The effects of PACAP and PACAP antagonist on the
neurobehavioral development of newborn rats
, Andrea Tama´s
, Istva´n Lengva´ri
Department of Human Anatomy, Neurohumoral Regulation Research Group of the Hungarian Academy of Sciences, University of Pe´cs, Szigeti u 12,
Pe´cs 7624, Hungary
Department of Human Anatomy, University of Pe´cs, Szigeti u 12, Pe´cs 7624, Hungary
Received 22 July 2002; received in revised form 2 September 2002; accepted 2 September 2002
Recent studies show that pituitary adenylate cyclase activating polypeptide (PACAP) plays an important role in the development
of the nervous system. The aim of the present study was to investigate the effects of PACAP38 and the PACAP antagonist
PACAP6-38 on the development of neonatal behavior in rats. Pups were treated subcutaneously until day 14, a period during which
the blood Á
brain barrier is not yet complete. Rats were tested daily for the appearance of physical features, sensory and motor
neurological signs, and for exploratory behavior on days 14 and 21. Facial development and most neurological signs were
accelerated by PACAP treatment, while anti-PACAP retarded ear unfolding, eye opening, hindlimb placing and righting reflex.
PACAP-treated animals also showed altered behavior in the open-field, in particular at 3 weeks of age. The number of areas entered
and rearings were much higher than in the vehicle-treated group, and they spent less time along the walls and in corners. Anti-
PACAP had little effect in the exploratory behavior of the pups. In summary, these data provide additional evidence for the
neurotrophic effects of both endogenously present and exogenously administered PACAP-38.
# 2002 Elsevier Science B.V. All rights reserved.
Keywords: Neurobehavioral development; PACAP; Rat; Exploratory behavior
Pituitary adenylate cyclase activating polypeptide
(PACAP) was isolated from ovine hypothalami, and it
is a member of the vasoactive intestinal polypeptide
(VIP)/secretin/glucagon peptide family [2,45,56]. It exists
in forms of 38 and 27 amino acid residues, with PACAP-
38 being predominant in human tissues . Since its
discovery, several effects have been attributed to PA-
CAP, and numerous studies show its neurotrophic and
neuroprotective actions .Invitro, PACAP stimu-
lates the growth and survival of neurons, prevents
apoptosis and protects neurons against cytotoxicity
induced by various agents [2,56].Invivo, it has
neuroprotective effects in global and focal cerebral
Recent studies show that PACAP plays an important
role in the development of the nervous system. PACAP
mRNA is present in different structures of the develop-
ing rat brain , and genes for PACAP and its receptor
are widely expressed in the mouse neural tube during
early embryonic stages . It is suggested that the
peptide acts in the neural tube during patterning to
control cell proliferation and gene expression .
Several other studies show that PACAP participates in
regulating mitosis, differentiation and apoptosis during
There are only few data on the effect of PACAP
treatment in neonatal rats. Local administration of
PACAP increases the volume of the cerebellar cortex
and stimulates neuronal migration in 8-day-old rats .
VIP, which shows closest structural homology to PA-
CAP, has also been demonstrated to participate in
neuronal development. VIP provides neuroprotection
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Behavioural Brain Research 140 (2003) 131 Á
0166-4328/02/$ - see front matter # 2002 Elsevier Science B.V. All rights reserved.
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