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Pharmacol Biochem Behav
1993; 44; 3; 601-604
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.
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
-Heaton JPW, Varrin SV Metoclopramide decreases apomorphine-induced yawning and penile erection Pharmacol Biochem Behav 1991;38; 4; 917-920
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.