Effects
of apomorphine, physostigmine and vasoactive
intestinal peptide on penile
erection
and
yawning in diabetic rats
Yamaguchi Y, Kobayashi H
Research Laboratory, Zenyaku
Kogyo, Tokyo, Japan
Abstract
The present report describes for the first
time the effects of systemic administration of
apomorphine and of physostigmine, as well as the
effects of central and systemic administration
of vasoactive intestinal peptide (VIP), on
penile erection and yawning in rats with
streptozotocin-induced diabetes. Systemic
administration of apomorphine induced both
penile erection and yawning in non-diabetic rats
but not in diabetic rats, while that of
physostigmine induced only yawning in
non-diabetic rats, and neither yawning nor
penile erection in diabetic rats.
Intracerebroventricular administration of VIP
induced both penile erection and yawning in
non-diabetic rats, but neither was induced in
diabetic rats. Application of VIP as an ointment
to the surface of the glans penis induced penile
erection but not yawning in both non-diabetic
and diabetic rats. Thus, penile erection and
yawning are less easily induced in diabetic rats
than in non-diabetic rats. Grooming occurred
whenever penile erection was induced, but was
not associated with yawning.
1. Introduction
Systemic injection of apomorphine, a
dopamine agonist, has been reported to induce
yawning (Mogilnicka and Klimek, 1977; Holmgren
and Urba-Holmgren, 1980) and both penile
erection and yawning in rats (Gower et al.,
1984; Holmgren et al., 1985). Physostigmine, an
inhibitor of acetylcholinesterase, induced only
yawning when administered systemically
(Urba-Holmgren et al., 1977; Holmgren and
Urba-Holmgren, 1980; Yamada and Furukawa, 1980),
but not penile erection (Gower et al., 1984).
Pilocarpine, an acetylcholine agonist, induced
penile erection (Maeda et al., 1990) and yawning
(Yamada and Furukawa, 1980).
In addition to drugs that act via
dopaminergic and cholinergic mechanisms,
peptidergic mechanisms are also involved in both
penile erection and yawning: adrenocorticotropin
(ACTH) and melanocyte-stimulating hormone (MSH)
were active in several species of mammals (see
Bertolini and Gessa, 1981, for review), and
oxytocin was active in rats (Argiolas et al.,
1985, 1986). Vasoactive intestinal peptide (VIP)
seems to participate in penile erection: during
erection, plasma VIP levels in the penile
circulation were markedly elevated in man (Virag
et al., 1982; Ottesen et al., 1984) and
injection of VIP into the cavernous space
stimulated penile erection in man (Ottesen et
al., 1984; Kiely et al., 1989). Furthermore, in
rats, systemic administration of VIP increased
the rate of copulation and decreased the time to
the first intromission. An antagonist of VIP, a
peptide of 28 amino acids composed of a portion
of VIP and a portion of neurotensin, inhibited
these sexual events (Gozes et al., 1989). In
these latter studies, yawning after
administration of VIP was not recorded. The
various reports together suggest that
dopaminergic, cholinergic and peptidergic nerves
are involved in the induction of penile erection
and/or yawning. However, the interrelation
between these three classes of nerves has not
been elucidated.
Penile dysfunction is a common complication
of diabetes mellitus (Rubbin and Babbott, 1958;
Sch6ffling et al., 1963; Ellenberg, 1971) and
the prevalence of impotence among diabetic men
is high (Kolodny et al., 1973). Lincoln et al.
(1987) observed that numbers of fibers showing
VIP-like immunoreactivity and the intensity of
staining for acetylcholinesterase activity were
markedly reduced, as were contents of
noradrenaline, in penile tissues of diabetic
men. They concluded that VIPergic, cholinergic
and adrenergic nerves in the penis are affected
in diabetes mellitus and, thus, dysfunction of
the nerves contributes to the development of
impotence in diabetic men. In diabetic rats, a
reduction in sexual behavior, such as
ejaculations, mounting or intromissions, was
demonstrated by Fernandez-Collazo and Foglia
(1970). However, Sachs et al. (1982) found that
none of the measures of sexual behavior, such as
sexual motivation, performance or penile
responsiveness, was depressed in diabetic rats.
It is not clear whether diabetic rats possess
normal potency with regard to penile erection
and yawning. Furthermore, as far as we know,
there have been no experiments dealing with
penile erection and yawning in relation to VIP
in diabetic rats.
The present study was designed to examine
the involvement of dopaminergic, cholinergic and
VIPergic mechanisms in penile erection and
yawning, and to explore the functional
relationship between the mechanisms in
non-diabetic and diabetic rats. The occurrence
of grooming was also noted during the course of
this study.
