Effects
of streptozotocin-induced diabetes on
dopaminergic functioning in the rat: analysis of
yawning behavior
Heaton JP, Varrin
SJ
Department Urology,
Queens'University, Kingston, Ontario,
Canada
APOMORPHINE (APO), a dopamine (DA)
receptor agonist, has been shown by us (7-9) and
others (5,22) to reliably produce bouts of
yawning in rats when administered in
microgram quantities. The ability of APO to
induce yawning behavior in rats is said
to be a result of its interaction with
dopaminergic autoreceptors (5,22,20) although
some authors have questioned the hypothesis of
autoreceptor mediation of yawning (19).
Electrophysiological techniques show that the
stimulation of dopaminergic autoreceptors
reduces the tonic firing of neurons (18).
Activation of autoreceptors located on
dopaminergic terminals causes decreased
synthesis and release of DA from these terminals
(4). Low doses of DA or the DA agonist APO given
parenterally act selectively on midbrain DA cell
autoreceptors without stimulating postsynaptic
DA receptors (15,18). Thus, it is felt that the
ability of APO to induce yawning behavior
may provide an index of central DA autoreceptor
function (5).
Numerous studies documented alterations in
yawning behavior as a result of various
pharmacologically induced neurochemical
challenges; for instance, yawning
behavior has been shown to be affected by such
substances as metoclopramide (6), haloperidol
(5), sulpiride (5), calcium channel blockers
(2), oxytocin antagonists (3), and several
cholinergic antagonists (22). Alterations in
yawning behavior as a function of disease
processes have not been investigated.
Diabetes mellitus alters many of the central
neurotransmitter mechanisms; however, its
effects on the central DA system are not well
established. DA turnover in the synaptosomes
prepared from striata and in the limbic
forebrain has been shown to be decreased in
diabetic rats following administration of
amphetamine or APO (17,21). Peripheral
alterations have also been shown to occur; both
norepinephrine and DA were documented to be
decreased in the cardiovascular system of
long-term diabetics at postmortem (14). Thus,
evidence is sparse outlining alterations in
dopaminergic functioning in diabetes mellitus;
moreover, to the best of our knowledge the
effects of diabetes upon the central substrate
necessary to stimulate APO-inducèd
yawning behavior have yet to be
examined.
The present study examines the effects of
short-term (4 weeks) and long-term (up to 20
weeks) streptozotocin (STZ)induced diabetes
mellitus in producing significant alterations in
dopaminergically mediated yawning
behavior. Alterations in the expression of
yawning behavior are postulated to
represent alterations in the substrate
(neurochemical or other) responsible for
yawning.
DISCUSSION
The results show that experimental
STZ-induced diabetes mellitus of relatively
short duration (4 weeks) produces a decreased
ability of APO to stimulate yawning
behavior in rats. As the duration of diabetes
progresses, a recovery in the ability of APO to
induce yawning behavior was observed.
Although animals appeared systemically more sick
(diarrhea, coat condition, cataracts) as
duration of diabetes progressed, yawning
behavior was increased above the level seen in
4week-diabetic rats and was not significantly
different from that seen in normal rats at any
of the APO doses tested. It is possible that as
animals adapt to the hyperglycemic state
alterations in the neurochemical milieu
responsible for the initially decreased
yawning behavior are restored or
compensatory physiological mechanisms are then
activated.
Although alterations in yawning
behavior in humans have been noted in diseases
known to affect the DA system, such as
Parkinson's disease, schizophrenia, and
Huntington's chorea
(il), we are not aware of any data
suggesting an alternation during diabetes
mellitus. However, the results of the present
study show that a malfunction in yawning
behavior does occur in an animal model of
chemically produced diabetes mellitus (at least
in the short term). The present study clearly
identified the ability of a pathologic process
such as diabetes mellitus to alter the necessary
milieu responsible for APO-induced
yawning behavior.
Although the precise circuitry involved in
the production of APO-induced yawning has
not yet been identified, it is clear that
yawning behavior seen as a result of APO
stimulation is due to central processes and is
not the result of peripheral stimulation. For
example, lesions of the paraventricular nucleus
of the hypothalamus abolish yawning
behaviour (1) while direct application of APO
(13) or oxytocin (12) to the paraventricular
nucleus stimulate yawning behavior in
rats. These substances produce no significant
effect on yawning when injected into the
caudate nucleus, preoptic area, or yentromedial
nucleus. In addition, while centrally acting DA
antagonists such as metoclopramide, sulpiride,
and haloperidol diminish yawning behavior
domperidone, a peripherally acting DA antagonist
that does not readily cross the bloodbrain
barrier (10), does not produce any diminution in
APOstimulated yawning (16).
