8-OH-DPAT does not interfere with habituation to motion-induced emesis in cats

Brain Research Bulletin,

Vol. 26, pp. 919-921.

‘c Pergamon Press plc, 1991. Printed in the U.S.A.

KS-9230191

$3.00

+ .oo

%OH-DPAT Does Not Interfere With Habituation Motion-Induced Emesis in Cats to

JAMES

B. LUCOT’

AND GEORGE

Received

9 January

H. CRAMPTON

1991

LUCOT, J. B. AND G. H. CRAMPTON. 8-OH-DPAT does not interfere with habituation ro motion-induced emesis in cats. BRAIN RES BULL 26(6) 919-921, 199~.-Ex~~ments were performed to determine if suppression of motion-induced emesis (motion sickness) by S-OH-DPAT altered the development or retention of habituation to the motion stimulus. Cats received S-OHDPAT followed by provocative motion on three consecutive treatment days. A drug-free test on the fourth day resulted in an incidence of emesis that was not different from that obtained on the fourth consecutive day of drug-free motion testing. Three consecutive days of treatment with 8-OH-DPAT without motion had no effect on the incidence of motion sickness on the fourth day. It was concluded that suppression of motion sickness by 8-OH-DPAT does not alter the acquisition or retention of habituation. Cat

Motion sickness

Response adaptation

Serotonin

current strategy for dealing with the Space Adaptation Syndrome is to pharmacologically suppress symptoms in those astronauts who are affected until they adapt to unusual vestibutar functioning under micro~avity conditions (IO.1 1). In a study designed to test the effect of drugs on the rate of habituation to motion sickness, an additional test was performed that led the authors to conclude that suppression of the symptoms by scopolamine produced a rebound sensitivity to motion sickness upon drug discontinuation (17). Such interference would be a disadvantage during space shuttle missions, making it desirable to find an effective medication that does not interfere with adaptation. Another issue that requires further study deals with the locus of habituation in the motion sickness process. The usual interpretation is that a sensory rearrangement occurs that reduces the emetic sitmulus (12,13). This interpretation underlies current strategies to deal with airsickness in pilots, which involve desensitization with repeated exposure to ground-based provocative stimuli to an endpoint short of emesis (14). An alternative explanation is that it is the emetic response that becomes habituated. If this is correct, then the response must be elicited repeatedly to produce habituation: Such an interpretation is supported by the observation that those astronauts exhibiting nausea during several ground tests tended to be less sick in space than those who were resistant to nausea during ground tests (9-l 1). In the present study, we conducted consecutive experiments to determine if suppression of the emetic response by 8-hydroxy2-(di-n-propylamino)tetralin (8-OH-DPAT) interferes with the development or retention of habituation. Important elements are the use of the same cats throughout, a fixed exposure time to

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should be addressed

Stimulus adaptation

provocative motion to avoid confounding the experience able, and suppression of motion sickness by 8-OH-DPAT.

THE

‘Requests 45435.

receptors

vari-

METHOD

Subjects Animals were procured by the University Laboratory Animal Resources Facility. The research conforms with the Guidelines for the Use of Animals in Neuroscience Research approved by the Society for Neuros~jence and the NIH Guide for the Care and Use of Laboratory Animals NIH Pub. No. 85-23 (revised 1985). Twenty-one female cats were selected on the basis of their responses to five screening tests, as described below, separated by at least two weeks. On these tests, eight vomited on five tests, three vomited on four, six vomited on three. two vomited on two and two vomited on one test. Normal free-fall and vestibulo-bull reflexes were displayed by the subjects. There was free access to food and water until the time of testing. Stimulus and Dependent Variable Motion sickness was elicited by a device resembling a Ferris wheel (2). Two plastic enclosures 0.51 m long X 0.25 m wide x 0.33 m high were suspended from the ends of a 0.89 m beam, the center of which was mounted on a horizontal axle that rotated at 0.28 Hz (17 rpm). The enclosures were stabilized and counterrotated about the horizontal axle so that the floors were always parallel to the laboratory floor. Cats could view the well-lighted laboratory through the clear sides of the test boxes and often moved about during the gentle motion. Each test pe-

to James B. Lucot, Department of Pharmacology, Wright State University, 060 FAWC,

919

Dayton,

OH

riod consisted of 30 min of constant motion, followed by one min of observation at rest, a total of 3 1 min. The 31 -min test period was never varied, even if the cat retched and vomited repeatedly. The dependent variable was the occurrence of retching. which was followed by vomiting in all cases.

