Yawning is a readily quantified behavioural
response which can be elicited in laboratory
animals by various pharmacological agents
including dopamine agonists, cholinomimetics and
centrally injected ACTH peptides. Drug-induced
yawning has been reported for a range of
laboratory animals including mouse, rat, guinea
pig, cat, dog and monkey.
There is evidence suggesting that
irrespective of the agent eliciting the
response, drug-induced yawning is subject to
androgenic influences. The incidence of
yawning produced by either apomorphine or
physostigmine is lower in female than in male
rats. Castration of male rats reduces the
levels of yawning to that typically obtained
in females. Furthermore enhancing the androgen
levels by pretreatment with dihydro-testosterone
(I)HT) permits a level of drug-induced yawning
in both female rats and in male castrates which
is equivalent to that obtained in normal male
animals. Similarly, testosterone treatment
increases ACTH-induced yawning in guinea
pigs.
Concomitant with yawning, dopamine agonists
and ACTH increase the incidence of penile
erections in normal rats. Physostigmine does not
have this effect. Spontaneous penile erections
are markedly reduced or absent in chronically
castrated rats but can be restored by
testosterone or DHT, indicating that, like
yawning, penile erections are androgen-de
pendent.
There are several lines of evidence for an
interaction between androgens and opiates.
Opiate binding sites in rat brain are doubled in
chronically castrated animals; this effect can
be prevented by repeated injection of
testosterone. Intracerebroventricular injection
of androsterone produces behavioural effects
similar to those produced by opiates including
wet dog shakes, analgesia, Straub tail and
excess grooming; these effects can be
antagonised by naloxone. Also data reported by
Cicero implicate an interaction between
opiates and androgens on the
hypothalamic-pituitary axis controlling LH
release; naloxone antagonised but morphine
mimicked the effects of testosterone in
castrated rats.
In view of this interaction between opiates
and androgens and the influence of androgens on
yawning and penile erections, we tested whether
an opiate-testosterone link was involved in
drug-induced yawning and pende erections by
investigating the effects of selected drugs on
yawning and pende erections induced in intact
and in castrated rats. [...]
Discussion
In accordance with previous studies both
apomorphine and physostigmine caused yawning in
intact rats but only apomorphine concomitantly
caused penile erections. In one experimental
situation, however, in which the animal is
placed on his back and restrained, the putative
dopamine stimulant RDS-127 reduces penile
reflexes. Results obtained with restrained rats
cannot be compared easily to results obtained
with freely moving and unstressed animals, but
an increase in ejaculations is also observed
under these restrained circumstances.
Yawning induced by apomorphine was
markedly reduced in chronically castrated
rats but was restored by pretreatment with
DHTP, confirming earlier results. Penile
erections were abolished by castration and could
not be elicited by apomorphine with or without
pretreatment with DHTP. Although the absence of
penile erections in castrated rats is well
documented, the failure to reinstate penile
erections with DHTP is at variance with
published findings. Under similar conditions of
long-term castration, penile erections were
restored within 3 days of implanting a 30-mm
silastic capsule filled with DHTP. Although the
actual dose was not reported, such treatment
would undoubtedly result in higher, sustained
plasma testosterone levels than those resulting
from 125 µg/rat once daily for 3 days as
used in the present experiments.
Naloxone partially blocked drug-induced
yawning in intact rats. This effect appears
to be androgen-dependent since in castrated rats
naloxone blocked the increases in yawning
occurring in the presence of DHTP but had no
effect on the residual apomorphine response in
castrated controls which did not receive DHTP.
However, there was no evidence of an opposite
enhancing action by morphine despite various
additional manipulations of the dosing schedule
in intact and castrated rats, e.g. repeated
daily injections ranging front 1 to 10 mg/kg or
implanting 75 mg morphine pellets subcutaneously
(data not shown). In fact, morphine reduced
drug-induced yawning, an effect which is
probably due to sedative side effects.
The effect of DHTP on apomorphine-induced
yawning has been accounted for in terms of a
permissive action by androgens. The naloxone
results suggest that this permissive role is
subject to opiate influences. However, both the
failure of morphine to modify the effect of
naloxone on yawning and penile erections in
intact rats and the lack of effect of morphine
on the DHTP-induced increases in apomorphine
yawning in castrated rats are inconsistent with
this hypothesis. From these results it must be
concluded that the naloxone-androgen interaction
is not mediated via an opiate receptor or, if it
is, then it is a subtype of opiate receptor for
which morphine is not sufficiently
selective.
The inability of DHTP to sustain
apomorphine-induced penile erections in
castrated rats precludes any comment as to
whether opiates modulate the effects of
androgens on this response. In normal rats
morphine, like haloperidol, blocked
apomorphine-induced penile erections whereas
naloxone enhanced the response. This latter
observation substantiates similar findings of
enhancement by naloxone of penile erections
induced by norpropylnorapomorphine and
apocodeine. Since there is no evidence to
suggest otherwise, it is possible that the
enhancement of apomorphine-induced penile
erections in normal rats by naloxone and the
antagonism by morphine is due to direct
interaction between dopamine and opiate
receptors as obtained with several other
dopamine-mediated behaviours.
The effects of haloperidol and atropine in
intact rats are in agreement with previous
findings that neuroleptics and anticholinergics
can block drug-induced yawning in normal animals
and accords with a proposed
dopaminergic-cholinergic mediation of
yawning. The ability of both drugs to block
apomorphine-induced yawning in castrated rats,
with or without DHTP pretreatment, indicates
that their effects are independent of androgen
influences. The blockade by both drugs of
apomorphine-induced penile erections shows that
this effect is also sensitive to both
dopaminergic and cholinergic influences.
However, the cholinergic influence is likely to
be indirect since physostigmine fails to elicit
penile erections in the rat but it does cause
yawning. Although atropine blocked physostigmine
yawning at all doses tested, haloperidol at the
lowest dose had an enhancing effect; higher
doses caused slight inhibition. The enhancing
effect may be explicable in terms of
postsynaptic blockade of dopamine receptors by
haloperidol thereby preventing inhibition by
dopamine on the cholinergic neurones. Yamada
and Furukawa reported similar enhancement by
fluphenazine of physostigmine-induced
yawning.
