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mise à jour du
15 mai 2003
Psychiatry Research
1988, 23, 245-255
Sensitization and tolerance to apomorphine in men: yawning, growth hormone, nausea, and hyperthermia
H Szechtman, JM Cleghorn, GM Brown, RD Kaplan, S Franco, K Rosenthal
Ontario Mental Health Foudation Canada


Various measures have been proposed as useful indices of the dopaminergic function postulated to be abnormal in schizophrenia. These include the growth hormone (GH) response to a challenge with the dopamine receptor agonist apomorphine, the change in body temperature induced by apomorphine, and plasma levels of homovanillic acid, a metabolite of dopamine. Although each reflects some aspect of dopamine function, there is no theoretical rationale for choosing among them. Since sensitization may be an important process in the development of amphetamine psychosis (considered similar to schizophrenia), various investigators have argued that responses which show sensitization, as opposed to tolerance with repeated treatment, are more appropriate indices of the dopamine systems involved in psychosis. While the lowering effect of apomorphine on body temperature shows tolerance, it is not known whether the often-used GH response shows sensitization or tolerance. Therefore, in the present study we investigated GH response to repeated injections in normal human volunteers.
In addition to GH, we measured another index of dopaminergic functionnamely, yawning. Yawning induced by apomorphine has been observed in animals and in humans, and there is much evidence in the animal literature to indicate that it involves stimulation of dopaminergic autoreceptors. Other effects of apomorphine (vomiting, feelings of nausea, sedation, and hyperthermia) were monitored as well. [...]

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.

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