This experiment included three separate series of observations lasting 32 days each, with the 32nd day of the first and second series serving as the first day of the second and third series respectively. The sequence within each series was motion with saline on control day 1, three treatment days (days 1.5, 16 and 17) in which differing drug and motion conditions prevailed. and motion with saline on test day 18 and control day 32. This schedule is based on an earlier parametric study in which it was determined that four daily motion tests produce a profound habituation and that complete spontaneous recovery is observed after 14 days of rest (3). The first series was designed to determine if three consecutive daily administrations of 8OH-DPAT would alter the incidence of motion sickness on the fourth day. On treatment days 15, 16 and 17, the cats received 8OH-DPAT without motion. In the second series, the cats received 8-OH-DPAT before motion on treatment days 15, 16 and 17. In the third series. the cats received saline before motion on treatment days 15, 16 and 17. Comparison of the responses for series two and three on test day I8 should indicate if suppression of motion sickness by 8OH-DPAT altered the habituation process. Drug und Statistics

X-OH-DPAT HBr (Research Biochemicals, Inc., Natick, MA) was dissolved in sterile saline such that the dose of 0.04 mglkg of the salt could be administered in an injection volume of 0.1 ml/kg. The drug was prepared each day and injections were made at the same time of day within 30 min. Drug or saline was administered SC 15 min before motion testing began or would have begun were it a motion-testing day. The dose of 0.04 mgikg reliably reduces motion sickness in cats without producing behavioral disruption (7). The repeated tests within a series were evaluated using the Co&ran Q test (1). Pairwise comparisons were evaluated using NcNemar’s binomial test (8).

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DAYS FIG. 1. Development of habituation to motion sickness with and without suppression of emesis by 8-OH-DPAT. For the second series, open squares are a saline test (day 18) or saline controls (days 1 and 32) and closed squares are treatment days with 8-OH-DPAT. Open circles represent the third series (all saline). Habituation was significant at ~~0.01 and p
no significant differences between control days 1 and 32 within either series. *p
tally different from the incidence seen after four consecutive days of saline plus motion testing. There were no differences between control days 1 and 32 in either series. These results show that habituation did proceed under the protection of the drug. DISCUSSION

RESULTS Series I

Twelve cats became motion sick on day 1 and 16 cats became motion sick on day 32, the pre- and posttest controls, respectively. On test day 18, after three consecutive days of drug administration, 17 cats became motion sick. There were no significant differences in the incidence of motion sickness. This series demonstrated that three consecutive daily drug administrations does not have residual effects on the following day. Series 2 and 3

8-OH-DPAT suppressed motion sickness over the three treatment days that it was administered, while four consecutive days of saline plus motion testing produced habituation to the stimulus (Pig. I). The habituation reached the extent that on the third consecutive day (day 17), there was no significant difference between the drug and no drug series. Saline plus motion testing after three consecutive days of 8-OH-DPAT (test day 18) resulted in an incidence of motion sickness that was not statisti-

The main finding of this study is that X-OH-DPAT did not interfere with the development or retention of habituation to the motion stimulus. There was no difference in the incidence of motion sickness on test day 18 of series 3, preceded by three treatment days of motion only, and test day 18 of series 2, preceded by three days of 8-OH-DPAT and motion (Fig. i). A residual effect of prior drug ~rni~s~ation on test day 18 of series 2 is unlikely to account for the low incidence of emesis, as this possibility was ruled out by the negative findings in series I. This suggests that drugs with the same mechanism of antiemetic action as 8-OH-DPAT may offer advantages over the benchmark drug, scopolamine, which may lead to a rebound sensitivity to motion sickness (17) and which produces several side effects (4). 8-OH-DPAT suppresses emesis by acting on postsynaptic 5-HT,, receptors (67). Full agonists at these sites would not interfere with habituation and would not be likely to produce serious side effects. indeed, clinical experience with buspirone, which is a partial agonist at postsynaptic 5-HT,, receptors (16), reveals a benign profile of side effects (15). A second issue addressed is where habituation occurs in the motion sickness sequence. In a recent study using Suncus muri-

8-OH-DPAT

AND HABITUATION

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TO MOTION SICKNESS

nus, 14 days of exposure to a motion stimulus that was subthreshold for eliciting emesis led to the development of habituation, as measured by a decreased emetic response when the subjects were subsequently tested under more provocative conditions (5). The authors concluded that emesis need not be elicited for habituation to occur. Their approach and data are similar to those of the desensitization programs designed to aid pilots who are susceptible to airsickness (see Introduction). The present study used repeated exposure to a motion stimulus sufficient to elicit emesis in the presence of a drug that suppressed the response; the results also lead to the conclusion that emesis need not be elicited for habituation to occur. There were 30 emetic responses over treatment days 15, 16 and 17 in the third series compared to 6 emetic responses over the same period in the second series. Despite the difference in the number of emetic episodes between the two series, there was no statistical difference in the incidence of emesis between the two series on test day 18. Thus, it is clear

that the emetic response does not have to be elicited for habituation to occur. Rather, the concept that habituation is part of the sensory rearrangement process (13) is supported. In conclusion, the suppression of motion sickness in cats by 8-OH-DPAT did not interfere with the development or retention of habituation to the motion stimulus. These findings suggest that stimulation of postsynaptic 5-HT,, receptors provides a useful strategy for preventing motion sickness during the early habituation period of a long exposure to a provocative environment ACKNOWLEDGEMENTS

Supported by Cooperative Agreement NCCZ-229 between NASAAmes Research Laboratory and Wright State University. We thank Stephanie A. Lake and Colleen M. Kennedy for their excellent technical assistance.

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