4. Discussion
In the present experiments, systemic
administration of apomorphine induced penile
erection and yawning in non-diabetic rats, as
reported by Gower et al. (1984), Holmgren et al.
(1985), Melis et al. (1987, 1989) and Argiolas
et al. (1987), and systemic administration of
physostigmine induced only yawning in
non-diabetic rats, as shown by Gower et al.
(1984). Therefore, it is apparent that penile
erection and yawning induced by apomorphine are
mediated by dopaminergic nerves and yawning
induced by physostigmine is mediated by
cholinergic nerves. It has been demonstrated
that apomorphine- induced yawning (Yamada and
Furukawa, 1980) and penile erection (Maeda et
al., 1990), as well as physostigmine-induced
yawning (Yamada and Furukawa, 1980), can be
completely inhibited by scopolamine, a
muscarinic receptor antagonist, but not by
methylscopolamine. These observations suggest
that dopaminergic mechanisms involved in penile
erection and yawning are under the control of
cholinergic nerves in the brain.
In diabetic rats, apomorphine failed to
induce penile erection and yawning, and
physostigmine failed to induce yawning. Lozovsky
et al. (1981) reported that, in
streptozotocin-treated diabetic rats, there were
changes in the sensitivity of postsynaptic
dopamine receptors in the brain. Welsh and
Wecker (1991) observed a significant reduction
in the rates of synthesis and release of
acetylcholine by striatal slices from
streptozotocintreated diabetic rats. These
dopaminergic and cholinergic dysfunctions might
have been causes of the insensitivity to
apomorphine and physostigmine, resulting in
impotence of diabetic rats. We found that i.c.v,
injection of VIP induced penile erection and
yawning in non-diabetic rats. Itoh et al. (1988)
reported that injection (i.c.v.) of VIP
facilitated the metabolism of dopamine in
various regions of the rat brain and Luine et
al. (1984) reported that addition of VIP to
brain homogenates of the hypothalamus and the
hippocampus increased choline acetyltransferase
activity. Thus, induction of penile erection and
yawning by VIP (i.c.v.) may be due to activation
of dopaminergic and/or cholinergic systems in
the brain. In diabetic rats, injection (i.c.v.)
of VIP failed to induce either penile erection
or yawning. It is likely that VIP was not
sufficiently stimulatory to induce penile
erection and yawning in diabetic rats with
dopaminergic (Lozovsky et al., 1981) and
cholinergic (Welsh and Wecker, 1991)
dysfunction.
It should be noted here that apomorphine
interacts with postsynaptic dopamine receptors
in the paraventricular nucleus, with a resultant
release of oxytocin (Melis et al., 1989), which
is known to induce penile erection and yawning
(Argiolas et al., 1985, 1986). Furthermore,
VIP-immunoreactive neurons can be found in the
paraventricular nucleus (Ceccatelli et al.,
1989). Therefore, there is a possibility that
induction of penile erection and yawning by
i.c.v. VIP is mediated via oxytocin. Neural
relationships between VIP, ACTH and MSH (see
Bertolini and Gessa, 1981, for review) in the
induction of penile erection and yawning are not
known at present.
Dermal application of VIP induced penile
erection but not yawning in both diabetic and
non-diabetic rats. Yawning seems to be induced
only through activation of the central nervous
system. It has been demonstrated that VIP,
injected into the cavernous space, induces
penile erections in men (Ottesen et al., 1984;
Kiely et al., 1989), and that topical
application of a conjugate of VIP and stearic
acid (stearyl-VIP) to the sex organ
significantly stimulates sexual behavior
(copulation rate) and penile reflexes (erection)
in testosterone-treated castrated rats (Gozes
and Fridkin, 1992). Dermal application or
intracavernous injection of VIP may result in a
direct action on blood vessels, since VIP nerve
terminals are found densely distributed around
penile erectile tissue (Polak et al., 1981; Dail
et al., 1983). Therefore, it is likely that a
reduction in the number of VIP-immunoreactive
nerves in the penis of diabetic rats (Crowe et
al., 1983) may be one of the causes of impotence
in these rats. Grooming occurred whenever a
penile erection was induced in the present
experiments, as previously reported with
apomorphine (Melis et al., 1989), ACTH and MSH
(see Bertolini and Gessa, 1981, for review).
There seems to be some neural relationship
between grooming and penile erection but it
remains to be characterized. Grooming has no
relationship to yawning, since yawning induced
by physostigmine was not accompanied by
grooming.
