Discussion
The present study indicates that in men only
some parameters of the response to apomorphine
change during chronic treatment. For yawning,
both the onset and the time of peak action
advance, but the total number of yawns induced
by apomorphine and the distribution of interyawn
intervals do not change. For GH, there is no
apparent change in the maximal response or in
the time course of release. For feelings of
nausea and hyperthermia, there is a decline in
intensity. These findings suggest that the
repeated injections result in a sensitization of
some components of the yawning response, do not
alter GH release, and produce tolerance to
feelings of nausea and hyperthermia.
Our observations that the yawning response is
augmented but apomorphineinduced feelings of
nausea and hyperthermia subside are consistent
with similar reports of differential
susceptibilities to sensitization and tolerance
for other effects of dopaminomimetic drugs. For
example, repeated injections in animals enhance
the locomotor stimulant and stereotypy-producing
effects of amphetamine but reduce the drug's
ability to produce autonomie effects. Moreover,
the various effects have different rates for the
development of sensitization as well as for the
development of tolerance. Thus, the phenomena of
sensitization and tolerance appear to develop
independently and at different rates.
Since repeated injections of apomorphine
advanced the onset of yawning, it may be
surprising that there was neither a prolongation
in the duration of yawning nor an increase in
intensity, as measured by frequency of
yawns. Although this may reflect a ceiling
effect of the dose of apomorphine used here,
nevertheless, our findings are not unusual.
Studies in rats indicate that repeated
treatments with amphetamine advance the onset of
hyperactivity or stereotypy but do not
necessarily increase the intensity or duration
of these responses. In fact, duration is often
decreased. Thus, behavioral sensitization may
not necessarily involve all correlates of
increasing dose.
Although the mechanisms of behavioral
sensitization are not known, it is unlikely that
the phenomenon observed here resulted from
altered peripheral drug metabolism because the
half-life of apomorphine is very short and
because both sensitization and tolerance
developed, a result not easily explainable by
altered metabolism. On the other hand, because
our subjects were tested under quite rigid
conditions, it is likely that sortie
drug-environment conditioning occurred, thus
yielding sensitization. However, one subject was
administered saline placebo on the 12th trial
and did not show any yawning (or GH release),
suggesting that conditioning is not the primary
mechanisrn. Indeed, while acknowledging the
influence of learning on drug effects, Robinson
and Becker (1986), in a comprehensive review of
the phenomenon of behavioral sensitization,
found little evidence to support the hypothesis
that conditioning is the primary cause of
sensitization.
Other possible mechanisms of behavioral
sensitization that have been considered, but for
which the evidence is equivocal, include
supersensitivity of dopamine receptors and
hyposensitivity of autoreceptors. On the other
hand, it is clear that repeated injections
produce an enduring effect on presynaptic
function, enhancing the release/utilization of
dopamine to subsequent administration of
amphetamine. The authors speculate that this
enhancement of dopamine release may be the
result of changes in a serotonergic presynaptic
facilitatory mechanism, as is the mechanism of
sensitization in Aplysia. Interestingly, since
apomorphine-induced yawning involves a
serotonergic link, this speculation warrants
further investigation.
Considering that the time course of action of
apomorphine is relatively short, it may seem
surprising that we observed long-term effects
with such a long interval between injections (2
weeks). However, there is increasing evidence
from animal studies that acute injections of
many centrally acting drugs have long-lasting
effects. For example, climbing behavior induced
by apomorphine in mice is enhanced for up to 2
weeks after a single priming dose of
apomorphine. Similarly, a single injection of
amphetamine may enhance some behavioral effects
of a subsequent injection administered 2-3 weeks
and even 12 weeks later. Neuroleptic agents
induce similar persistent effects. Although the
phenomenon of drug-induced long-term effects has
not been studied systematically in the human,
our findings are consistent with the animal
literature, and suggest that such effects
deserve closer scrutiny in man.
Our subjects were tested concurrently over a
6-month period. It is conceivable, therefore,
that the changes we observed reflect a seasonal
variation in the response to apomorphine rather
than an effect of repeated treatment. Although
this possibility ought to be addressed
experimentally, it should be noted that a
seasonal variation in the response to
apomorphine, if one exists, would need to
account for the simultaneous development of
apparent tolerance, sensitization, and no
effect.
It has been suggested that a process of
sensitization may underlie the development and
exacerbation of psychosis. Therefore, since
yawning shows sensitization but GH release does
not, it may be asked whether yawning is not a
better "wlndow" onto brain dopamine systems that
may be abnormal in schizophrenia. At first
glance, the answer is yes. However, the observed
sensitization advanced the time course of
yawning by approximately 3.5 to 6 min, and we
sampled GH every 20 min. Therefore, it is
conceivable that GH sampling was too gross and,
in fact, there is no qualitative difference
between apomorphine's effects on GH release and
on yawning. While this possibility can be
answered empirically, our study nevertheless
demonstrates that yawning is potentially useful
as an index of brain processes that may underlie
psychosis. The usefulness of yawning is
strengthened even more by the availability of a
recently developed method for the automatic
recording of yawns.
The reports by some subjects of feeling hot
or warm may seem contradictory to apomorphine's
known reduction of body temperature. However,
since peripheral injections of drugs may act on
the thermostat, or on the pathways elther
afferent or efferent to it, perceived body
temperature may be congruent or opposite to
actual body temperature. Although it is known
that apomorphine acts to promote heat
dissipation in monkeys, further studies are
necessary to determine the precise mechanism of
apomorphine-induced feeling of hyperthermia.
In summary, repeated injections of the
dopamine agonist apomorphine sensitize the
yawning response, do not affect GH release, and
induce tolerance to the drug's effects on nausea
and feelings of hyperthermia. In view of the
fact that sensitization may be an important
element in the development of psychosis, it is
suggested that yawning may be a useful "window"
onto brain dopamine mechanisms of this
abnormality.