Further experimental work is needed to
determine the precise pathway(s) and cascade of
neurochemical events responsible for the
induction of dopaminergically mediated
yawning. However, as the elucidation of
the specific mechanisms necessary for the
stimulation of yawning behavior become
available these may provide significant insight
into diabetes mellitus and its manifestations as
a result of alterations in the CNS. An
alteration in the neurochemical milieu as a
function of diabetes mellitus may contribute to
the manifestations of the disease and an
increased focus directed toward the
establishment of these changes occurring within
the CNS should be carried out.
-Heaton JP,
Varrin SJ Effects of streptozotocin-induced
diabetes on dopaminergic functioning in the rat:
analysis of yawning behavior. Pharmacol Biochem
Behav. 1993; 44; 3; 601-604
The
conditioned response erection (CRE) a new
approach to modelling erectile responses in the
rat.
Brien SE, Wilson E, Heaton JP, Adams
MA.
Int J Impot Res. 2000;12(2):91-6.
Department of Pharmacology
and Toxicology, Queen's University, Kingston,
Canada.
Several animal models are currently used in
erectile (dys)function research; these models
fail to account for the conditions involving the
more spontaneous erections in humans. Recently,
we observed an increase in the number of
'spontaneously' occurring erections in rats with
previous exposure to apomorphine (APO), a
centrally acting drug that initiates penile
erections and yawns. Based on this
observation, we designed a series of experiments
to characterize the development of enhanced,
non-apomorphine-induced erections or
'spontaneous' erectile responses to vehicle
administration in rats with previous exposure to
APO. We further examined the effects of
castration on these conditioned erections. Naive
(ie never received APO) rats were administered
vehicle (1 ml/kg saline) to determine the
frequency of baseline erections and
yawns. An alternating series of APO (80
microg/kg s.c.) and vehicle administrations were
performed over several days and subsequent
erectile and yawning responses were
recorded. Following 3 sets of 3 APO
administrations (with vehicle administered
between sets), and the 3rd vehicle
administration, these rats were then surgically
castrated and allowed 30 days to recover.
Following this, APO was administered 3 times to
determine erectile and yawning responses
post-castration, followed by vehicle
administration to determine the effects of
castration on conditioned APO responses. The
major findings were: (1) that although naive
rats had a basal spontaneous erectile response
(0.75 +/- 0.88; 4 of 8 rats with at least one
erection), repetitive administration (up to 22
treatments) of the central initiator apomorphine
significantly increased the number of erections
(1.8 +/- 0.7; 7 of 8 rats with at least one
erection) and yawning (2.5 +/- 2.47)
responses to vehicle administration; and (2)
both spontaneous yawning and erectile
responses were found to be androgen dependent
since castration dramatically lowered the number
of erections (0.13 +/- 0.35; 1 of 8 rats with at
least one erection) and yawns (0).
Therefore, this method of producing erections
without a pharmacological manipulation provides
an additional animal model which can be used in
conjunction with the APO-induced erections in
characterizing the physiology and
pathophysiology of erectile function in
conscious rats.
Effects
of castration and exogenous testosterone
supplementation in an animal model of penile
erection.
Heaton JP, Varrin SJ.
J Urol. 1994;151(3):797-800
Department of Urology,
Queen's University, Kingston, Ontario,
Canada.
The dependence of erectile behavior on
androgen functioning is well established.
Castration produces loss of both libido and
potency in man and animals. The present study,
using an animal model for potency, demonstrates
the dependence of centrally induced erectile
behavior on an intact androgen milieu. Castrated
rats failed to produce an erection in response
to apomorphine, an agent shown to produce
erection in nearly all normal rats.
Administration of exogenous testosterone
propionate in dosages exceeding 60
micrograms./kg. produced a significant increase
in erectile behavior. Yawning, an essentially
parallel phenomenon to the stimulation of the
erectile response, was also decreased following
castration and responded similarly to increasing
amounts of exogenous testosterone, demonstrating
the influence of androgen functioning on the
central nervous system. It was concluded that
testosterone is a necessary prerequisite for the
maintenance of a centrally induced erectile and
yawning response. In an animal model of
penile erection, testosterone increases the
number of erections in a dose-dependent manner
in castrated rats. The dependence of the
erectile response on testosterone is, at least
in part, centrally mediated.
