contains both NOS-
containing neurons and a high density of a1andb1
subunits of soluble guanylate cyclase, suggesting the
existence of a NO-cGMP system [32]. These anatomical
areas are closely involved in the modulation of defen-
sive responses to threatening stimuli and seem to be the
neurochemical and neuroanatomical substrate of fear
* Corresponding author. Tel.: + 55-48-2224164; fax: +55-48-
3319491.
E-mail address
:
thereza@farmaco.ufsc.br (T.C.M. De Lima).
0166-4328/01/$ - see front matter © 2001 Elsevier Science B.V. All rights reserved.
PII: S0166-4328(01)00165-6