Old rats
are unresponsive to the behavioral
effects
of
adrenocorticotropin
Rosanna Poggioli Augusta Benelli, Rossana
Arletti, Anna Valeria Vergoni, Barbara Menozzi,
Alfio Bertolini
Department of Biomedical
Sciences, Section of Pharmacology, University of
Modena, Italy
Abstract
In 28 month-old male rats, the i.c.v.
injection of adrenocorticotropin
[ACTH-(1-24)} (4 pg/rat) did not induce the
typical behavioral syndrome (excessive grooming,
stretching, yawning, penile erections). This
indicates that the behavioral effects of
melanocortins are age-dependent, suggesting
either an aging-linked impairment of the nervous
circuitries involved or a reduction of the
number (or affinity, or both) of the brain
melanocortin receptors in the elderly
1. Introduction
In mammals, the administration of
melanocytestimulating hormone and of
adrenocorticotropin hormone (MSH-ACTH
neuropeptides, melanocortins, melanopeptides)
into the cerebral ventricles or into selected
brain areas induces a complex and unique
behavioral syndrome, characterized by compulsive
care of body surface (grooming), by repeated
episodes of stretching and yawning, and by
recurrent episodes of penile erection with
ejaculation (the picture induced by
pharmacological amounts of melanocortins is a
remarkable and curious concentrate of
physiologic behaviors) (Ferrari et al., 1955,
1963; Ferrari, 1958; Bertolini and Vergoni,
1968; Bertolini et al. 1969, 1975, 1988; Gispen
et al., 1975; Bertolini and Gessa, 1981).
Moreover, melanocortins improve short-term
memory processes (De Wied, 1964, 1966; De Wied
and Bohus, 1966; De Wied and Jolies, 1982), and
increase motivation and attention (De Wied,
1965, 1969). Structure-activity studies (Spruijt
et al., 1985; De Wied and Jolles, 1982; Eberle,
1988; De Wied and Woiterink, 1988) have shown
that these behavioral effects of melanocortins
are related to the melanocyte-stimulating,
rather than to the adrenocorticotrophic activity
of these peptides.
A physiological meaning of such effects has
been repeatedly suggested (for reviews see: De
Wied and Jolies, 1982; De Wied and Ferrari,
1986) and is also strongly supported by the
finding that binding sites for melanocortins are
found throughout the brain (Tatro, 1990;
Mountjoy et al., 1992).
Adequate brain cholinergic activity is
required for the display of the
melanocortin-induced behavioral syndrome, which
is prevented by the i.c.v. administration of
hemicholinium-3 (Poggioli et al., 1991).
Aging is characteristically associated with
progressive impairment of brain cholinergic
function (Bartus et al., 1982; Palmer and
Gershon, 1990) and stretching, yawning and
penile erection are much more frequent in young
than in old animals (Preyer, 1923; Lehmann,
1979). In humans, yawning and stretching are
already present at birth, and spontaneous penile
erections occur very frequently in babies,
whereas old people rarely yawn and even more
rarely stretch or display full penile erection.
Moreover, self-care and body cleaning are often
neglected in the old, and deterioration of
short-term memory - together with reduced
motivation and attention - is typical of aging.
These considerations prompted us to study the
influence of aging on the behavioral response to
melanocortins.
4. Discussion
These data show that old rats are
unresponsive to the behavioral effects of
adrenocorticotropin. The i.c.v. injection of
ACTH-(1-24) at a dose (4 jig/rat) that is
maximally active to induce the most typical
behavioral symptoms (excessive grooming,
stretchings, yawnings, penile erections) in
adult (3- to 4-month-old) animals (Bertolini et
al., 1988), has no behavioral activity in
28-month-old rats.
Previous data for grooming showed that the
level of ACTH-induced excessive grooming in aged
rats was not significantly different from that
displayed by young animals. However, such data
were obtained in 24-
month-old rats, and an accurate analysis of
grooming activity indicated a loss in sequential
organisation of such behavior in aging rats
(Spruijt et al., 1988).
The loss of behavioral responsivity to
ACTH-(1-24) in 28-month-old rats may depend on
(i) an aging-linked progressive reduction, and
eventual loss, of responsivity of the nervous
structures involved in the behavioral effects of
melanopeptides; (ii) an aging-linked,
progressive impairment of the neurotransmitter
systems (typically cholinergic systems)
(Poggioli et ai., 1991) involved in the
behavioral effects of melanopeptides; (iii) an
aging-linked progressive reduction of the
production of permissive hormones, typically
sexual steroid hormones; however this may be the
case only for penile erection, because
testosterone plays a fundamental permissive role
only for this behavioral effect of melanocortins
(Bertolini and Vergoni, 1968); (iv) an
aging-linked reduction of the number (or
affinity, or both) of brain melanocortin
receptors. One possibility does not exclude the
others.
Melanocortins are well known trophic factors
for nervous tissue, and their concentration is
significantly reduced in the brain of aging
mammals (Barnea et ai., 1982; Bell and Lipton,
1987), as well as in defined brain areas of
patients with Alzheimer's disease (Arai et ai.,
1986). On the other hand, the highest
concentrations of a-MSH are found during fetal
life, and this neuropeptide seems to be involved
in brain development as injections of a-MSH
antisera into the fetal rat produce a decrease
in brain weight and a delay in neuron
development (for a review see: O'Donohue and
Dorsa, 1982; Eberle, 1988), whereas treatment of
neonatal rats with MSH peptides improves their
performance in learning, memory and attention
(Beckwith et al., 1977), accelerates motor
behavior and the onset of eye opening (Van de
Helm-Hylkema and De Wied, 1976).
Melanocortins exert atrophic action on both
the central and peripheral nervous system also
in adulthood, during nerve regeneration after
mechanical lesion (Verhaagen and Gispen, 1988;
Gispen, 1990; Strand and Kung, 1980; Bijlsma et
al., 1981, 1983, 1984; Saint-Côme et al.,
1982; De Koning et al., 1986; Verhaagen at ai.,
1986; De Koning and Gispen, 1987) or after
lesions of the brain (Nyakas et ai, 1985;
Isaacson and Poplawsky, 1983; Benelli et al.,
1988). Ischemic injury to brain neurons is
attenuated by adrenalectomy - which causes an
increased production of melanocortins - and
adrenalectomy also prevents the aginglinked loss
of central neurons (Sapolsky and Pulsineili,
1985; Sapolsky et al., 1985).
Our present data, showing that the brain of
old animals is no longer responsive to the
behavioral effects of melanocortins - together
with the notion that the behavioral signs
stimulated by melanocortins are rare in the
elderly - suggest that a decreased neuronal
responsivity to melanocortins may play some role
in the aging-related decline in brain
functioning.
-Poggioli
R, Valerja Vergoni A, et al. Influence of
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-Poggioli R
et al Nitric oxide is involved in the
ACTH-induced behavioral syndrome Peptides
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