Age-related changes
in apomorphine-induced
erections.
Varrin S, Heaton JP.
Neurobiol Aging. 1992;13(1):175-7.
Department of Urology,
Queen's University, Kingston, Ontario,
Canada.
Advancing age produces a noticeable and
well-documented decline in erectile function in
humans. The effects of aging on the ability of
apomorphine to stimulate erection and
yawning behavior in rats was studied in
our bioassay for potency. At the age of seven
months, rats failed to respond to the same dose
of apomorphine which, just one month earlier,
produced erections. Erectile function was then
tested in thirty-two seven-month-old rats naive
to apomorphine injections, and these rats also
failed to respond. Experimentally naive rats of
six months of age were then tested and
apomorphine produced reliable erections. It is
felt that an alteration in dopamine autoreceptor
function may be occurring in the central nervous
system of rats at approximately seven months of
age rendering them incapable of responding to
apomorphine with penile erections.
The
characterization of a bio-assay of erectile
function in a rat model.
Heaton JP, Varrin SJ, Morales A.
J Urol. 1991;145(5):1099-102.
Human Sexuality Group,
Department of Urology, Queen's University,
Kingston, Ontario, Canada.
The investigation of biological phenomena in
impotence using an animal system requires a
determination of the erectile capabilities of
the animal. Rats respond reliably to apomorphine
by the exhibition of a phenomenon of erections
and yawns. This property has been used to form
the basis of a bio-assay of erectile integrity
in the rat. We compared rats treated with
placebo alone, sham operated rats, rats rendered
surgically impotent and castrated rats with and
without testosterone. Rats did not respond to
placebo. The sham operated rats remained normal
in all measured respects (2.66 erections/rat/30
minutes). Surgically impotent rats yawned
normally but had no erections. Castrated rats
did not have erections and had diminished
yawning (3.21 yawns/rat/30 minutes vs.
7.7 for controls p less than .001) but responded
normally after testosterone administration. The
bio-assay is useful as a standard test of
erectile function in the rat.
Metoclopramide
decreases apomorphine-induced yawning and penile
erection.
Heaton JP, Varrin SJ.
Pharmacol Biochem Behav.
1991;38(4):917-20.
Department of Urology &
Human Sexuality Group, Faculty of Medicine,
Queen's University, Kingston,
Ontario.
Acute administration of metoclopramide, a
dopamine (D2) antagonist, reduced both
apomorphine-induced yawning and penile
erections. Metoclopramide, prominent in clinical
use as an effective antiemetic, has been shown
to be associated with decreased erectile
function in humans. Experimentally naive rats
were given a standardized dose of apomorphine
and one of a range of doses of metoclopramide.
The study shows that metoclopramide decreases
the erectile response to apomorphine and
suggests that the erectile difficulties
experienced in humans after metoclopramide
treatment may be a result of interference with a
central dopaminergic mechanism(s).
The impact of
alcohol ingestion on erections in rats as
measured by a novel bio-assay.
Heaton JP, Varrin S.
J Urol. 1991;145(1):192-4.
Department of Urology,
Queen's University, Kingston, Ontario,
Canada.
In rats, a syndrome of yawning and
penile erection results from the administration
of low doses of apomorphine, a dopamine receptor
agonist shown to stimulate dopamine
autoreceptors. Ethanol has been shown to
influence dopamine metabolism. Low doses of
ethyl alcohol (0.25 mg./kg.) failed
significantly to alter apomorphine-induced
yawning or penile erection, while 0.5
mg./kg. decreased erectile behavior but did not
significantly alter the number of yawns. A
reduction in both yawning and penile
erection in response to apomorphine challenge
was seen after the acute intraperitoneal
injection of relatively high doses (1.0-3.0
mg./kg.) of ethanol. Two possible mechanisms of
action may explain these phenomena. Alcohol may
interfere with dopaminergic receptor mechanisms,
or conversely, alcohol, through its actions on
central dopamine metabolism may alter a second
neurotransmitter/neuropeptide more directly
responsible for the production of
apomorphine-induced yawning and penile
erection, possibly oxytocin.
